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Sample records for exacerbates tau pathology

  1. Accelerated aging exacerbates a pre-existing pathology in a tau transgenic mouse model.

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    Bodea, Liviu-Gabriel; Evans, Harrison Tudor; Van der Jeugd, Ann; Ittner, Lars M; Delerue, Fabien; Kril, Jillian; Halliday, Glenda; Hodges, John; Kiernan, Mathew C; Götz, Jürgen

    2017-04-01

    Age is a critical factor in the prevalence of tauopathies, including Alzheimer's disease. To observe how an aging phenotype interacts with and affects the pathological intracellular accumulation of hyperphosphorylated tau, the tauopathy mouse model pR5 (expressing P301L mutant human tau) was back-crossed more than ten times onto a senescence-accelerated SAMP8 background to establish the new strain, SApT. Unlike SAMP8 mice, pR5 mice are characterized by a robust tau pathology particularly in the amygdala and hippocampus. Analysis of age-matched SApT mice revealed that pathological tau phosphorylation was increased in these brain regions compared to those in the parental pR5 strain. Moreover, as revealed by immunohistochemistry, phosphorylation of critical tau phospho-epitopes (P-Ser202/P-Ser205 and P-Ser235) was significantly increased in the amygdala of SApT mice in an age-dependent manner, suggesting an age-associated effect of tau phosphorylation. Anxiety tests revealed that the older cohort of SApT mice (10 months vs. 8 months) exhibited a behavioural pattern similar to that observed for age-matched tau transgenic pR5 mice and not the SAMP8 parental mice. Learning and memory, however, appeared to be governed by the accelerated aging background of the SAMP8 strain, as at both ages investigated, SAMP8 and SApT mice showed a decreased learning capacity compared to pR5 mice. We therefore conclude that accelerated aging exacerbates pathological tau phosphorylation, leading to changes in normal behaviour. These findings further suggest that SApT mice may be a useful novel model in which to study the role of a complex geriatric phenotype in tauopathy. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  2. 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.

  3. A Simple Model to Study Tau Pathology

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    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.

  4. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain.

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    Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N; Jiang, Shanya; Cardona, Astrid; Ransohoff, Richard M; Lamb, Bruce T; Bhaskar, Kiran

    2015-06-01

    Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1(-/-) mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret®) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

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    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.

  6. 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.

  7. Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model.

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    Schoch, Kathleen M; DeVos, Sarah L; Miller, Rebecca L; Chun, Seung J; Norrbom, Michaela; Wozniak, David F; Dawson, Hana N; Bennett, C Frank; Rigo, Frank; Miller, Timothy M

    2016-06-01

    Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. 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.

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

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    Wen Hu

    2017-09-01

    Full Text Available 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.

  10. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models.

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    Sethu Sankaranarayanan

    Full Text Available In Alzheimer's disease (AD, an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19 led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies.

  11. Structure and Pathology of Tau Protein in Alzheimer Disease

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    Michala Kolarova

    2012-01-01

    Full Text Available Alzheimer's disease (AD is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.

  12. GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils.

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    Gibbons, Garrett S; Banks, Rachel A; Kim, Bumjin; Xu, Hong; Changolkar, Lakshmi; Leight, Susan N; Riddle, Dawn M; Li, Chi; Gathagan, Ronald J; Brown, Hannah J; Zhang, Bin; Trojanowski, John Q; Lee, Virginia M-Y

    2017-11-22

    Neurodegenerative proteinopathies characterized by intracellular aggregates of tau proteins, termed tauopathies, include Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau), and related disorders. Pathological tau proteins derived from human AD brains (AD-tau) act as proteopathic seeds that initiate the templated aggregation of soluble tau upon intracerebral injection into tau transgenic (Tg) and wild-type mice, thereby modeling human tau pathology. In this study, we found that aged Tg mice of both sexes expressing human tau proteins harboring a pathogenic P301L MAPT mutation labeled with green fluorescent protein (T40PL-GFP Tg mouse line) exhibited hyperphosphorylated tau mislocalized to the somatodentritic domain of neurons, but these mice did not develop de novo insoluble tau aggregates, which are characteristic of human AD and related tauopathies. However, intracerebral injections of either T40PL preformed fibrils (PFFs) or AD-tau seeds into T40PL-GFP mice induced abundant intraneuronal pathological inclusions of hyperphosphorylated T40PL-GFP. These injections of pathological tau resulted in the propagation of tau pathology from the injection site to neuroanatomically connected brain regions, and these tau inclusions consisted of both T40PL-GFP and WT endogenous mouse tau. Primary neurons cultured from the brains of neonatal T40PL-GFP mice provided an informative in vitro model for examining the uptake and localization of tau PFFs. These findings demonstrate the seeded aggregation of T40PL-GFP in vivo by synthetic PFFs and human AD-tau and the utility of this system to study the neuropathological spread of tau aggregates.SIGNIFICANCE STATEMENT The stereotypical spread of pathological tau protein aggregates have recently been attributed to the transmission of proteopathic seeds. Despite the extensive use of transgenic mouse models to investigate the propagation of tau pathology in vivo, details of the aggregation

  13. Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy.

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    Armstrong, Richard A; McKee, Ann C; Alvarez, Victor E; Cairns, Nigel J

    2017-02-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer's disease neuropathologic change (ADNC) without CTE. In CTE: (1) all aspects of tau-immunoreactive pathology were clustered and the clusters were frequently regularly distributed parallel to the tissue boundary, (2) clustering was similar in two CTE cases with minimal co-pathology compared with cases with associated ADNC or TDP-43 proteinopathy, (3) in a proportion of cortical gyri, estimated cluster size was similar to that of cell columns of the cortico-cortical pathways, and (4) clusters of the tau-immunoreactive pathology were infrequently spatially correlated with blood vessels. The NFT and NP in ADNC without CTE were less frequently randomly or uniformly distributed and more frequently in defined clusters than in CTE. Hence, the spatial pattern of the tau-immunoreactive pathology observed in CTE is typical of the tauopathies but with some distinct differences compared to ADNC alone. The spread of pathogenic tau along anatomical pathways could be a factor in the pathogenesis of the disease.

  14. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains

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    Boluda, Susana; Iba, Michiyo; Zhang, Bin; Raible, Kevin M.; Lee, Virginia M-Y.; Trojanowski, John Q.

    2015-01-01

    Filamentous tau pathologies are hallmark lesions of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and corticobasal degeneration (CBD) which show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. Here, we describe the rapid and distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau (designated CBD-Tau and AD-Tau, respectively) in young human mutant P301S tau transgenic (Tg) mice (line PS19) ~6–9 months before they show onset of mutant tau transgene-induced tau pathology. At 1 month post-injection of CBD-Tau, tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of AD-Tau in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 month post-injection. With longer post-injection survival intervals of up to 6 months, CBD-Tau- and AD-Tau-induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type-specific pattern noted above. Finally, CA3 neuron loss was detected 3 months post-injection of AD-Tau but not CBD-Tau. Thus, AD-Tau and CBD-Tau represent specific pathological tau strains that spread differentially and may underlie distinct clinical and pathological features of these two tauopathies. Hence, these strains could become targets to develop disease-modifying therapies for CBD and AD. PMID:25534024

  15. Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections.

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    Iba, Michiyo; McBride, Jennifer D; Guo, Jing L; Zhang, Bin; Trojanowski, John Q; Lee, Virginia M-Y

    2015-09-01

    Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed (Iba et al., J Neurosci 33:1024-1037, 2013) that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle-bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle-bearing neurons gradually cleared tau pathology by 6-12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread

  16. Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain.

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    Narasimhan, Sneha; Guo, Jing L; Changolkar, Lakshmi; Stieber, Anna; McBride, Jennifer D; Silva, Luisa V; He, Zhuohao; Zhang, Bin; Gathagan, Ronald J; Trojanowski, John Q; Lee, Virginia M Y

    2017-11-22

    Pathological tau aggregates occur in Alzheimer's disease (AD) and other neurodegenerative tauopathies. It is not clearly understood why tauopathies vary greatly in the neuroanatomical and histopathological patterns of tau aggregation, which contribute to clinical heterogeneity in these disorders. Recent studies have shown that tau aggregates may form distinct structural conformations, known as tau strains. Here, we developed a novel model to test the hypothesis that cell-to-cell transmission of different tau strains occurs in nontransgenic (non-Tg) mice, and to investigate whether there are strain-specific differences in the pattern of tau transmission. By injecting pathological tau extracted from postmortem brains of AD (AD-tau), progressive supranuclear palsy (PSP-tau), and corticobasal degeneration (CBD-tau) patients into different brain regions of female non-Tg mice, we demonstrated the induction and propagation of endogenous mouse tau aggregates. Specifically, we identified differences in tau strain potency between AD-tau, CBD-tau, and PSP-tau in non-Tg mice. Moreover, differences in cell-type specificity of tau aggregate transmission were observed between tau strains such that only PSP-tau and CBD-tau strains induce astroglial and oligodendroglial tau inclusions, recapitulating the diversity of neuropathology in human tauopathies. Furthermore, we demonstrated that the neuronal connectome, but not the tau strain, determines which brain regions develop tau pathology. Finally, CBD-tau- and PSP-tau-injected mice showed spatiotemporal transmission of glial tau pathology, suggesting glial tau transmission contributes to the progression of tauopathies. Together, our data suggest that different tau strains determine seeding potency and cell-type specificity of tau aggregation that underlie the diversity of human tauopathies. SIGNIFICANCE STATEMENT Tauopathies show great clinical and neuropathological heterogeneity, despite the fact that tau aggregates in each disease

  17. Ubiquilin 2 is not associated with tau pathology.

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    Anna Nölle

    Full Text Available Accumulation of aberrant proteins in inclusion bodies is a hallmark of many neurodegenerative diseases. Impairment of proteolytic systems is a common event in these protein misfolding diseases. Recently, mutations in the UBQLN 2 gene encoding ubiquilin 2 have been identified in X-linked amyotrophic lateral sclerosis (ALS. Furthermore, ubiquilin 2 is associated with inclusions in familial and sporadic ALS/dementia, synucleinopathies and polyglutamine diseases. Ubiquilin 2 exerts a regulatory role in proteostasis and thus it has been suggested that ubiquilin 2 pathology may be a common event in neurodegenerative diseases. Tauopathies, a heterogenous group of neurodegenerative diseases accompanied with dementia, are characterized by inclusions of the microtubule-binding protein tau. In the present study, we investigate whether ubiquilin 2 is connected with tau pathology in Alzheimer's disease (AD, supranuclear palsy (PSP and Pick's disease (PiD and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17. We show that ubiquilin 2 positive inclusions are absent in these tauopathies. Furthermore, we find decreased ubiquilin 2 protein levels in AD patients, but our results do not indicate a correlation with tau pathology. Our data show no evidence for involvement of ubiquilin 2 and indicate that other mechanisms underly the proteostatic disturbances in tauopathies.

  18. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo

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    Yanamandra, Kiran; Kfoury, Najla; Jiang, Hong; Mahan, Thomas E.; Ma, Shengmei; Maloney, Susan E.; Wozniak, David F.

    2014-01-01

    Summary Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein, and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused 3 effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy. PMID:24075978

  19. Amyloid-beta and tau pathology following repetitive mild traumatic brain injury.

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    Edwards, George; Moreno-Gonzalez, Ines; Soto, Claudio

    2017-02-19

    Neurodegenerative diseases are characterized by distinctive neuropathological alterations, including the cerebral accumulation of misfolded protein aggregates, neuroinflammation, synaptic dysfunction, and neuronal loss, along with behavioral impairments. Traumatic brain injury (TBI) is believed to be an important risk factor for certain neurodegenerative diseases, such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). TBI represents a ubiquitous problem in the world and could play a major role in the pathogenesis and etiology of AD or CTE later in life. TBI events appear to trigger and exacerbate some of the pathological processes in these diseases, in particular, the formation and accumulation of misfolded protein aggregates composed of amyloid-beta (Aβ) and tau. Here, we describe the relationship between repetitive mild TBI and the development of Aβ and tau pathology in patients affected by AD or CTE on the basis of epidemiological and pathological studies in human cases, and a thorough overview of data obtained in experimental animal models. We also discuss the possibility that TBI may contribute to initiate the formation of misfolded oligomeric species that may subsequently spread the pathology through a prion-like process of seeding of protein misfolding. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. The role of tau in the pathological process and clinical expression of Huntington's disease

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    Vuono, Romina; Winder-Rhodes, Sophie; de Silva, Rohan

    2015-01-01

    in Huntington's disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post...... not only on the tau pathology in the Huntington's disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some...... instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington's disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau...

  1. Development of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

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    2016-02-01

    induced TBI causes progressive tau pathology in 2 lines of transgenic mice. First, we commissioned construction , shipping and assembly of a CHIMERA...AD_________________ Award Number: W81XWH-13-2-0016 TITLE: Development of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic...of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury 5b. GRANT NUMBER W81XWH-13-2-0016 5c. PROGRAM ELEMENT NUMBER 6

  2. What is the evidence that tau pathology spreads through prion-like propagation?

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    Mudher, Amrit; Colin, Morvane; Dujardin, Simon; Medina, Miguel; Dewachter, Ilse; Alavi Naini, Seyedeh Maryam; Mandelkow, Eva-Maria; Mandelkow, Eckhard; Buée, Luc; Goedert, Michel; Brion, Jean-Pierre

    2017-12-19

    Emerging experimental evidence suggests that the spread of tau pathology in the brain in Tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. This propagation could occur through a "prion-like" mechanism involving transfer of abnormal tau seeds from a "donor cell" to a "recipient cell" and recruitment of normal tau in the latter to generate new tau seeds. This review critically appraises the evidence that the spread of tau pathology occurs via such a "prion-like" mechanism and proposes a number of recommendations for directing future research. Recommendations for definitions of frequently used terms in the tau field are presented in an attempt to clarify and standardize interpretation of research findings. Molecular and cellular factors affecting tau aggregation are briefly reviewed, as are potential contributions of physiological and pathological post-translational modifications of tau. Additionally, the experimental evidence for tau seeding and "prion-like" propagation of tau aggregation that has emerged from cellular assays and in vivo models is discussed. Propagation of tau pathology using "prion-like" mechanisms is expected to incorporate several steps including cellular uptake, templated seeding, secretion and intercellular transfer through synaptic and non-synaptic pathways. The experimental findings supporting each of these steps are reviewed. The clinical validity of these experimental findings is then debated by considering the supportive or contradictory findings from patient samples. Further, the role of physiological tau release in this scenario is examined because emerging data shows that tau is secreted but the physiological function (if any) of this secretion in the context of propagation of pathological tau seeds is unclear. Bona fide prions exhibit specific properties, including transmission from cell to cell, tissue to tissue and organism to organism. The propagation of tau pathology has so

  3. Humanized Tau Mice with Regionalized Amyloid Exhibit Behavioral Deficits but No Pathological Interaction.

    Directory of Open Access Journals (Sweden)

    Michael J Yetman

    Full Text Available Alzheimer's disease (AD researchers have struggled for decades to draw a causal link between extracellular Aβ aggregation and intraneuronal accumulation of microtubule-associated protein tau. The amyloid cascade hypothesis posits that Aβ deposition promotes tau hyperphosphorylation, tangle formation, cell loss, vascular damage, and dementia. While the genetics of familial AD and the pathological staging of sporadic disease support this sequence of events, attempts to examine the molecular mechanism in transgenic animal models have largely relied on models of other inherited tauopathies as the basis for testing the interaction with Aβ. In an effort to more accurately model the relationship between Aβ and wild-type tau in AD, we intercrossed mice that overproduce human Aβ with a tau substitution model in which all 6 isoforms of the human protein are expressed in animals lacking murine tau. We selected an amyloid model in which pathology was biased towards the entorhinal region so that we could further examine whether the anticipated changes in tau phosphorylation occurred at the site of Aβ deposition or in synaptically connected regions. We found that Aβ and tau had independent effects on locomotion, learning, and memory, but found no behavioral evidence for an interaction between the two transgenes. Moreover, we saw no indication of amyloid-induced changes in the phosphorylation or aggregation of human tau either within the entorhinal area or elsewhere. These findings suggest that robust amyloid pathology within the medial temporal lobe has little effect on the metabolism of wild type human tau in this model.

  4. Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, Brent C. [Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC 20037 (United States); Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States); Constant, Stephanie L. [Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC 20037 (United States); Patierno, Steven R. [Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States); GW Cancer Institute, The George Washington University, Washington, DC 20037 (United States); Jurjus, Rosalyn A. [Department of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20037 (United States); Ceryak, Susan M., E-mail: phmsmc@gwumc.edu [Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States)

    2012-02-15

    Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. -- Highlights: ► Allergic asthma correlated with exposure to certain inhaled particulate chromates. ► Direct causal association between Cr(VI) and allergic asthma not established. ► Cr exacerbated pathology and airway hyperresponsiveness in an OVA-challenged mouse. ► Particulate Cr

  5. Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology.

    Science.gov (United States)

    Laurent, Cyril; Eddarkaoui, Sabiha; Derisbourg, Maxime; Leboucher, Antoine; Demeyer, Dominique; Carrier, Sébastien; Schneider, Marion; Hamdane, Malika; Müller, Christa E; Buée, Luc; Blum, David

    2014-09-01

    Tau pathology found in Alzheimer's disease (AD) is crucial in cognitive decline. Epidemiologic evidences support that habitual caffeine intake prevents memory decline during aging and reduces the risk to develop Alzheimer's disease. So far, experimental studies addressed the impact of caffeine in models mimicking the amyloid pathology of AD. However, in vivo effects of caffeine in a model of AD-like tauopathy remain unknown. Here, we evaluated effects of chronic caffeine intake (0.3 g/L through drinking water), given at an early pathologic stage, in the THY-Tau22 transgenic mouse model of progressive AD-like tau pathology. We found that chronic caffeine intake prevents from the development of spatial memory deficits in tau mice. Improved memory was associated with reduced hippocampal tau phosphorylation and proteolytic fragments. Moreover, caffeine treatment mitigated several proinflammatory and oxidative stress markers found upregulated in the hippocampus of THY-Tau22 animals. Together, our data support that moderate caffeine intake is beneficial in a model of AD-like tau pathology, paving the way for future clinical evaluation in AD patients. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. The involvement of cholinergic neurons in the spreading of tau pathology

    Directory of Open Access Journals (Sweden)

    Diana eSimon

    2013-06-01

    Full Text Available Long time ago, it was described the selective loss of cholinergic neurons during the development of Alzheimer disease. Recently, it has been suggested that tau protein may play a role in that loss of cholinergic neurons through a mechanism involving the interaction of extracellular tau with M1/M3 muscarinic receptors present in the cholinergic neurons. This interaction between tau and muscarinic receptors may be a way, although not the only one, to explain the spreading of tau pathology occurring in Alzheimer disease.

  7. Development of In Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

    Science.gov (United States)

    2015-02-01

    In general, we are interested in determining in both a clinical and experimental setting whether additional factors such as alcohol abuse , anabolic ... steroids , narcotics, sleep deprivation, sleep apnea, systemic injuries and inflammatory states contribute to axonal injury, tau pathology, and

  8. Tau Pathology Spread in PS19 Tau Transgenic Mice Following Locus Coeruleus (LC) Injections of Synthetic Tau Fibrils is Determined by the LC’s Afferent and Efferent Connections

    Science.gov (United States)

    Iba, Michiyo; McBride, Jennifer D.; Guo, Jing L.; Zhang, Bin; Trojanowski, John Q.; Lee, Virginia M.-Y.

    2015-01-01

    Filamentous tau inclusions are hallmarks of Alzheimer’s disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed [25] that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle bearing neurons gradually cleared tau pathology by 6–12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique

  9. 3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice.

    Directory of Open Access Journals (Sweden)

    Hongjun Fu

    Full Text Available 3D volume imaging using iDISCO+ was applied to observe the spatial and temporal progression of tau pathology in deep structures of the brain of a mouse model that recapitulates the earliest stages of Alzheimer's disease (AD. Tau pathology was compared at four timepoints, up to 34 months as it spread through the hippocampal formation and out into the neocortex along an anatomically connected route. Tau pathology was associated with significant gliosis. No evidence for uptake and accumulation of tau by glia was observed. Neuronal cells did appear to have internalized tau, including in extrahippocampal areas as a small proportion of cells that had accumulated human tau protein did not express detectible levels of human tau mRNA. At the oldest timepoint, mature tau pathology in the entorhinal cortex (EC was associated with significant cell loss. As in human AD, mature tau pathology in the EC and the presence of tau pathology in the neocortex correlated with cognitive impairment. 3D volume imaging is an ideal technique to easily monitor the spread of pathology over time in models of disease progression.

  10. Pathological conformations involving the amino terminus of tau occur early in Alzheimer's disease and are differentially detected by monoclonal antibodies.

    Science.gov (United States)

    Combs, Benjamin; Hamel, Chelsey; Kanaan, Nicholas M

    2016-10-01

    Conformational changes involving the amino terminus of the tau protein are among the earliest alterations associated with tau pathology in Alzheimer's disease and other tauopathies. This region of tau contains a phosphatase-activating domain (PAD) that is aberrantly exposed in pathological forms of the protein, an event that is associated with disruptions in anterograde fast axonal transport. We utilized four antibodies that recognize the amino terminus of tau, TNT1, TNT2 (a novel antibody), Tau12, and Tau13, to further study this important region. Using scanning alanine mutations in recombinant tau proteins, we refined the epitopes of each antibody. We examined the antibodies' relative abilities to specifically label pathological tau in non-denaturing and denaturing assays to gain insight into some of the mechanistic details of PAD exposure. We then determined the pattern of tau pathology labeled by each antibody in human hippocampal sections at various disease stages in order to characterize PAD exposure in the context of disease progression. The characteristics of reactivity for the antibodies fell into two groups. TNT1 and TNT2 recognized epitopes within amino acids 7-12 and specifically identified recombinant tau aggregates and pathological tau from Alzheimer's disease brains in a conformation-dependent manner. These antibodies labeled early pre-tangle pathology from neurons in early Braak stages and colocalized with thiazine red, a marker of fibrillar pathology, in classic neurofibrillary tangles. However, late tangles were negative for TNT1 and TNT2 indicating a loss of the epitope in later stages of tangle evolution. In contrast, Tau12 and Tau13 both identified discontinuous epitopes in the amino terminus and were unable to differentiate between normal and pathological tau in biochemical and tissue immunohistological assays. Despite the close proximity of these epitopes, the antibodies demonstrated remarkably different abilities to identify pathological

  11. Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.

    Science.gov (United States)

    Stygelbout, Virginie; Leroy, Karelle; Pouillon, Valérie; Ando, Kunie; D'Amico, Eva; Jia, Yonghui; Luo, H Robert; Duyckaerts, Charles; Erneux, Christophe; Schurmans, Stéphane; Brion, Jean-Pierre

    2014-02-01

    ITPKB phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate and controls signal transduction in various hematopoietic cells. Surprisingly, it has been reported that the ITPKB messenger RNA level is significantly increased in the cerebral cortex of patients with Alzheimer's disease, compared with control subjects. As extracellular signal-regulated kinases 1/2 activation is increased in the Alzheimer brain and as ITPKB is a regulator of extracellular signal-regulated kinases 1/2 activation in some hematopoietic cells, we tested whether this increased activation in Alzheimer's disease might be related to an increased activity of ITPKB. We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation. No impact on pathology was observed in the 5X familial Alzheimer's disease mouse model when a catalytically inactive ITPKB protein was overexpressed. Together, our results point to the ITPKB/inositol 1,3,4,5-tetrakisphosphate/extracellular signal-regulated kinases 1

  12. Presence of tau pathology within foetal neural allografts in patients with Huntington's and Parkinson's disease.

    Science.gov (United States)

    Cisbani, Giulia; Maxan, Alexander; Kordower, Jeffrey H; Planel, Emmanuel; Freeman, Thomas B; Cicchetti, Francesca

    2017-11-01

    Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington's and Parkinson's disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington's and Parkinson's disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington's disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson's disease who came to autopsy 18 months and 16 years post-transplantation. We show that grafts also contain tau pathology in both types of transplanted patients. In two patients with Huntington's disease, the grafted tissue showed the presence of hyperphosphorylated tau [both AT8 (phospho-tau Ser202 and Thr205) and CP13 (pSer202) immunohistochemical stainings] pathological inclusions, neurofibrillary tangles and neuropil threads. In patients with Parkinson's disease, the grafted tissue was characterized by hyperphosphorylated tau (AT8; immunofluorescent staining) pathological inclusions, neurofibrillary tangles and neuropil threads but only in the patient who came to autopsy 16 years post-transplantation. Abundant tau-related pathology was observed in the cortex and striatum of all cases studied. While the striatum of the grafted Huntington's disease patient revealed an equal amount of 3-repeat and 4-repeat isoforms of tau, the grafted tissue showed elevated 4-repeat isoforms by western blot. This suggests that transplants may have acquired tau pathology from the host brain, although another possibility is that this was due to acceleration of ageing. This finding not only adds to the recent reports that tau pathology is a feature of these neurodegenerative

  13. First-in-man tau vaccine targeting structural determinants essential for pathological tau–tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model

    OpenAIRE

    Kontsekova, Eva; Zilka, Norbert; Kovacech, Branislav; Novak, Petr; Novak, Michal

    2014-01-01

    Introduction We have identified structural determinants on tau protein that are essential for pathological tau–tau interaction in Alzheimer’s disease (AD). These regulatory domains, revealed by monoclonal antibody DC8E8, represent a novel target for tau-directed therapy. In order to validate this target, we have developed an active vaccine, AADvac1. Methods A tau peptide encompassing the epitope revealed by DC8E8 was selected for the development of an active vaccine targeting structural deter...

  14. Early-onset axonal pathology in a novel P301S-Tau transgenic mouse model of frontotemporal lobar degeneration.

    Science.gov (United States)

    van Eersel, Janet; Stevens, Claire H; Przybyla, Magdalena; Gladbach, Amadeus; Stefanoska, Kristie; Chan, Chesed Kai-Xin; Ong, Wei-Yi; Hodges, John R; Sutherland, Greg T; Kril, Jillian J; Abramowski, Dorothee; Staufenbiel, Matthias; Halliday, Glenda M; Ittner, Lars M

    2015-12-01

    Tau becomes hyperphosphorylated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-tau), resulting in functional deficits of neurones, neurofibrillary tangle (NFT) formation and eventually dementia. Expression of mutant human tau in the brains of transgenic mice has produced different lines that recapitulate various aspects of FTLD-tau and AD. In this study, we characterized the novel P301S mutant tau transgenic mouse line, TAU58/2. Both young and aged TAU58/2 mice underwent extensive motor testing, after which brain tissue was analysed with immunohistochemistry, silver staining, electron microscopy and Western blotting. Tissue from various FTLD subtypes and AD patients was also analysed for comparison. TAU58/2 mice presented with early-onset motor deficits, which became more pronounced with age. Throughout the brains of these mice, tau was progressively hyperphosphorylated resulting in increased NFT formation with age. In addition, frequent axonal swellings that stained intensively for neurofilament (NF) were present in young TAU58/2 mice prior to NFT formation. Similar axonal pathology was also observed in human FTLD-tau and AD. Interestingly, activated microglia were found in close proximity to neurones harbouring transgenic tau, but were not associated with NF-positive axonal swellings. In TAU58/2 mice, early tau pathology induces functional deficits of neurones associated with NF pathology. This appears to be specific to tau, as similar changes are observed in FTLD-tau, but not in FTLD with TDP-43 inclusions. Therefore, TAU58/2 mice recapitulate aspects of human FTLD-tau and AD pathology, and will become instrumental in studying disease mechanisms and therapeutics in the future. © 2015 British Neuropathological Society.

  15. Genetic suppression of β2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies.

    Science.gov (United States)

    Wisely, Elena V; Xiang, Yang K; Oddo, Salvatore

    2014-08-01

    Accumulation of the microtubule-binding protein tau is a key event in several neurodegenerative disorders referred to as tauopathies, which include Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Thus, understanding the molecular pathways leading to tau accumulation will have a major impact across multiple neurodegenerative disorders. To elucidate the pathways involved in tau pathology, we removed the gene encoding the beta-2 adrenergic receptors (β2ARs) from a mouse model overexpressing mutant human tau. Notably, the number of β2ARs is increased in brains of AD patients and epidemiological studies show that the use of beta-blockers decreases the incidence of AD. The mechanisms underlying these observations, however, are not clear. We show that the tau transgenic mice lacking the β2AR gene had a reduced mortality rate compared with the parental tau transgenic mice. Removing the gene encoding the β2ARs from the tau transgenic mice also significantly improved motor deficits. Neuropathologically, the improvement in lifespan and motor function was associated with a reduction in brain tau immunoreactivity and phosphorylation. Mechanistically, we provide compelling evidence that the β2AR-mediated changes in tau were linked to a reduction in the activity of GSK3β and CDK5, two of the major tau kinases. These studies provide a mechanistic link between β2ARs and tau and suggest the molecular basis linking the use of beta-blockers to a reduced incidence of AD. Furthermore, these data suggest that a detailed pharmacological modulation of β2ARs could be exploited to develop better therapeutic strategies for AD and other tauopathies. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies.

    Science.gov (United States)

    Lewis, Jada; Dickson, Dennis W

    2016-01-01

    Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles-a principle neuropathological hallmark of Alzheimer's disease (AD)-as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross-sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that

  17. Similar brain tau pathology in DM2/PROMM and DM1/Steinert disease.

    Science.gov (United States)

    Maurage, C A; Udd, B; Ruchoux, M M; Vermersch, P; Kalimo, H; Krahe, R; Delacourte, A; Sergeant, N

    2005-11-22

    Neurofibrillary degeneration (NFD) occurs in the brains of patients with myotonic dystrophy (DM) type 1. The authors report a similar tau pathology in the CNS of a patient with DM2 and compare it to that of patients with DM1. A reduced expression of tau exon 2 and exon 3 epitopes is observed in both DM1 and DM2. This suggests a similar physiopathologic process that may contribute to common neurologic features in patients with DM.

  18. Pathological tau deposition in Motor Neurone Disease and frontotemporal lobar degeneration associated with TDP-43 proteinopathy.

    Science.gov (United States)

    Behrouzi, Roya; Liu, Xiawei; Wu, Dongyue; Robinson, Andrew C; Tanaguchi-Watanabe, Sayuri; Rollinson, Sara; Shi, Jing; Tian, Jinzhou; Hamdalla, Hisham H M; Ealing, John; Richardson, Anna; Jones, Matthew; Pickering-Brown, Stuart; Davidson, Yvonne S; Strong, Michael J; Hasegawa, Masato; Snowden, Julie S; Mann, David M A

    2016-03-31

    It has been suggested that patients with motor neurone disease (MND) and those with MND combined with behavioural variant frontotemporal dementia (bvFTD) (ie FTD + MND) or with FTD alone might exist on a continuum based on commonalities of neuropathology and/or genetic risk. Moreover, it has been reported that both a neuronal and a glial cell tauopathy can accompany the TDP-43 proteinopathy in patients with motor neurone disease (MND) with cognitive changes, and that the tauopathy may be fundamental to disease pathogenesis and clinical phenotype. In the present study, we sought to substantiate these latter findings, and test this concept of a pathological continuum, in a consecutive series of 41 patients with MND, 16 with FTD + MND and 23 with FTD without MND. Paraffin sections of frontal, entorhinal, temporal and occipital cortex and hippocampus were immunostained for tau pathology using anti-tau antibodies, AT8, pThr(175) and pThr(217), and for amyloid β protein (Aβ) using 4G8 antibody. Twenty four (59 %) patients with MND, 7 (44 %) patients with FTD + MND and 10 (43 %) patients with FTD showed 'significant' tau pathology (ie more than just an isolated neurofibrillary tangle or a few neuropil threads in one or more brain regions examined). In most instances, this bore the histological characteristics of an Alzheimer's disease process involving entorhinal cortex, hippocampus, temporal cortex, frontal cortex and occipital cortex in decreasing frequency, accompanied by a deposition of Aβ up to Thal phase 3, though 2 patients with MND, and 1 with FTD did show tau pathology beyond Braak stage III. Four other patients with MND showed novel neuronal tau pathology, within the frontal cortex alone, specifically detected by pThr(175) antibody, which was characterised by a fine granular or more clumped aggregation of tau without neurofibrillary tangles or neuropil threads. However, none of these 4 patients had clinically evident cognitive disorder, and

  19. The role of tau in the pathological process and clinical expression of Huntington’s disease

    Science.gov (United States)

    Vuono, Romina; Winder-Rhodes, Sophie; de Silva, Rohan; Cisbani, Giulia; Drouin-Ouellet, Janelle; Spillantini, Maria G.; Cicchetti, Francesca

    2015-01-01

    Huntington’s disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington’s disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington’s disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington’s disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington’s disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype–phenotype analysis of a large cohort of patients with Huntington’s disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington’s disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington’s disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington’s disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT

  20. The role of tau in the pathological process and clinical expression of Huntington's disease.

    Science.gov (United States)

    Vuono, Romina; Winder-Rhodes, Sophie; de Silva, Rohan; Cisbani, Giulia; Drouin-Ouellet, Janelle; Spillantini, Maria G; Cicchetti, Francesca; Barker, Roger A

    2015-07-01

    Huntington's disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington's disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington's disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington's disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington's disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype-phenotype analysis of a large cohort of patients with Huntington's disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington's disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington's disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington's disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT haplotypes affect the rate

  1. Different Populations of Human Locus Ceruleus Neurons Contain Heavy Metals or Hyperphosphorylated Tau: Implications for Amyloid-β and Tau Pathology in Alzheimer's Disease.

    Science.gov (United States)

    Pamphlett, Roger; Kum Jew, Stephen

    2015-01-01

    A marked loss of locus ceruleus (LC) neurons is a striking pathological feature of Alzheimer's disease (AD). LC neurons are particularly prone to taking up circulating toxicants such as heavy metals, and hyperphosphorylated tau (tau(HYP)) appears early in these neurons. In an attempt to find out if both heavy metals and tau(HYP) could be damaging LC neurons, we looked in the LC neurons of 21 sporadic AD patients and 43 non-demented controls for the heavy metals mercury, bismuth, and silver using autometallography, and for tau(HYP) using AT8 immunostaining. Heavy metals or tau(HYP) were usually seen in separate LC neurons, and rarely co-existed within the same neuron. The number of heavy metal-containing LC neurons did not correlate with the number containing tau(HYP). Heavy metals therefore appear to occupy a mostly different population of LC neurons to those containing tau(HYP), indicating that the LC in AD is vulnerable to two different assaults. Reduced brain noradrenaline from LC damage is linked to amyloid-β deposition, and tau(HYP) in the LC may seed neurofibrillary tangles in other neurons. A model is described, incorporating the present findings, that proposes that the LC plays a part in both the amyloid-β and tau pathologies of AD.

  2. PET radioligands for imaging of Tau pathology: Current status

    Energy Technology Data Exchange (ETDEWEB)

    Choe, Yearn Seong [Dept. of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lee, Kyung Han [Dept. of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul (Korea, Republic of)

    2015-12-15

    The incidence of Alzheimer’s disease (AD), a progressive neurodegenerative disorder, continues to soar with the rapid growth of the elderly population, thus creating an enormous social and economic burden. Although disease-modifying drugs to treat AD are not yet available, several candidate drugs are in clinical trials. Most of these drugs are expected to be effective at the early stages of the disease, and therefore the early and accurate diagnosis of AD will be a critical factor in efforts to improve the prognosis of patients with AD. This review focuses on lead radioligands developed to date and their preclinical data in order to facilitate the development of tau-specific positron emission tomography radioligands that are of great interest to the scientific community.

  3. Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy.

    Science.gov (United States)

    Zimova, Ivana; Brezovakova, Veronika; Hromadka, Tomas; Weisova, Petronela; Cubinkova, Veronika; Valachova, Bernadeta; Filipcik, Peter; Jadhav, Santosh; Smolek, Tomas; Novak, Michal; Zilka, Norbert

    2016-09-06

    Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

  4. Two Novel Tau Antibodies Targeting the 396/404 Region Are Primarily Taken Up by Neurons and Reduce Tau Protein Pathology*

    Science.gov (United States)

    Gu, Jiaping; Congdon, Erin E.; Sigurdsson, Einar M.

    2013-01-01

    Aggregated Tau proteins are hallmarks of Alzheimer disease and other tauopathies. Recent studies from our group and others have demonstrated that both active and passive immunizations reduce Tau pathology and prevent cognitive decline in transgenic mice. To determine the efficacy and safety of targeting the prominent 396/404 region, we developed two novel monoclonal antibodies (mAbs) with distinct binding profiles for phospho and non-phospho epitopes. The two mAbs significantly reduced hyperphosphorylated soluble Tau in long term brain slice cultures without apparent toxicity, suggesting the therapeutic importance of targeting the 396/404 region. In mechanistic studies, we found that neurons were the primary cell type that internalized the mAbs, whereas a small amount of mAbs was taken up by microglia cells. Within neurons, the two mAbs were highly colocalized with distinct pathological Tau markers, indicating their affinity toward different stages or forms of pathological Tau. Moreover, the mAbs were largely co-localized with endosomal/lysosomal markers, and partially co-localized with autophagy pathway markers. Additionally, the Fab fragments of the mAbs were able to enter neurons, but unlike the whole antibodies, the fragments were not specifically localized in pathological neurons. In summary, our Tau mAbs were safe and efficient to clear pathological Tau in a brain slice model. Fc-receptor-mediated endocytosis and the endosome/autophagosome/lysosome system are likely to have a critical role in antibody-mediated clearance of Tau pathology. PMID:24089520

  5. Alzheimer's Disease: Characterization of the Brain Sites of the Initial Tau Cytoskeletal Pathology Will Improve the Success of Novel Immunological Anti-Tau Treatment Approaches.

    Science.gov (United States)

    Rüb, Udo; Stratmann, Katharina; Heinsen, Helmut; Seidel, Kay; Bouzrou, Mohamed; Korf, Horst-Werner

    2017-01-01

    Alzheimer's disease (AD) represents the most frequent neurodegenerative disease of the human brain worldwide. Currently practiced treatment strategies for AD only include some less effective symptomatic therapeutic interventions, which unable to counteract the disease course of AD. New therapeutic attempts aimed to prevent, reduce, or remove the extracellular depositions of the amyloid-β protein did not elicit beneficial effects on cognitive deficits or functional decline of AD. In view of the failure of these amyloid-β-based therapeutic trials and the close correlation between the brain pathology of the cytoskeletal tau protein and clinical AD symptoms, therapeutic attention has since shifted to the tau cytoskeletal protein as a novel drug target. The abnormal hyperphosphorylation and intraneuronal aggregation of this protein are early events in the evolution of the AD-related neurofibrillary pathology, and the brain spread of the AD-related tau aggregation pathology may possibly follow a corruptive protein templating and seeding-like mechanism according to the prion hypothesis. Accordingly, immunotherapeutic targeting of the tau aggregation pathology during the very early pre-tangle phase is currently considered to represent an effective and promising therapeutic approach for AD. Recent studies have shown that the initial immunoreactive tau aggregation pathology already prevails in several subcortical regions in the absence of any cytoskeletal changes in the cerebral cortex. Thus, it may be hypothesized that the subcortical brain regions represent the "port of entry" for the pathogenetic agent from which the disease ascends anterogradely as an "interconnectivity pathology".

  6. Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury.

    Science.gov (United States)

    Gyoneva, Stefka; Kim, Daniel; Katsumoto, Atsuko; Kokiko-Cochran, O Nicole; Lamb, Bruce T; Ransohoff, Richard M

    2015-12-03

    Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes. We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 (RFP/+) and Ccr2 (RFP/RFP) ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3 days later in order to determine the effects of altered monocyte entry into the brain. Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot. Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2(+) monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation.

  7. High-Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo.

    Science.gov (United States)

    Audouard, Emilie; Houben, Sarah; Masaracchia, Caterina; Yilmaz, Zehra; Suain, Valérie; Authelet, Michèle; De Decker, Robert; Buée, Luc; Boom, Alain; Leroy, Karelle; Ando, Kunie; Brion, Jean-Pierre

    2016-10-01

    In Alzheimer disease, the development of tau pathology follows neuroanatomically connected pathways, suggesting that abnormal tau species might recruit normal tau by passage from cell to cell. Herein, we analyzed the effect of stereotaxic brain injection of human Alzheimer high-molecular-weight paired helical filaments (PHFs) in the dentate gyrus of wild-type and mutant tau THY-Tau22 mice. After 3 months of incubation, wild-type and THY-Tau22 mice developed an atrophy of the dentate gyrus and a tau pathology characterized by Gallyas and tau-positive grain-like inclusions into granule cells that extended in the hippocampal hilus and eventually away into the alveus, and the fimbria. Gallyas-positive neuropil threads and oligodendroglial coiled bodies were also observed. These tau inclusions were composed only of mouse tau, and were immunoreactive with antibodies to 4R tau, phosphotau, misfolded tau, ubiquitin, and p62. Although local hyperphosphorylation of tau was increased in the dentate gyrus in THY-Tau22 mice, the development of neurofibrillary tangles made of mutant human tau was not accelerated in the hippocampus, indicating that wild-type human PHFs were inefficient in seeding tau aggregates made of G272V/P301S mutant human tau. Our results indicate thus that injection of human wild-type Alzheimer PHF seeded aggregation of wild-type murine tau into an argyrophilic 4R tau pathology, and constitutes an interesting model independent of expression of a mutant tau protein. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology

    NARCIS (Netherlands)

    Bronner, I.F.; ter Meulen, B.C.; Azmani, A.; Severijnen, L.A.; Willemsen, R.; Kamphorst, W.; Ravid, R.; Heutink, P.; van Swieten, J.C.

    2005-01-01

    Frontotemporal dementia and parkinsonism linked to chromosome 17 have been associated with mutations in the microtubule associated protein tau (MAPT or tau) gene. This disorder is characterized by a large spectrum of neuronal and glial tau lesions in different brain regions. Pick bodies were found

  9. Axonal disruption in white matter underlying cortical sulcus tau pathology in chronic traumatic encephalopathy.

    Science.gov (United States)

    Holleran, Laurena; Kim, Joong Hee; Gangolli, Mihika; Stein, Thor; Alvarez, Victor; McKee, Ann; Brody, David L

    2017-03-01

    Chronic traumatic encephalopathy (CTE) is a progressive degenerative disorder associated with repetitive traumatic brain injury. One of the primary defining neuropathological lesions in CTE, based on the first consensus conference, is the accumulation of hyperphosphorylated tau in gray matter sulcal depths. Post-mortem CTE studies have also reported myelin loss, axonal injury and white matter degeneration. Currently, the diagnosis of CTE is restricted to post-mortem neuropathological analysis. We hypothesized that high spatial resolution advanced diffusion MRI might be useful for detecting white matter microstructural changes directly adjacent to gray matter tau pathology. To test this hypothesis, formalin-fixed post-mortem tissue blocks from the superior frontal cortex of ten individuals with an established diagnosis of CTE were obtained from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank. Advanced diffusion MRI data was acquired using an 11.74 T MRI scanner at Washington University with 250 × 250 × 500 µm3 spatial resolution. Diffusion tensor imaging, diffusion kurtosis imaging and generalized q-sampling imaging analyses were performed in a blinded fashion. Following MRI acquisition, tissue sections were tested for phosphorylated tau immunoreactivity in gray matter sulcal depths. Axonal disruption in underlying white matter was assessed using two-dimensional Fourier transform analysis of myelin black gold staining. A robust image co-registration method was applied to accurately quantify the relationship between diffusion MRI parameters and histopathology. We found that white matter underlying sulci with high levels of tau pathology had substantially impaired myelin black gold Fourier transform power coherence, indicating axonal microstructural disruption (r = -0.55, p = 0.0015). Using diffusion tensor MRI, we found that fractional anisotropy (FA) was modestly (r = 0.53) but significantly (p = 0.0012) correlated with

  10. Tau Pathology and Parietal White Matter Lesions Have Independent but Synergistic Effects on Early Development of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Joakim Hertze

    2013-04-01

    Full Text Available Background: White matter lesions (WMLs are a common finding in patients with dementia. This study investigates the relationship between WMLs, hyperphosphorylated tau (P-tau in cerebrospinal fluid (CSF and apolipoprotein E (APOE ε4 genotype in prodromal Alzheimer's disease (AD. Methods: Baseline levels of tau, P-tau and β-amyloid 1-42 in CSF, the presence of WMLs in the brain, and the APOE genotype were ascertained in 159 patients with mild cognitive impairment (MCI and 38 cognitively healthy controls. Results: After 5.7 years, 58 patients had developed AD. In this group, patients with normal levels of CSF P-tau had higher levels of WMLs in the parietal regions than those with pathological P-tau levels (p Conclusions: We suggest that WMLs in parietal lobes and tau pathology likely have independent but synergistic effects on the reduction of the cognitive reserve capacity of the brain. In patients with a more low-grade AD pathology, WMLs in the parietal lobes might increase the risk of developing dementia.

  11. Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology.

    Science.gov (United States)

    Kulbe, Jacqueline R; Hall, Edward D

    2017-11-01

    In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, American football, Australian football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy have been confirmed to have deposits of hyperphosphorylated tau in locations that make its anatomical distribution distinct for other tauopathies. The fact that these individuals experienced repetitive TBI episodes during their athletic or military careers suggests that the secondary injury mechanisms that have been extensively characterized in acute TBI preclinical models, and in TBI patients, including glutamate excitotoxicity, intracellular calcium overload, mitochondrial dysfunction, free radical-induced oxidative damage and neuroinflammation, may contribute to the brain damage associated with CTE. Thus, the current review begins with an in depth analysis of what is known about the tau protein and its functions and dysfunctions followed by a discussion of the major TBI secondary injury mechanisms, and how the latter have been shown to contribute to tau pathology. The value of this review is that it might lead to improved neuroprotective strategies for either prophylactically attenuating the development of CTE or slowing its progression. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Mixed tau and TDP-43 pathology in a patient with unclassifiable primary progressive aphasia.

    Science.gov (United States)

    Flanagan, Eoin P; Duffy, Joseph R; Whitwell, Jennifer L; Vemuri, Prashanthi; Dickson, Dennis W; Josephs, Keith A

    2016-01-01

    Classifying primary progressive aphasia (PPA) into variants that may predict the underlying pathology is important. However, some PPA patients cannot be classified. A 78-year-old woman had unclassifiable PPA characterized by anomia, dysarthria, and apraxia of speech without agrammatism. Magnetic resonance imaging revealed left mesial temporal atrophy and 18-flourodeoxy-glucose positron emission tomography showed left anterior temporal and posterior frontal (premotor) hypometabolism. Autopsy revealed a mixed tauopathy (argyrophilic grain disease) and transactive response-DNA-binding-protein-43 proteinopathy. Dual pathologies may explain the difficulty classifying some PPA patients and recognizing this will be important as new imaging techniques (particularly tau-positron emission tomography) are introduced and patients begin enrollment in clinical trials targeting the underlying proteinopathy.

  13. Familial Prion Disease with Alzheimer Disease-Like Tau Pathology and Clinical Phenotype

    Science.gov (United States)

    Jayadev, Suman; Nochlin, David; Poorkaj, Parvoneh; Steinbart, Ellen J.; Mastrianni, James A.; Montine, Thomas J.; Ghetti, Bernardino; Schellenberg, Gerard D.; Bird, Thomas D.; Leverenz, James B.

    2011-01-01

    Objective To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). Methods Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aβ deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. Results The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aβ, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. Interpretation We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs. PMID:21416485

  14. Atrophy of the Posterior Subiculum Is Associated with Memory Impairment, Tau- and Aβ Pathology in Non-demented Individuals

    Directory of Open Access Journals (Sweden)

    Olof Lindberg

    2017-09-01

    Full Text Available Alzheimer’s disease (AD is associated with atrophy of the cornu ammonis (CA 1 and the subiculum subfield of the hippocampus (HC, and with deficits in episodic memory and spatial orientation. These deficits are mainly associated with the functionality of the posterior HC. We therefore hypothesized that key AD pathologies, i.e., β-amyloid and tau pathology would be particularly associated with the volume of the posterior subiculum in non-demented individuals. In our study we included 302 cognitively normal elderly participants (CN, 183 patients with subjective cognitive decline (SCD and 171 patients with amnestic mild cognitive impairment (MCI, all of whom underwent 3T magnetic resonance images (MRI. The subicular subfield was segmented using Freesurfer 5.3 and divided into 10 volumetric segments moving from the most posterior (segment 1 to the most anterior part along the axis of the hippocampal head and body (segment 10. Cerebrospinal fluid (CSF Aβ42 and phosphorylated tau (P-tau were quantified using ELISA and were used as biomarkers for β-amyloid and tau pathology, respectively. In the total sample, tau-pathology and Aβ-pathology and (measured by elevated P-tau and low Aβ42 levels in CSF and mild memory dysfunction were mostly associated with the volume changes of the posterior subiculum. Both SCD and MCI patients with elevated P-tau or low Aβ42 levels displayed predominantly posterior subicular atrophy in comparisons to control subjects with normal CSF biomarker levels. Finally, there was no main effect of Aβ42 or P-tau when comparing SCD with abnormal P-tau or Aβ42 with SCD with normal levels of these CSF-biomarkers. However, in the left subiculum there was a significant interaction revealing atrophy in the left posterior but not the anterior subiculum in participants with low Aβ42 levels. The same pattern was observed on the contralateral side in participants with elevated P-tau levels. In conclusion, AD pathologies and mild

  15. Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements

    National Research Council Canada - National Science Library

    Asuni, Ayodeji A; Boutajangout, Allal; Quartermain, David; Sigurdsson, Einar M

    2007-01-01

    .... Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype...

  16. A quantitative study of tau pathology in 11 cases of chronic traumatic encephalopathy.

    Science.gov (United States)

    Armstrong, R A; McKee, A C; Stein, T D; Alvarez, V E; Cairns, N J

    2017-02-01

    To quantify tau pathology of chronic traumatic encephalopathy (CTE) and investigate influence of dot-like lesions (DL), brain region, comorbidity and sporting career length. Densities of neurofibrillary tangles (NFT), astrocytic tangles (AT), DL, oligodendroglial inclusions (GI), neuropil threads (NT), vacuoles, neurons and enlarged neurons (EN) were measured in tau-immunoreactive sections of upper cortical laminae of frontal and temporal lobes, hippocampus (HC), amygdala and substantia nigra (SN) in 11 cases of CTE. DL were a consistent finding in CTE. Densities of NFT, NT and DL were greatest in sectors CA1 and CA2 of the HC. Densities of AT were lower than NFT, small numbers of GI were recorded in temporal lobe and low densities of vacuoles and EN were consistently present. β-Amyloid-containing neuritic plaques (NP) also occurred at low density. Densities of NFT, NT, DL and AT were greater in sulci than gyri, while vacuole density was greater in gyri. Principal components analysis (PCA) suggested that sporting career length and densities of NFT in entorhinal cortex, NT in CA2 and SN and vacuolation in the DG were significant sources of variation among cases. DL are frequent in CTE suggesting affinity with argyrophilic grain disease (AGD) and Parkinson's disease dementia (PD-Dem). Densities of AT in all regions and NT/DL in sectors CA2/4 were consistent features of CTE. The 11 cases are neuropathologically heterogeneous which may result from genetic diversity, and variation in anatomical pathways subjected to trauma. © 2016 British Neuropathological Society.

  17. Longitudinal Assessment of Tau Pathology in Patients with Alzheimer's Disease Using [18F]THK-5117 Positron Emission Tomography.

    Directory of Open Access Journals (Sweden)

    Aiko Ishiki

    Full Text Available The formation of neurofibrillary tangles is believed to contribute to the neurodegeneration observed in Alzheimer's disease (AD. Postmortem studies have shown strong associations between the neurofibrillary pathology and both neuronal loss and the severity of cognitive impairment. However, the temporal changes in the neurofibrillary pathology and its association with the progression of the disease are not well understood. Tau positron emission tomography (PET imaging is expected to be useful for the longitudinal assessment of neurofibrillary pathology in the living brain. Here, we performed a longitudinal PET study using the tau-selective PET tracer [18F]THK-5117 in patients with AD and in healthy control subjects. Annual changes in [18F]THK-5117 binding were significantly elevated in the middle and inferior temporal gyri and in the fusiform gyrus of patients with AD. Compared to patients with mild AD, patients with moderate AD showed greater changes in the tau load that were more widely distributed across the cortical regions. Furthermore, a significant correlation was observed between the annual changes in cognitive decline and regional [18F]THK-5117 binding. These results suggest that the cognitive decline observed in patients with AD is attributable to the progression of neurofibrillary pathology. Longitudinal assessment of tau pathology will contribute to the assessment of disease progression and treatment efficacy.

  18. Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study.

    Science.gov (United States)

    Wharton, Stephen B; Minett, Thais; Drew, David; Forster, Gillian; Matthews, Fiona; Brayne, Carol; Ince, Paul G

    2016-02-08

    Deposition of abnormally phosphorylated tau (phospho-tau) occurs in Alzheimer's disease but also with brain ageing. The Braak staging scheme focused on neurofibrillary tangles, but abundant p-tau is also present in neuropil threads, and a recent scheme has been proposed by the BrainNet Europe consortium for staging tau pathology based on neuropil threads. We determined the relationship of threads to tangles, and the value of staging for threads in an unselected population-representative ageing brain cohort. We also determined the prevalence of astroglial tau pathologies, and their relationship to neuronal tau. Phospho-tau pathology was determined by immunohistochemistry (AT8 antibody) in the MRC-CFAS neuropathology cohort. Neuropil threads were staged using the BrainNet Europe protocol for tau pathology, and compared with Braak tangle stages. Astroglial tau pathology was assessed in neo-cortical, mesial temporal and subcortical areas. Cases conformed well to the hierarchical neuropil threads staging of the BrainNet Europe protocol and correlated strongly with Braak staging (r=0.84, p pathology.

  19. FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration

    DEFF Research Database (Denmark)

    Urwin, Hazel; Josephs, Keith A; Rohrer, Jonathan D

    2010-01-01

    % (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural...... variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date......, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full...

  20. 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.

  1. Chronic Sleep Deprivation Exacerbates Learning-Memory Disability and Alzheimer's Disease-Like Pathologies in AβPP(swe)/PS1(ΔE9) Mice.

    Science.gov (United States)

    Qiu, Hongyan; Zhong, Rujia; Liu, Hui; Zhang, Feng; Li, Song; Le, Weidong

    2016-01-01

    Recently, there is an increasing concern over the association between sleep disorders and Alzheimer's disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AβPP(swe)/PS1(ΔE9) transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-β protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-β(1-42) production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD.

  2. Influence of Water Quality on Cholesterol-Induced Tau Pathology: Preliminary Data

    Directory of Open Access Journals (Sweden)

    D. Larry Sparks

    2011-01-01

    Full Text Available The studies employed the cholesterol-fed rabbit model of Alzheimer's disease (AD to investigate the relationship between AD-like neurofibrillary tangle (NFT neuropathology and tau protein levels as the main component of NFT. We measured brain and plasma tau levels and semiquantified NFT-like neuropathology in cholesterol-fed rabbits administered drinking water of varying quality (distilled, tap, and distilled+copper compared to animals receiving normal chow and local tap water. Total tau levels in plasma were increased in all cholesterol-fed rabbits compared to animals on normal chow, regardless of quality of water. In contrast, increased tau in brain and increased AT8 immunoreactive NFT-like lesions were greatest in cholesterol-fed rabbits administered distilled water. A substantial decrease in brain tau and incidence and density of AT8 immunoreactive NFT-like lesions occurred in cholesterol-fed rabbits administered copper water, and an even greater decrease was observed in cholesterol-fed animals on local tap water. These studies suggest the possibility that circulating tau could be the source of the tau accumulating in the brain.

  3. CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Koppel, Jeremy; Vingtdeux, Valerie; Marambaud, Philippe; d'Abramo, Cristina; Jimenez, Heidy; Stauber, Mark; Friedman, Rachel; Davies, Peter

    2014-03-14

    The endocannabinoid CB2 receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB2 receptor system on AD pathology, a colony of mice with a deleted CB2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2(-/-) (Cnr2(tm1Dgen)/J) mice to produce a colony of J20 CNR2(+/+) and J20 CNR2(-/-) mice. Seventeen J20 CNR2(+/+) mice (12 females, 5 males) and 16 J20 CNR2(-/-) mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble Aβ production and plaque deposition quantified with 6E10 staining, the effect of CB2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble Aβ42 and plaque deposition were significantly increased in J20 CNR2(-/-) mice relative to CNR2(+/+) mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2(-/-) mice. Total tau was significantly suppressed in J20 CNR2(-/-) mice relative to J20 CNR2(+/+) mice. The results confirm the constitutive role of the CB2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB2 to reduce Aβ; however, the results suggest that interventions may have a divergent effect on tau pathology.

  4. Accumulation of Pathological Tau Species and Memory Loss in a Conditional Model of Tauopathy

    National Research Council Canada - National Science Library

    Berger, Zdenek; Roder, Hanno; Hanna, Amanda; Carlson, Aaron; Rangachari, Vijayaraghavan; Yue, Mei; Wszolek, Zbigniew; Ashe, Karen; Knight, Joshua; Dickson, Dennis; Andorfer, Cathy; Rosenberry, Terrone L; Lewis, Jada; Hutton, Mike; Janus, Christopher

    2007-01-01

    ...) have suggested that NFT formation can be dissociated from memory loss and neurodegeneration. This suggests that NFTs are not the major neurotoxic tau species, at least during the early stages of pathogenesis...

  5. Etanercept Exacerbates Inflammation and Pathology in a Rabbit Model of Active Pulmonary Tuberculosis

    Science.gov (United States)

    Tsenova, Liana; O'Brien, Paul; Holloway, Jennifer; Peixoto, Blas; Soteropoulos, Patricia; Fallows, Dorothy; Subbian, Selvakumar

    2014-01-01

    Treatment of chronic inflammatory diseases with tumor necrosis factor alpha (TNF-α) antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology, and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared with infected untreated animals. Reduced collagen and fibrin deposition in the granulomas was associated with significant downregulation of the collagen metabolism and fibrosis network genes and upregulation of genes in the inflammatory response and cell recruitment networks in the lungs of etanercept treated, compared with untreated rabbits. Our results suggest that targeting the TNF-α signaling pathway disrupts the tissue remodeling process, which is required for the formation and maintenance of well-differentiated granulomas and for control of Mtb growth in the lungs. These results validate the use of the rabbit model for investigating the impact of selected human immune modulatory drugs, such as a TNF-α antagonist, on the host immune response and pathogenesis in TB. PMID:24831609

  6. 7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

    Directory of Open Access Journals (Sweden)

    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.

  7. Peripheral treatment with enoxaparin exacerbates amyloid plaque pathology in Tg2576 mice.

    Science.gov (United States)

    Cui, Hao; King, Anna E; Jacobson, Glenn A; Small, David H

    2017-04-01

    Alzheimer's disease (AD) is a complex, progressive neurological disorder characterized by the formation of extracellular amyloid plaques composed of β-amyloid protein (Aβ), the key component in pathogenesis of AD. Peripheral administration of enoxaparin (ENO) reportedly reduces the level of Aβ and the amyloid plaques in the cortex of amyloid precursor protein (APP) transgenic mice. However, the exact mechanism of these effects is unclear. Our previous studies indicated that ENO can inhibit APP processing to Aβ in primary cortical cells from Tg2576 mice by downregulating BACE1 levels. This study examines whether ENO-induced reduction of amyloid load is due to the decreased APP processing to Aβ in Tg2576 mice. Surprisingly, our results indicated that ENO significantly increases the Aβ42/Aβ40 ratio in cortex and enhances the amyloid plaque load in both cortex and hippocampus, although overall APP processing was not influenced by ENO. Moreover, ENO stimulated the aggregation of both Aβ40 and Aβ42 in vitro. Although ENO has been reported to improve cognition in vivo and has potential as a therapeutic agent for AD, the results from our study suggest that ENO can exacerbate the amyloid pathology, and the strategy of using ENO for the treatment of AD may require further assessment. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. The GLP-1 receptor agonist liraglutide reduces pathology-specific tau phosphorylation and improves motor function in a transgenic hTauP301L mouse model of tauopathy.

    Science.gov (United States)

    Hansen, Henrik H; Barkholt, Pernille; Fabricius, Katrine; Jelsing, Jacob; Terwel, Dick; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-03-01

    In addition to a prominent role in glycemic control, glucagon-like peptide 1 (GLP-1) receptor agonists exhibit neuroprotective properties. There is mounting experimental evidence that GLP-1 receptor agonists, including liraglutide, may enhance synaptic plasticity, counteract cognitive deficits and ameliorate neurodegenerative features in preclinical models of Alzheimer's disease (AD), predominantly in the context of β-amyloid toxicity. Here we characterized the effects of liraglutide in a transgenic mutant tau (hTauP301L) mouse tauopathy model, which develops age-dependent pathology-specific neuronal tau phosphorylation and neurofibrillary tangle formation with progressively compromised motor function (limb clasping). Liraglutide (500 µg/kg/day, s.c., q.d., n=18) or vehicle (n=18) was administered to hTauP301L mice for 6 months from the age of three months. Vehicle-dosed wild-type FVB/N mice served as normal control (n=17). The onset and severity of hind limb clasping was markedly different in liraglutide and vehicle-dosed transgenic mice. Clasping behavior was observed in 61% of vehicle-dosed hTauP301L mice with a 55% survival rate in 9-month old transgenic mice. In contrast, liraglutide treatment reduced the clasping rate to 39% of hTauP301L mice, and fully prevented clasping-associated lethality resulting in a survival rate of 89%. Stereological analyses demonstrated that hTauP301L mice exhibited hindbrain-dominant neuronal accumulation of phosphorylated tau closely correlated to the severity of clasping behavior. In correspondence, liraglutide treatment significantly reduced neuronal phospho-tau load by 61.9±10.2% (ptransgenic mouse tauopathy model. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Analysis of ribosomal protein S6 baseline phosphorylation and effect of tau pathology in the murine brain and human hippocampus.

    Science.gov (United States)

    Klingebiel, Maria; Dinekov, Maja; Köhler, Christoph

    2017-03-15

    We examined the distribution pattern of the phosphorylated 40S ribosomal subunit protein S6, a downstream target of the mTOR pathway, in the brains of 24-months-old human tau transgenic pR5 mice, non-transgenic littermates and in human hippocampi. We studied baseline levels of phosphorylated S6 and a possible effect of tau pathology. S6 phosphorylated at Ser235/236 (pS6Ser235/236) or Ser240/244 (pS6Ser240/244) has been used as a read-out of mTOR activity in several studies. The mTOR pathway regulates a wide variety of cellular functions including cell growth, ribosome biosynthesis, translational control and autophagy. Its dysregulation might underlie the neurodegenerative pathology of Alzheimer's disease and other tauopathies. pS6Ser235/236 and pS6Ser240/244 immunoreactivity in the mouse brain were widespread and similar distributed, but intensive pS6Ser235/236 immunoreactivity was more selective, especially highlighting certain brainstem regions. In the human hippocampus mainly granulovacuolar inclusions in neurons displayed pS6Ser235/236 immunoreactivity. In contrast, a considerable number of neurons displayed pS6Ser240/244 immunoreactivity in the cytoplasm without labeling of granulovacuolar inclusions. Except for a tendency of lower numbers of intensely phosphorylated S6-positive neurons in pR5 mice, the pattern of distribution of pS6Ser235/236 and pS6Ser240/244 immunoreactivity was largely unchanged when compared with non-transgenic mice and also when human hippocampi from AD cases and controls were compared. Similar to pR5 mice most neurons with hyper-phosphorylated tau in human hippocampi displayed no or only weak labeling for phosphorylated S6, suggesting that phosphorylated S6 is not especially associated with pathological tau, but is rather a feature of unaffected neurons. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

    Science.gov (United States)

    Revett, Timothy J.; Baker, Glen B.; Jhamandas, Jack; Kar, Satyabrata

    2013-01-01

    Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid β peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid β and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid β production, but also amyloid β can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness. PMID:22894822

  11. Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology.

    Science.gov (United States)

    Revett, Timothy J; Baker, Glen B; Jhamandas, Jack; Kar, Satyabrata

    2013-01-01

    Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid ß peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid ß and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid ß production, but also amyloid ß can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness.

  12. Exacerbation of brain pathology after partial restraint in hypertensive rats following SiO₂ nanoparticles exposure at high ambient temperature.

    Science.gov (United States)

    Sharma, Hari S; Muresanu, Dafin F; Patnaik, Ranjana; Sharma, Aruna

    2013-10-01

    This investigation examines the possibility that exposure to silica dust of hypertensive individuals may exacerbate brain pathology and sensory motor dysfunction at high environmental temperature. Hypertension was produced in rats (200-250 g) by two-kidney one clip (2K1C) method, and in these animals, SiO2 nanoparticles (NPs; 50 to 60 nm) were administered at 50 mg/kg, i.p. daily for 1 week. On the 8th day, these rats were subjected to partial restraint in a Perspex box for 4 h either at room temperature (21 °C) or at 33 °C in a biological oxygen demand incubator (wind velocity, 2.6 cm/s; relative humidity, 65 to 67 %). In these animals, behavioral functions, blood-brain barrier (BBB) permeability to Evans blue albumin (EBA) and radioiodine (([131]-)Iodine), brain water content and neuronal injuries were determined. Hypertensive rats subjected to 4 h restraint at room temperature did not exhibit BBB dysfunction, brain edema, neural injury, or alterations in rotarod or inclined plane angle performances. However, when these hypertensive rats were subjected to restraint at 33 °C, breakdown of the cortical BBB (EBA, +38 %; radioiodine, +56 %), brain water (+0.88 %), neuronal damages (+18 %), and behavioral impairment were exacerbated. Interestingly, SiO2 exposure to these rats further exacerbated BBB breakdown (EBA, 280 %; radioiodine, 350 %), brain edema (4 %), and neural injury (30 %) after identical restraint depending on the ambient temperature. SiO2 treatment also induced brain pathology and alteration in behavioral functions in normotensive rats after restraint at high temperature. These observations clearly show that hypertension significantly enhances restraint-induced brain pathology, and behavioral anomalies particularly at high ambient temperature and SiO2 intoxication further exacerbated these brain pathologies and cognitive dysfunctions.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Extravascular CD3+ T Cells in Brains of Alzheimer Disease Patients Correlate with Tau but Not with Amyloid Pathology: An Immunohistochemical Study.

    Science.gov (United States)

    Merlini, Mario; Kirabali, Tunahan; Kulic, Luka; Nitsch, Roger M; Ferretti, Maria Teresa

    2018-02-07

    Strong genetic and epidemiological evidence points to a crucial role of the immune system in the development of Alzheimer disease (AD). CD3+ T lymphocytes have been described in brains of postmortem AD patients and in transgenic models of AD-like cerebral amyloidosis and tau pathology. However, the occurrence of T cells in AD brains is still controversial; furthermore, the relationship between T cells and hallmarks of AD pathology (amyloid plaques and neurofibrillary tangles) remains to be established. We have studied the occurrence of T cells in postmortem hippocampi and mid frontal gyrus (MFG) samples of AD patients (Braak stage V-VI) and nondemented control subjects and correlated it with amyloid and tau pathology burden. Confocal microscopy and bright-field immunohistochemistry were used to identify brain-associated T cells. Extravascular CD3+ T cells were quantified and compared to nondemented controls. In addition, numbers of extravascular CD3+ T cells were correlated with amyloid (6E10 staining) and tau pathology (AT8 staining) in the same sections. Several CD3+, extravascular T cells were observed in the brains of AD patients, mostly of the CD8+ subtype. AD hippocampi harbored significantly increased numbers of extravascular CD3+ T cells compared to nondemented controls. CD3+ T cells significantly correlated with tau pathology but not with amyloid plaques in AD samples. Our data support the notion of T-cell occurrence in AD brains and suggest that, in advanced stages of AD, T-cell extravasation is driven by tau-related neurodegenerative changes rather than by cerebral amyloidosis. T cells could be crucial for driving the amyloid-independent phase of the AD pathology. © 2018 S. Karger AG, Basel.

  15. Precortical Phase of Alzheimer's Disease (AD)-Related Tau Cytoskeletal Pathology

    NARCIS (Netherlands)

    Stratmann, Katharina; Heinsen, Helmut; Korf, Horst-Werner; Del Turco, Domenico; Ghebremedhin, Estifanos; Seidel, Kay; Bouzrou, Mohamed; Grinberg, Lea T.; Bohl, Juergen; Wharton, Stephen B.; den Dunnen, Wilfred; Rueb, Udo

    Alzheimer's disease (AD) represents the most frequent progressive neuropsychiatric disorder worldwide leading to dementia. We systematically investigated the presence and extent of the AD-related cytoskeletal pathology in serial thick tissue sections through all subcortical brain nuclei that send

  16. PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI, and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI).

    Science.gov (United States)

    Rafii, Michael S; Lukic, Ana S; Andrews, Randolph D; Brewer, James; Rissman, Robert A; Strother, Stephen C; Wernick, Miles N; Pennington, Craig; Mobley, William C; Ness, Seth; Matthews, Dawn C

    2017-01-01

    Adults with Down syndrome (DS) represent an enriched population for the development of Alzheimer's disease (AD), which could aid the study of therapeutic interventions, and in turn, could benefit from discoveries made in other AD populations. 1) Understand the relationship between tau pathology and age, amyloid deposition, neurodegeneration (MRI and FDG PET), and cognitive and functional performance; 2) detect and differentiate AD-specific changes from DS-specific brain changes in longitudinal MRI. Twelve non-demented adults, ages 30 to 60, with DS were enrolled in the Down Syndrome Biomarker Initiative (DSBI), a 3-year, observational, cohort study to demonstrate the feasibility of conducting AD intervention/prevention trials in adults with DS. We collected imaging data with 18F-AV-1451 tau PET, AV-45 amyloid PET, FDG PET, and volumetric MRI, as well as cognitive and functional measures and additional laboratory measures. All amyloid negative subjects imaged were tau-negative. Among the amyloid positive subjects, three had tau in regions associated with Braak stage VI, two at stage V, and one at stage II. Amyloid and tau burden correlated with age. The MRI analysis produced two distinct volumetric patterns. The first differentiated DS from normal (NL) and AD, did not correlate with age or amyloid, and was longitudinally stable. The second pattern reflected AD-like atrophy and differentiated NL from AD. Tau PET and MRI atrophy correlated with several cognitive and functional measures. Tau accumulation is associated with amyloid positivity and age, as well as with progressive neurodegeneration measurable using FDG and MRI. Tau correlates with cognitive decline, as do AD-specific hypometabolism and atrophy.

  17. Mixed Tau and TDP-43 pathology in a patient with unclassifiable primary progressive aphasia

    OpenAIRE

    Flanagan, Eoin P.; Duffy, Joseph R.; Jennifer L. Whitwell; Vemuri, Prashanthi; Dickson, Dennis W.; Josephs, Keith A.

    2015-01-01

    Classifying primary progressive aphasia (PPA) into variants that may predict the underlying pathology is important. However, some PPA patients cannot be classified. A 78-year-old woman had unclassifiable PPA characterized by anomia, dysarthria and apraxia of speech without agrammatism. MRI revealed left mesial temporal atrophy and 18-flourodeoxy-glucose PET showed left anterior temporal and posterior frontal (premotor) hypometabolism. Autopsy revealed a mixed tauopathy (argyrophilic grain dis...

  18. Mitochondrial oxidative stress causes hyperphosphorylation of tau.

    Directory of Open Access Journals (Sweden)

    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.

  19. Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry

    DEFF Research Database (Denmark)

    Kromann, Sofie; Kudirkiene, Egle; Li, Lili

    2017-01-01

    infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline...... combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens....... the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending...

  20. Environmental novelty exacerbates stress hormones and A? pathology in an Alzheimer?s model

    OpenAIRE

    Stuart, Kimberley E.; King, Anna E.; Fernandez-Martos, Carmen M.; Summers, Mathew J.; James C Vickers

    2017-01-01

    Cognitive stimulation has been proposed as a non-pharmacological intervention to be used in primary, secondary and tertiary prevention approaches for Alzheimer?s disease. A common familial Alzheimer?s disease transgenic model showed heightened levels of the stress hormone, corticosterone. When exposed to periodic enhanced cognitive stimulation, these animals demonstrated further heightened levels of corticosterone as well as increased A? pathology. Hence, Alzheimer?s disease may be associated...

  1. Early-Life Antibiotic Exposure Causes Intestinal Dysbiosis and Exacerbates Skin and Lung Pathology in Experimental Systemic Sclerosis.

    Science.gov (United States)

    Mehta, Heena; Goulet, Philippe-Olivier; Mashiko, Shunya; Desjardins, Jade; Pérez, Gemma; Koenig, Martial; Senécal, Jean-Luc; Constante, Marco; Santos, Manuela M; Sarfati, Marika

    2017-11-01

    Patients with systemic sclerosis (SSc) display altered intestinal microbiota. However, the influence of intestinal dysbiosis on the development of experimental SSc remains unknown. Topoisomerase I peptide-loaded dendritic cell immunization induces SSc-like disease, with progressive skin and lung fibrosis. Breeders were given streptomycin and pups continued to receive antibiotic (ATB) until endpoint (lifelongATB). Alternately, ATB was withdrawn (earlyATB) or initiated (adultATB) during adulthood. Topoisomerase I peptide-loaded dendritic cell (no ATB) immunization induced pronounced skin fibrosis, with increased matrix (Col1a1), profibrotic (Il13, Tweakr), and vascular function (Serpine1) gene expression. Remarkably, earlyATB exposure was sufficient to augment skin Col5a1 and Il13 expression, and inflammatory cell infiltration, which included IL-13+ cells, mononuclear phagocytes, and mast cells. Moreover, skin pathology exacerbation was also observed in lifelongATB and adultATB groups. Oral streptomycin administration induced intestinal dysbiosis, with exposure limited to early life (earlyATB) being sufficient to cause long-term modification of the microbiota and a shift toward increased Bacteroidetes/Firmicutes ratio. Finally, aggravated lung fibrosis and dysregulated pulmonary T-cell responses were observed in earlyATB and lifelongATB but not adultATB-exposed mice. Collectively, intestinal microbiota manipulation with streptomycin exacerbated pathology in two distinct sites, skin and lungs, with early life being a critical window to affect the course of SSc-like disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  2. The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling.

    Science.gov (United States)

    Ji, Yan-Xiao; Zhang, Peng; Zhang, Xiao-Jing; Zhao, Yi-Chao; Deng, Ke-Qiong; Jiang, Xi; Wang, Pi-Xiao; Huang, Zan; Li, Hongliang

    2016-06-01

    Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a ubiquitin E3 ligase that regulates important biological processes. However, the role of TRAF6 in cardiac hypertrophy remains unknown. Here, we show that TRAF6 levels are increased in human and murine hypertrophied hearts, which is regulated by reactive oxygen species (ROS) production. Cardiac-specific Traf6 overexpression exacerbates cardiac hypertrophy in response to pressure overload or angiotensin II (Ang II) challenge, whereas Traf6 deficiency causes an alleviated hypertrophic phenotype in mice. Mechanistically, we show that ROS, generated during hypertrophic progression, triggers TRAF6 auto-ubiquitination that facilitates recruitment of TAB2 and its binding to transforming growth factor beta-activated kinase 1 (TAK1), which, in turn, enables the direct TRAF6-TAK1 interaction and promotes TAK1 ubiquitination. The binding of TRAF6 to TAK1 and the induction of TAK1 ubiquitination and activation are indispensable for TRAF6-regulated cardiac remodelling. Taken together, we define TRAF6 as an essential molecular switch leading to cardiac hypertrophy in a TAK1-dependent manner.

  3. Exacerbation of pathology by oxidative stress in respiratory and locomotor muscles with Duchenne muscular dystrophy.

    Science.gov (United States)

    Lawler, John M

    2011-05-01

    Duchenne muscular dystrophy (DMD) is the most devastating type of muscular dystrophy, leading to progressive weakness of respiratory (e.g. diaphragm) and locomotor muscles (e.g. gastrocnemius). DMD is caused by X-linked defects in the gene that encodes for dystrophin, a key scaffolding protein of the dystroglycan complex (DCG) within the sarcolemmal cytoskeleton. As a result of a compromised dystroglycan complex, mechanical integrity is impaired and important signalling proteins (e.g. nNOS, caveolin-3) and pathways are disrupted. Disruption of the dystroglycan complex leads to high susceptibility to injury with repeated, eccentric contractions as well as inflammation, resulting in significant damage and necrosis. Chronic damage and repair cycling leads to fibrosis and weakness. While the link between inflammation with damage and weakness in the DMD diaphragm is unresolved, elevated oxidative stress may contribute to damage, weakness and possibly fibrosis. While utilization of non-specific antioxidant interventions has yielded inconsistent results, recent data suggest that NAD(P)H oxidase could play a pivotal role in elevating oxidative stress via integrated changes in caveolin-3 and stretch-activated channels (SACs). Oxidative stress may act as an amplifier, exacerbating disruption of the dystroglycan complex, upregulation of the inflammatory transcription factor NF-B, and thus functional impairment of force-generating capacity.

  4. Alterations of brain and cerebellar proteomes linked to Aβ and tau pathology in a female triple-transgenic murine model of Alzheimer's disease

    Science.gov (United States)

    Ciavardelli, D; Silvestri, E; Viscovo, A Del; Bomba, M; Gregorio, D De; Moreno, M; Ilio, C Di; Goglia, F; Canzoniero, L M T; Sensi, S L

    2010-01-01

    The triple-transgenic Alzheimer (3 × Tg-AD) mouse expresses mutant PS1M146V, APPswe, and tauP301L transgenes and progressively develops plaques and neurofibrillary tangles with a temporal- and region-specific profile that resembles the neuropathological progression of Alzheimer's disease (AD). In this study, we used proteomic approaches such as two-dimensional gel electrophoresis and mass spectrometry to investigate the alterations in protein expression occurring in the brain and cerebellum of 3 × Tg-AD and presenilin-1 (PS1) knock-in mice (animals that do not develop Aβ- or tau-dependent pathology nor cognitive decline and were used as control). Finally, using the Ingenuity Pathway Analysis we evaluated novel networks and molecular pathways involved in this AD model. We identified several differentially expressed spots and analysis of 3 × Tg-AD brains showed a significant downregulation of synaptic proteins that are involved in neurotransmitter synthesis, storage and release, as well as a set of proteins that are associated with cytoskeleton assembly and energy metabolism. Interestingly, in the cerebellum, a structure not affected by AD, we found an upregulation of proteins involved in carbohydrate metabolism and protein catabolism. Our findings help to unravel the pathogenic brain mechanisms set in motion by mutant amyloid precursor protein (APP) and hyperphosphorylated tau. These data also reveal cerebellar pathways that may be important to counteract the pathogenic actions of Aβ and tau, and ultimately offer novel targets for therapeutic intervention. PMID:21368863

  5. NK cells exacerbate the pathology of influenza virus infection in mice.

    Science.gov (United States)

    Zhou, Gang; Juang, Shih Wei W; Kane, Kevin P

    2013-04-01

    NK cells offer a first line of defense against viruses and are considered beneficial to the host during infection. Nevertheless, little is understood regarding the phenotype and function of NK cells in the lung during influenza virus infection. We found that the frequency of NK cells in mouse lung increased during influenza infection, with the majority of a mature phenotype. Cell surface CD107a and intracellular IFN-γ were detected in cells expressing multiple NK-cell receptors in infected lung, suggesting that NK cells were activated during infection. The activating receptor NKp46 was predominantly negative on such cells, possibly as a result of encountering influenza HA. Depletion of NK cells in vivo with anti-asialo GM1 or anti-NK1.1 reduced mortality from influenza infection and surviving mice recovered their body weight. Pathology induced by NK cells was only observed with high, not medium or low-dose influenza infection, indicating that the severity of infection influences NK-cell-mediated pathology. Furthermore, adoptive transfer of NK cells from influenza-infected lung, but not uninfected lung, resulted in more rapid weight loss and increased mortality of influenza-infected mice. Our results indicate that during severe influenza infection of the lung, NK cells have a deleterious impact on the host, promoting mortality. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Asymptomatic cattle naturally infected with Mycobacterium bovis present exacerbated tissue pathology and bacterial dissemination.

    Directory of Open Access Journals (Sweden)

    Álvaro Menin

    Full Text Available Rational discovery of novel immunodiagnostic and vaccine candidate antigens to control bovine tuberculosis (bTB requires knowledge of disease immunopathogenesis. However, there remains a paucity of information on the Mycobacterium bovis-host immune interactions during the natural infection. Analysis of 247 naturally PPD+ M. bovis-infected cattle revealed that 92% (n = 228 of these animals were found to display no clinical signs, but presented severe as well as disseminated bTB-lesions at post-mortem examination. Moreover, dissemination of bTB-lesions positively correlated with both pathology severity score (Spearman r = 0.48; p<0.0001 and viable tissue bacterial loads (Spearman r = 0.58; p = 0.0001. Additionally, granuloma encapsulation negatively correlated with M. bovis growth as well as pathology severity, suggesting that encapsulation is an effective mechanism to control bacterial proliferation during natural infection. Moreover, multinucleated giant cell numbers were found to negatively correlate with bacterial counts (Spearman r = 0.25; p = 0.03 in lung granulomas. In contrast, neutrophil numbers in the granuloma were associated with increased M. bovis proliferation (Spearman r = 0.27; p = 0.021. Together, our findings suggest that encapsulation and multinucleated giant cells control M. bovis viability, whereas neutrophils may serve as a cellular biomarker of bacterial proliferation during natural infection. These data integrate host granuloma responses with mycobacterial dissemination and could provide useful immunopathological-based biomarkers of disease severity in natural infection with M. bovis, an important cattle pathogen.

  7. Propofol Sedation Exacerbates Kidney Pathology and Dissemination of Bacteria during Staphylococcus aureus Bloodstream Infections.

    Science.gov (United States)

    Visvabharathy, Lavanya; Freitag, Nancy E

    2017-07-01

    Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for large numbers of postsurgical nosocomial infections across the United States and worldwide. Propofol anesthesia is widely used in surgery and in intensive care units, and recent evidence indicates that even brief exposure to propofol can substantially increase host susceptibility to microbial infection. Here, we delineate the impact of propofol sedation on MRSA bloodstream infections in mice in the presence and absence of prophylactic antibiotic treatment. Consistent with previous reports, brief periods of anesthesia with propofol were sufficient to significantly increase bacterial burdens and kidney pathology in mice infected with MRSA. Propofol exposure increased neutrophilic infiltrates into the kidney and enhanced bacterial dissemination throughout kidney tissue. Propofol sedation reduced populations of effector phagocytes and mature dendritic cells within the kidney and led to the apparent expansion of myeloid-derived suppressor cell-like populations. When propofol was coadministered with vancomycin prophylaxis, it dramatically increased kidney abscess formation and bacterial dissemination throughout kidney tissue at early times post-S. aureus infection compared to antibiotic-treated but nonsedated animals. Taken together, our data indicate that short-term sedation with propofol significantly increases the severity of bloodstream MRSA infection, even when administered in conjunction with vancomycin prophylaxis. Copyright © 2017 American Society for Microbiology.

  8. Extra-virgin olive oil attenuates amyloid-β and tau pathologies in the brains of TgSwDI mice.

    Science.gov (United States)

    Qosa, Hisham; Mohamed, Loqman A; Batarseh, Yazan S; Alqahtani, Saeed; Ibrahim, Baher; LeVine, Harry; Keller, Jeffrey N; Kaddoumi, Amal

    2015-12-01

    Extra-virgin olive oil (EVOO) is one of the main elements of Mediterranean diet. Several studies have suggested that EVOO has several health promoting effects that could protect from and decrease the risk of Alzheimer's disease (AD). In this study, we investigated the effect of consumption of EVOO-enriched diet on amyloid- and tau-related pathological alterations that are associated with the progression of AD and cerebral amyloid angiopathy (CAA) in TgSwDI mice. Feeding mice with EVOO-enriched diet for 6months, beginning at an age before amyloid-β (Aβ) accumulation starts, has significantly reduced total Aβ and tau brain levels with a significant improvement in mouse cognitive behavior. This reduction in brain Aβ was explained by the enhanced Aβ clearance pathways and reduced brain production of Aβ via modulation of amyloid-β precursor protein processing. On the other hand, although feeding mice with EVOO-enriched diet for 3months, beginning at an age after Aβ accumulation starts, showed improved clearance across the blood-brain barrier and significant reduction in Aβ levels, it did not affect tau levels or improve cognitive functions of TgSwDI mouse. Collectively, results of this study suggest that the long-term consumption of EVOO-containing diet starting at early age provides a protective effect against AD and its related disorder CAA. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Small-Animal PET Imaging of Tau Pathology with 18F-THK5117 in 2 Transgenic Mouse Models.

    Science.gov (United States)

    Brendel, Matthias; Jaworska, Anna; Probst, Federico; Overhoff, Felix; Korzhova, Viktoria; Lindner, Simon; Carlsen, Janette; Bartenstein, Peter; Harada, Ryuichi; Kudo, Yukitsuka; Haass, Christian; Van Leuven, Fred; Okamura, Nobuyuki; Herms, Jochen; Rominger, Axel

    2016-05-01

    Abnormal accumulation of tau aggregates in the brain is one of the hallmarks of Alzheimer disease neuropathology. We visualized tau deposition in vivo with the previously developed 2-arylquinoline derivative (18)F-THK5117 using small-animal PET in conjunction with autoradiography and immunohistochemistry gold standard assessment in 2 transgenic mouse models expressing hyperphosphorylated tau. Small-animal PET recordings were obtained in groups of P301S (n = 11) and biGT mice (n = 16) of different ages, with age-matched wild-type (WT) serving as controls. After intravenous administration of 16 ± 2 MBq of (18)F-THK5117, a dynamic 90-min emission recording was initiated for P301S mice and during 20-50 min after injection for biGT mice, followed by a 15-min transmission scan. After coregistration to the MRI atlas and scaling to the cerebellum, we performed volume-of-interest-based analysis (SUV ratio [SUVR]) and statistical parametric mapping. Small-animal PET results were compared with autoradiography ex vivo and in vitro and further validated with AT8 staining for neurofibrillary tangles. SUVRs calculated from static recordings during the interval of 20-50 min after tracer injection correlated highly with estimates of binding potential based on the entire dynamic emission recordings (R = 0.85). SUVR increases were detected in the brain stem of aged P301S mice (+11%; P transgenic tauopathy mouse models using the tau tracer (18)F-THK5117, the temporal and spatial progression could be visualized in good correlation with gold standard assessments of tau accumulation. The serial small-animal PET method could afford the means for preclinical testing of novel therapeutic approaches by accommodating interanimal variability at baseline, while detection thresholds in young animals have to be considered. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  10. Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aβ and Tau pathologies.

    Science.gov (United States)

    Li, Cong; Guo, Xiao-Dan; Lei, Min; Wu, Jia-Yi; Jin, Jia-Zhen; Shi, Xiao-Fan; Zhu, Zhi-Yuan; Rukachaisirikul, Vatcharin; Hu, Li-Hong; Wen, Tie-Qiao; Shen, Xu

    2017-01-01

    Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both Aβ level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both Aβ levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APP swe , PS1dE9)] were administered THA (300 mg·kg -1 ·d -1 , ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate Aβ and sAPPβ contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, THΑ (1, 10, 20 μg/mL) significantly stimulated PI 3 K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of Aβ clearance as both a PI 3 K inhibitor and an AMPK indirect activator, and restrained Aβ production as a suppressor against PERK/eIF2α-mediated BACE1 expression. Additionally, THA functioned as a GSK3β inhibitor with an IC 50 of 1.32±0.85 μg/mL, repressing Tau hyperphosphorylation. Similar effects on Aβ accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA

  11. Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway.

    Science.gov (United States)

    Lee, Sungho; Xu, Guixiang; Jay, Taylor R; Bhatta, Sabina; Kim, Ki-Wook; Jung, Steffen; Landreth, Gary E; Ransohoff, Richard M; Lamb, Bruce T

    2014-09-10

    Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD--extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)--remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the "frustrated phagocytosis" concept and suggest that neuronal-microglial communication link the two central AD pathologies. Copyright © 2014 the authors 0270-6474/14/3412538-09$15.00/0.

  12. Propofol directly increases tau phosphorylation.

    Directory of Open Access Journals (Sweden)

    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

  13. Cold Environment Exacerbates Brain Pathology and Oxidative Stress Following Traumatic Brain Injuries: Potential Therapeutic Effects of Nanowired Antioxidant Compound H-290/51.

    Science.gov (United States)

    Sharma, Aruna; Muresanu, Dafin F; Lafuente, José Vicente; Sjöquist, Per-Ove; Patnaik, Ranjana; Ryan Tian, Z; Ozkizilcik, Asya; Sharma, Hari S

    2017-08-30

    The possibility that traumatic brain injury (TBI) occurring in a cold environment exacerbates brain pathology and oxidative stress was examined in our rat model. TBI was inflicted by making a longitudinal incision into the right parietal cerebral cortex (2 mm deep and 4 mm long) in cold-acclimatized rats (5 °C for 3 h daily for 5 weeks) or animals at room temperature under Equithesin anesthesia. TBI in cold-exposed rats exhibited pronounced increase in brain lucigenin (LCG), luminol (LUM), and malondialdehyde (MDA) and marked pronounced decrease in glutathione (GTH) as compared to identical TBI at room temperature. The magnitude and intensity of BBB breakdown to radioiodine and Evans blue albumin, edema formation, and neuronal injuries were also exacerbated in cold-exposed rats after injury as compared to room temperature. Nanowired delivery of H-290/51 (50 mg/kg) 6 and 8 h after injury in cold-exposed group significantly thwarted brain pathology and oxidative stress whereas normal delivery of H-290/51 was neuroprotective after TBI at room temperature only. These observations are the first to demonstrate that (i) cold aggravates the pathophysiology of TBI possibly due to an enhanced production of oxidative stress, (ii) and in such conditions, nanodelivery of antioxidant compound has superior neuroprotective effects, not reported earlier.

  14. 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.)

  15. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy

    National Research Council Canada - National Science Library

    Iba, Michiyo; Guo, Jing L; McBride, Jennifer D; Zhang, Bin; Trojanowski, John Q; Lee, Virginia M-Y

    2013-01-01

    ...) comprising filamentous tau protein. Although emerging evidence suggests that tau pathology may be transmitted, we demonstrate here that synthetic tau fibrils are sufficient to transmit tau inclusions in a mouse model...

  16. Characterization of TauC3 antibody and demonstration of its potential to block tau propagation.

    Directory of Open Access Journals (Sweden)

    Samantha B Nicholls

    Full Text Available The spread of neurofibrillary tangle (NFT pathology through the human brain is a hallmark of Alzheimer's disease (AD, which is thought to be caused by the propagation of "seeding" competent soluble misfolded tau. "TauC3", a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW protein fraction of human AD brain. Using a specific TauC3 antibody, we were able to substantially block the HMW tau seeding activity of human AD brain extracts in an in vitro tau seeding FRET assay. We propose that TauC3 could contribute to the templated tau misfolding that leads to NFT spread in AD brains.

  17. Lessons from Tau-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Yazi D. Ke

    2012-01-01

    Full Text Available Both Alzheimer's disease (AD and frontotemporal dementia (FTD are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to the umbrella term “tauopathies” for these conditions, also emphasizing the central role of tau in AD and FTD. Generation of transgenic mouse models expressing human tau in the brain has contributed to the understanding of the pathomechanistic role of tau in disease. To reveal the physiological functions of tau in vivo, several knockout mouse strains with deletion of the tau-encoding MAPT gene have been established over the past decade, using different gene targeting constructs. Surprisingly, when initially introduced tau knockout mice presented with no overt phenotype or malformations. The number of publications using tau knockout mice has recently markedly increased, and both behavioural changes and motor deficits have been identified in aged mice of certain strains. Moreover, tau knockout mice have been instrumental in identifying novel functions of tau, both in cultured neurons and in vivo. Importantly, tau knockout mice have significantly contributed to the understanding of the pathophysiological interplay between Aβ and tau in AD. Here, we review the literature that involves tau knockout mice to summarize what we have learned so far from depleting tau in vivo.

  18. 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...

  19. Tau Now

    Science.gov (United States)

    Fargion, D.; Oliva, P.

    2016-10-01

    Ultra High Energy Cosmic Rays and UHE neutrinos may lead to a new deep astronomy. However the most recent results on their correlations and clustering seem to most authors inconclusive. We briefly remind some UHECR models and past and recent results. Our reading and overlapping of IR-gamma-UHECR maps and their correlations seem to answer to several key puzzles, offering a first hope of the UHECR astronomy, mostly ruled by lightest nuclei from nearby Universe. Regarding the UHE neutrino we recently noted that the flavor ratio and the absence of double bang in IceCube within highest energetic ten events may suggest still a dominant noisy prompt component. However a first correlated UHE crossing muon with expected location (through going upward muon neutrino or horizontally) in IceCube is in our view a milestone in neutrino astronomy road map, possibly partially related, to galactic UHECR narrow clustering. The disturbing and persistent atmospheric neutrino noises, both conventional and prompt, call for a better filtered neutrino astronomy: the tau neutrino ones. There are no yet (at present, detectable) TeV-PeVs or more energetic tau neutrino of atmospheric, conventional or prompt nature; only astrophysical ones might soon shine. Double bangs in IceCube and in particular the tau air-showers in large array are the unique definitive expected signatures of astrophysical signals. In particular tau air-shower amplify in a huge way the otherwise single lepton track, once in decay in flight, into a richest three of secondaries (up to a million of billion Cherenkov photons for PeV tau energy) whose wide areas may extend up to nearly kilometer size. Such airshowers are very directional. PeVs energetic tau lepton penetrate hundreds meters inside the rock before its decay. Therefore horizontal tau air-shower in front of deep, wide valleys or mountain cliff [D. Fargion, A. Aiello, R. Conversano; 26th ICRC, He 6.1.09, 6 p. 396-398. (1999). Ed. D. Kieda, et al. arxiv

  20. Moderately elevated intracranial pressure after diffuse traumatic brain injury is associated with exacerbated neuronal pathology and behavioral morbidity in the rat.

    Science.gov (United States)

    Lafrenaye, Audrey D; Krahe, Thomas E; Povlishock, John T

    2014-10-01

    Traumatic brain injury (TBI)-induced elevated intracranial pressure (ICP) is correlated with ensuing morbidity/mortality in humans. This relationship is assumed to rely mostly on the recognition that extremely elevated ICP either indicates hematoma/contusions capable of precipitating herniation or alters cerebral perfusion pressure (CPP), which precipitates global ischemia. However, whether subischemic levels of elevated ICP without hematoma/contusion contribute to increased morbidity/mortality remains unknown. To address this knowledge gap, we utilized a model of moderate diffuse TBI in rats followed by either intraventricular ICP monitoring or manual ICP elevation to 20 mm Hg, in which CPP was above ischemic levels. The effects of ICP elevation after TBI on acute and chronic histopathology, as well as on behavioral morbidity, were evaluated. ICP elevation after TBI resulted in increased acute neuronal membrane perturbation and was also associated with reduced neuronal density at 4 weeks after injury. Somatosensory hypersensitivity was exacerbated by ICP elevation and was correlated to the observed neuronal loss. In conclusion, this study indicates that morbidity and increased neuronal damage/death associated with elevated ICP can occur without concurrent global ischemia. Therefore, understanding the pathologies associated with subischemic levels of elevated ICP could lead to the development of better therapeutic strategies for the treatment and management of TBI patients.

  1. Ethanol enhances tau accumulation in neuroblastoma cells that inducibly express tau

    Science.gov (United States)

    Gendron, Tania F.; McCartney, Sharon; Causevic, Ena; Ko, Li-wen; Yen, Shu-Hui

    2008-01-01

    Chronic alcohol consumption causes pathological changes in the brain and neuronal loss. Ethanol toxicity may partially result from the perturbation of microtubule associated proteins, like tau. Tau dysfunction is well known for its involvement in certain neurodegenerative diseases, such as Alzheimer's disease. In the present study, the effect of ethanol on tau was examined using differentiated human neuroblastoma cells that inducibly express the 4R0N isoform of tau via a tetracycline-off expression system. During tau induction, ethanol exposure (1.25-5 mg/ml) dose-dependently increased tau protein levels and reduced cell viability. The increase in cell death likely resulted from tau accumulation since increased levels of tau were sufficient to reduce cell viability and ethanol was toxic to cells expressing tau but not to non-induced controls. Tau accumulation did not result from greater tetracycline-off induction since ethanol neither increased tau mRNA expression nor the expression of the tetracycline-controlled transactivator. Additionally, ethanol increased endogenous tau protein levels in neuroblastoma cells lacking the tetracycline-off induction system for tau. Ethanol delayed tau clearance suggesting ethanol impedes its degradation. Though ethanol inhibited neither cathepsin B, cathepsin D, nor chymotrypsin-like activity, it did significantly reduce calpain 1 expression and activity. Calpain I knockdown by shRNA increased tau levels indicating that calpain participates in tau degradation in this model. Moreover, the activation of calpain, by the calcium ionophore A23187, partially reversed the accumulation of tau resulting from ethanol exposure. Impaired calpain-mediated degradation may thus contribute to the increased accumulation of tau caused by ethanol. PMID:18672021

  2. 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

  3. 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.

  4. Heterogeneous Tau-Tubulin Complexes Accelerate Microtubule Polymerization.

    Science.gov (United States)

    Li, Xiao-Han; Rhoades, Elizabeth

    2017-06-20

    Tau is an intrinsically disordered protein with a central role in the pathology of a number of neurodegenerative diseases. Tau normally functions to stabilize neuronal microtubules, although the mechanism underlying this function is not well understood. Of note is that the interaction between tau and soluble tubulin, which has implications both in understanding tau function as well as its role in disease, is underexplored. Here we investigate the relationship between heterogeneity in tau-tubulin complexes and tau function. Specifically, we created a series of truncated and scrambled tau constructs and characterized the size and heterogeneity of the tau-tubulin complexes formed under nonpolymerizing conditions. Function of the constructs was verified by tubulin polymerization assays. We find that, surprisingly, the pseudo-repeat region of tau, which flanks the core microtubule-binding domain of tau, contributes largely to the formation of large, heterogeneous tau tubulin complexes; additional independent tubulin binding sites exist in repeats two and three of the microtubule binding domain. Of particular interest is that we find positive correlation between the size and heterogeneity of the complexes and rate of tau-promoted microtubule polymerization. We propose that tau-tubulin can be described as a "fuzzy" complex, and our results demonstrate the importance of heterogeneous complex formation in tau function. This work provides fundamental insights into the functional mechanism of tau, and more broadly underscores the relevance of heterogeneous and dynamic complexes in the functions of intrinsically disordered proteins. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  5. Distinct Therapeutic Mechanisms of Tau Antibodies

    Science.gov (United States)

    Funk, Kristen E.; Mirbaha, Hilda; Jiang, Hong; Holtzman, David M.; Diamond, Marc I.

    2015-01-01

    Tauopathies are neurodegenerative diseases characterized by accumulation of Tau amyloids, and include Alzheimer disease and certain frontotemporal dementias. Trans-neuronal propagation of amyloid mediated by extracellular Tau may underlie disease progression. Consistent with this, active and passive vaccination studies in mouse models reduce pathology, although by unknown mechanisms. We previously reported that intracerebroventricular administration of three anti-Tau monoclonal antibodies (HJ8.5, HJ9.3, and HJ9.4) reduces pathology in a model overexpressing full-length mutant (P301S) human Tau. We now study effects of these three antibodies and a negative control antibody (HJ3.4) on Tau aggregate uptake into BV2 microglial-like cells and primary neurons. Antibody-independent Tau uptake into BV2 cells was blocked by heparin, consistent with a previously described role for heparan sulfate proteoglycans. Two therapeutic antibodies (HJ8.5 and HJ9.4) promoted uptake of full-length Tau fibrils into microglia via Fc receptors. Surprisingly, HJ9.3 promoted uptake of fibrils composed of the Tau repeat domain or Alzheimer disease-derived Tau aggregates, but failed to influence full-length recombinant Tau fibrils. Size fractionation of aggregates showed that antibodies preferentially promote uptake of larger oligomers (n ≥∼20-mer) versus smaller oligomers (n ∼10-mer) or monomer. No antibody inhibited uptake of full-length recombinant fibrils into primary neurons, but HJ9.3 blocked neuronal uptake of Tau repeat domain fibrils and Alzheimer disease-derived Tau. Antibodies thus have multiple potential mechanisms, including clearance via microglia and blockade of neuronal uptake. However these effects are epitope- and aggregate size-dependent. Establishing specific mechanisms of antibody activity in vitro may help in design and optimization of agents that are more effective in vivo. PMID:26126828

  6. Pathology

    Directory of Open Access Journals (Sweden)

    Huihong Xu MD

    2016-08-01

    Full Text Available Medical students are often unsure about the viability of a career as a physician in pathology. In particular, they are concerned that pathologists may not have a gratifying lifestyle or be well compensated. These worries may cause angst among medical students considering pathology and among junior pathology residents wondering if they made the correct career choice. A 2016 survey of nearly 20 000 physicians including nearly 400 pathologists provides reassuring data about compensation and career choice. This survey showed that 52% of pathologists are satisfied with their career choice and 63% are satisfied with their compensation. Among the 26 specialties that were surveyed, pathologists ranked 2 in believing that they were fairly compensated. Moreover, 66% of pathologists find that making diagnostic decisions, a core aspect of our discipline, is the most rewarding aspect of their career. Pathologists also ranked among the highest groups of physicians in reporting happiness at work and among the lowest groups reporting burnout. Overall, these 2016 surveys show that the majority of pathologists find deep satisfaction in their careers as pathologists.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Long and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimer´s mice

    Directory of Open Access Journals (Sweden)

    John Fredy Castro-Alvarez

    2014-09-01

    Full Text Available CDK5 is a member of the cyclin-dependent kinase family with diverse functions in both the developing and mature nervous system. The inappropriate activation of CDK5 due to the proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles and chronic neurodegeneration. At 18 months of age 3xTg-AD mice were sacrificed after one year (long term or three weeks (short term of CDK5 knockdown. In long-term animals CDK5 knockdown prevented insoluble Tau formation in the hippocampi and prevented spatial memory impairment. In short-term animals, CDK5 knockdown showed reduction of CDK5, reversed Tau aggregation, and improved spatial memory compared to scrambled treated old 3xTg-AD mice. Neither long-term nor short-term CDK5 knock-down had an effect on old littermates. These findings further validate CDK5 as a target for Alzheimer’s disease both as a preventive measure and after the onset of symptoms.

  9. The release and trans-synaptic transmission of Tau via exosomes.

    Science.gov (United States)

    Wang, Yipeng; Balaji, Varun; Kaniyappan, Senthilvelrajan; Krüger, Lars; Irsen, Stephan; Tepper, Katharina; Chandupatla, RamReddy; Maetzler, Walter; Schneider, Anja; Mandelkow, Eckhard; Mandelkow, Eva-Maria

    2017-01-13

    Tau pathology in AD spreads in a hierarchical pattern, whereby it first appears in the entorhinal cortex, then spreads to the hippocampus and later to the surrounding areas. Based on this sequential appearance, AD can be classified into six stages ("Braak stages"). The mechanisms and agents underlying the progression of Tau pathology are a matter of debate. Emerging evidence indicates that the propagation of Tau pathology may be due to the transmission of Tau protein, but the underlying pathways and Tau species are not well understood. In this study we investigated the question of Tau spreading via small extracellular vesicles called exosomes. Exosomes from different sources were analyzed by biochemical methods and electron microscopy (EM) and cryo-EM. Microfluidic devices that allow the culture of cell populations in different compartments were used to investigate the spreading of Tau. We show that Tau protein is released by cultured primary neurons or by N2a cells overexpressing different Tau constructs via exosomes. Neuron-derived exosomal Tau is hypo-phosphorylated, compared with cytosolic Tau. Depolarization of neurons promotes release of Tau-containing exosomes, highlighting the importance of neuronal activity. Using microfluidic devices we show that exosomes mediate trans-neuronal transfer of Tau depending on synaptic connectivity. Tau spreading is achieved by direct transmission of exosomes between neurons. In organotypic hippocampal slices, Tau-containing exosomes in conditioned medium are taken up by neurons and microglia, not astrocytes. In N2a cells, Tau assemblies are released via exosomes. They can induce inclusions of other Tau molecules in N2a cells expressing mutant human Tau. We also studied exosomes from cerebrospinal fluid in AD and control subjects containing monomeric and oligomeric Tau. Split-luciferase complementation reveals that exosomes from CSF can promote Tau aggregation in cultured cells. Our study demonstrates that exosomes contribute

  10. 2017 Tau Trigger Efficiencies

    CERN Document Server

    CMS Collaboration

    2018-01-01

    Triggers selecting events with hadronically decaying $\\tau$ leptons ($\\tau_h$) are used in a wide variety of CMS analyses, in particular those targeting processes with a $H \\rightarrow \\tau\\tau$ decay. The performance of the $\\tau_h$ triggers is presented for data collected in 2017, corresponding to an integrated luminosity of 41.5\\,fb$^{-1}$ at 13 TeV, and compared with simulation.

  11. An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease.

    Science.gov (United States)

    Cavallini, Annalisa; Brewerton, Suzanne; Bell, Amanda; Sargent, Samantha; Glover, Sarah; Hardy, Clare; Moore, Roger; Calley, John; Ramachandran, Devaki; Poidinger, Michael; Karran, Eric; Davies, Peter; Hutton, Michael; Szekeres, Philip; Bose, Suchira

    2013-08-09

    Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3α, GSK3β, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3α and GSK3β using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies.

  12. Roles of tau pathology in the locus coeruleus (LC) in age-associated pathophysiology and Alzheimer's disease pathogenesis: Potential strategies to protect the LC against aging.

    Science.gov (United States)

    Satoh, Akiko; Iijima, Koichi M

    2017-12-21

    The locus coeruleus (LC) is the noradrenaline (norepinephrine, NE)-containing nucleus in the brainstem and innervates into widespread brain regions. This LC-NE system plays a critical role in a variety of brain functions, including attention, arousal, emotion, cognition, and the sleep-wake cycle. The LC is one of the brain regions vulnerable to the occurrence of neurofibrillary tangles (NFTs), which is associated with "primary age-related tauopathy (PART)" that describes the pathology commonly observed in the brains of aged individuals. In Alzheimer's disease (AD), the LC is one of the first places to develop NFTs, which may act as a seed for subsequent spreading of the pathology throughout the brain upon amyloid-β (Aβ) accumulation. As AD progresses, significant neuron loss occurs in the LC. Moreover, LC neurodegeneration is not only a consequence of AD, but also drives clinical and pathological manifestations of AD, such as microglial dysregulation, sleep disturbance, cognitive decline, and neurovascular dysfunction. Therefore, prevention of NFT pathology and neuron loss in the LC-NE system is critical for suppressing the progression of AD. We propose that targeting aging itself may be a proactive intervention against age-associated changes in the LC. Such an approach could open the way for novel interventions against age-associated neurodegenerative disorders, in particular, AD. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. TiO2-Nanowired Delivery of Mesenchymal Stem Cells Thwarts Diabetes- Induced Exacerbation of Brain Pathology in Heat Stroke: An Experimental Study in the Rat Using Morphological and Biochemical Approaches.

    Science.gov (United States)

    Sharma, Hari S; Feng, Lianyuan; Lafuente, José V; Muresanu, Dafin F; Tian, Zhenrong R; Patnaik, Ranjana; Sharma, Aruna

    2015-01-01

    We have shown previously that heat stroke produced by whole body hyperthermia (WBH) for 4 h at 38°C in diabetic rats exacerbates blood-brain barrier breakdown, brain edema formation and neuronal cell injury as compared to healthy animals after identical heat exposure. In this combination of diabetes and WBH, normal therapeutic measures do not induce sufficient neuroprotection. Thus, we investigated whether nanowired mesenchymal cells (MSCs) when delivered systemically may have better therapeutic effects on brain damage in diabetic rats after WBH. Diabetes induced by streptozotocin administration (75 mg/kg, i.p, daily for 3 days) in rats resulted in clinical symptoms of the disease within 4 to 6 weeks (blood glucose level 20 to 30 mmoles/l as compared to saline control groups (4 to 6 mmoles/l). When subjected to WBH, these diabetic rats showed a 4-to 6-fold exacerbation of blood-brain barrier breakdown to Evans blue and radioiodine, along with brain edema formation and neuronal cell injury. Intravenous administration of rat MSCs (1x10(6)) to diabetic rats one week before WBH slightly reduced brain pathology, whereas TiO2 nanowired MSCs administered in an identical manner resulted in almost complete neuroprotection. On the other hand, MSCs alone significantly reduced brain pathology in saline-treated rats after WBH. These observations indicate that nanowired delivery of stem cells has superior therapeutic potential in heat stroke with diabetes, pointing to novel clinical perspectives in the future.

  14. 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...

  15. Chronic Noise Exposure Acts Cumulatively to Exacerbate Alzheimer's Disease-Like Amyloid-β Pathology and Neuroinflammation in the Rat Hippocampus.

    Science.gov (United States)

    Cui, Bo; Li, Kang; Gai, Zhihui; She, Xiaojun; Zhang, Na; Xu, Chuanxiang; Chen, Xuewei; An, Gaihong; Ma, Qiang; Wang, Rui

    2015-08-07

    A putative etiological association exists between noise exposure and Alzheimer's disease (AD). Amyloid-β (Aβ) pathology is thought to be one of the primary initiating factors in AD. It has been further suggested that subsequent dysregulation of Aβ may play a mechanistic role in the AD-like pathophysiology associated with noise exposure. Here, we used ELISA, immunoblotting, cytokine arrays, and RT-PCR, to examine both hippocampal Aβ pathology and neuroinflammation in rats at different time points after noise exposure. We found that chronic noise exposure significantly accelerated the progressive overproduction of Aβ, which persisted for 7 to 14 days after the cessation of exposure. This effect was accompanied by up-regulated expression of amyloid precursor protein (APP) and its cleavage enzymes, β- and γ-secretases. Cytokine analysis revealed that chronic noise exposure increased levels of tumor necrosis factor-α and the receptor for advanced glycation end products, while decreasing the expression of activin A and platelet-derived growth factor-AA. Furthermore, we found persistent elevations of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 expression that closely corresponded to the noise-induced increases in Aβ and neuroinflammation. These studies suggest that lifelong environmental noise exposure may have cumulative effects on the onset and development of AD.

  16. 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.

  17. Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition.

    Science.gov (United States)

    Selenica, Maj-Linda; Benner, Leif; Housley, Steven B; Manchec, Barbara; Lee, Daniel C; Nash, Kevin R; Kalin, Jay; Bergman, Joel A; Kozikowski, Alan; Gordon, Marcia N; Morgan, Dave

    2014-01-01

    Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology.

  18. Depletion of microglia and inhibition of exosome synthesis halt tau propagation

    Science.gov (United States)

    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

  19. Specific Profile of Tau Isoforms in Argyrophylic Grain Disease

    Directory of Open Access Journals (Sweden)

    Alberto Rábano

    2013-01-01

    Full Text Available Argyrophylic grain disease (AGD is a neurodegenerative condition that has been classified among the sporadic tauopathies. Entities in this group present intracellular aggregates of hyperphosphorylated tau, giving rise to characteristic neuronal and glial inclusions. In different tauopathies, the proportion of several tau isoforms present in the aggregates shows specific patterns. AGD has been tentatively classified in the 4R group (predominance of 4R tau isoforms together with progressive supranuclear palsy and corticobasal degeneration. Pick's disease is included in the 3R group (predominance of 3R isoforms, whereas tau pathology of Alzheimer's disease represents and intermediate group (3 or 4 repeats [3R plus 4R, respectively] isoforms. In this work, we have analyzed tau present in aggregates isolated from brain samples of patients with argyrophylic grain disease. Our results indicate that the main tau isoform present in aggregates obtained from patients with AGD is a hyperphosphorylated isoform containing exons 2 and 10 but lacking exon 3.

  20. AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy.

    Science.gov (United States)

    Ising, Christina; Gallardo, Gilbert; Leyns, Cheryl E G; Wong, Connie H; Stewart, Floy; Koscal, Lauren J; Roh, Joseph; Robinson, Grace O; Remolina Serrano, Javier; Holtzman, David M

    2017-05-01

    Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the Fc domain of HJ8.5 is required for the therapeutic effect, we engineered single-chain variable fragments (scFvs) derived from HJ8.5 with variable linker lengths, all specific to human tau. Based on different binding properties, we selected two anti-tau scFvs and tested their efficacy in vivo by adeno-associated virus-mediated gene transfer to the brain of P301S-tg mice. The scFvs significantly reduced levels of hyperphosphorylated, aggregated tau in brain tissue of P301S-tg mice, associated with a decrease in detergent-soluble tau species. Interestingly, these mice showed substantial levels of scFvs in the cerebrospinal fluid without significant effects on total extracellular tau levels. Therefore, our study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response. © 2017 Ising et al.

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

    CERN Document Server

    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; Rangel, Murilo; Raniuk, Iurii; Ratnikov, Fedor; Raven, Gerhard; Redi, Federico; Reichert, Stefanie; dos Reis, Alberto; Remon Alepuz, Clara; Renaudin, Victor; Ricciardi, Stefania; Richards, Sophie; Rihl, Mariana; Rinnert, Kurt; Rives Molina, Vicente; Robbe, Patrick; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Lopez, Jairo Alexis; Rodriguez Perez, Pablo; Rogozhnikov, Alexey; Roiser, Stefan; Rollings, Alexandra Paige; Romanovskiy, Vladimir; Romero Vidal, Antonio; Ronayne, John William; Rotondo, Marcello; Rudolph, Matthew Scott; Ruf, Thomas; Ruiz Valls, Pablo; Saborido Silva, Juan Jose; Sadykhov, Elnur; Sagidova, Naylya; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Gonzalo, David; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santimaria, Marco; Santovetti, Emanuele; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saunders, Daniel Martin; Savrina, Darya; Schael, Stefan; Schellenberg, Margarete; Schiller, Manuel; Schindler, Heinrich; Schlupp, Maximilian; Schmelling, Michael; Schmelzer, Timon; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schreiner, HF; Schubert, Konstantin; Schubiger, Maxime; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Semennikov, Alexander; Sergi, Antonino; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Siddi, Benedetto Gianluca; Silva Coutinho, Rafael; Silva de Oliveira, Luiz Gustavo; Simi, Gabriele; Simone, Saverio; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Eluned; Smith, Iwan Thomas; Smith, Jackson; Smith, Mark; Soares Lavra, Lais; Sokoloff, Michael; Soler, Paul; Souza De Paula, Bruno; Spaan, Bernhard; Spradlin, Patrick; Sridharan, Srikanth; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Stefko, Pavol; Stefkova, Slavomira; Steinkamp, Olaf; Stemmle, Simon; Stenyakin, Oleg; Stevens, Holger; Stoica, Sabin; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Stramaglia, Maria Elena; Straticiuc, Mihai; Straumann, Ulrich; Sun, Liang; Sutcliffe, William; Swientek, Krzysztof; Syropoulos, Vasileios; Szczekowski, Marek; Szumlak, Tomasz; T'Jampens, Stephane; Tayduganov, Andrey; Tekampe, Tobias; Tellarini, Giulia; Teubert, Frederic; Thomas, Eric; van Tilburg, Jeroen; Tilley, Matthew James; Tisserand, Vincent; Tobin, Mark; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Topp-Joergensen, Stig; Toriello, Francis; Tourinho Jadallah Aoude, Rafael; Tournefier, Edwige; Tourneur, Stephane; Trabelsi, Karim; Traill, Murdo; Tran, Minh Tâm; Tresch, Marco; Trisovic, Ana; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tully, Alison; Tuning, Niels; Ukleja, Artur; Ustyuzhanin, Andrey; Uwer, Ulrich; Vacca, Claudia; 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; 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^-\

  2. Inactivation of Nitric Oxide Synthesis Exacerbates the Development of Alzheimer Disease Pathology in APPPS1 Mice (Amyloid Precursor Protein/Presenilin-1).

    Science.gov (United States)

    Cifuentes, Diana; Poittevin, Marine; Bonnin, Philippe; Ngkelo, Anta; Kubis, Nathalie; Merkulova-Rainon, Tatyana; Lévy, Bernard I

    2017-07-31

    The epidemiological link between hypertension and Alzheimer disease is established. We previously reported that hypertension aggravates the Alzheimer-like pathology in APPPS1 mice (amyloid precursor protein/presenilin-1, mouse model of Alzheimer disease) with angiotensin II-induced hypertension, in relation with hypertension and nitric oxide deficiency. To provide further insights into the role of nitric oxide in the hypertension-Alzheimer disease cross-talk, we studied the effects of nitric oxide blockade in APPPS1 mice using N(ω)-nitro-l-arginine methyl ester (l-NAME) alone or in combination with hydralazine, to normalize blood pressure. Compared with normotensive APPPS1 mice, those with l-NAME-induced hypertension had greater amyloid burden (Pmicrovascular density (Phypertension-induced arterial wall remodeling. By testing the cerebrovascular response to hypercapnic breathing, we evidenced early functional impairment of cerebral vasomotor activity in APPPS1 mice. Whereas in control wild-type normotensive mice, carbon dioxide breathing resulted in 15±1.3% increase in the mean blood flow velocity (Phypertensive APPPS1 mice (2.5±1.2%) and partly reversed to mild vasodilation by hydralazine (3.2±1.5%, Phypertension. Only cerebral amyloid angiopathy seems to be dependent on hypertension. © 2017 American Heart Association, Inc.

  3. $\\tau$ decays at LEP

    CERN Document Server

    Sobie, Randall J

    1997-01-01

    The measurements of the properties of the tau lepton are becoming increasingly more precise. We show that these results can be used to test the Standard Model. In addition, we illustrate how the hadronic decays of the tau can be used to study the strong interaction. (12 refs).

  4. Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation.

    Science.gov (United States)

    McEwan, William A; Falcon, Benjamin; Vaysburd, Marina; Clift, Dean; Oblak, Adrian L; Ghetti, Bernardino; Goedert, Michel; James, Leo C

    2017-01-17

    Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.

  5. 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.

  6. Paired Helical Filaments from Alzheimer Disease Brain Induce Intracellular Accumulation of Tau Protein in Aggresomes*

    Science.gov (United States)

    Santa-Maria, Ismael; Varghese, Merina; Ksiȩżak-Reding, Hanna; Dzhun, Anastasiya; Wang, Jun; Pasinetti, Giulio M.

    2012-01-01

    Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer disease and tauopathies. A specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated it propagates between neighboring neuronal cells, possibly spreading along the axonal network. We studied whether PHFs released from degenerating neurons could be taken up by surrounding cells and promote spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green fluorescent protein-tagged tau (GFP-Tau) were treated with isolated fractions of human Alzheimer disease-derived PHFs for 24 h. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was particularly evident by the perinuclear localization of aggregates and redistribution of the vimentin intermediate filament network and retrograde motor protein dynein. Furthermore, the content of Sarkosyl-insoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. An exosome-related mechanism did not appear to be involved in the release of GFP-Tau from untreated cells. The evidence that cells can internalize PHFs, leading to formation of aggresome-like bodies, opens new therapeutic avenues to prevent propagation and spreading of tau pathology. PMID:22496370

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy

    Science.gov (United States)

    Ferrer, Isidro; Grinberg, Lea T.; Alafuzoff, Irina; Attems, Johannes; Budka, Herbert; Cairns, Nigel J.; Crary, John F.; Duyckaerts, Charles; Ghetti, Bernardino; Halliday, Glenda M.; Ironside, James W.; Love, Seth; Mackenzie, Ian R.; Munoz, David G.; Murray, Melissa E.; Nelson, Peter T.; Takahashi, Hitoshi; Trojanowski, John Q.; Ansorge, Olaf; Arzberger, Thomas; Baborie, Atik; Beach, Thomas G.; Bieniek, Kevin F.; Bigio, Eileen H.; Bodi, Istvan; Dugger, Brittany N.; Feany, Mel; Gelpi, Ellen; Gentleman, Stephen M.; Giaccone, Giorgio; Hatanpaa, Kimmo J.; Heale, Richard; Hof, Patrick R.; Hofer, Monika; Hortobágyi, Tibor; Jellinger, Kurt; Jicha, Gregory A.; Ince, Paul; Kofler, Julia; Kövari, Enikö; Kril, Jillian J.; Mann, David M.; Matej, Radoslav; McKee, Ann C.; McLean, Catriona; Milenkovic, Ivan; Montine, Thomas J.; Murayama, Shigeo; Lee, Edward B.; Rahimi, Jasmin; Rodriguez, Roberta D.; Rozemüller, Annemieke; Schneider, Julie A.; Schultz, Christian; Seeley, William; Seilhean, Danielle; Smith, Colin; Tagliavini, Fabrizio; Takao, Masaki; Thal, Dietmar Rudolf; Toledo, Jon B.; Tolnay, Markus; Troncoso, Juan C.; Vinters, Harry V.; Weis, Serge; Wharton, Stephen B.; White, Charles L.; Wisniewski, Thomas; Woulfe, John M.; Yamada, Masahito

    2016-01-01

    Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of

  9. Alternative polyadenylation and miR-34 family members regulate tau expression

    DEFF Research Database (Denmark)

    Dickson, John R; Kruse, Carla; Montagna, Daniel R

    2013-01-01

    Tau pathologically aggregates in Alzheimer's disease, and evidence suggests that reducing tau expression may be safe and beneficial for the prevention or treatment of this disease. We sought to examine the role of the 3'-untranslated region (3'-UTR) of human tau mRNA in regulating tau expression....... Tau expresses two 3'-UTR isoforms, long and short, as a result of alternative polyadenylation. Using luciferase reporter constructs, we found that expression from these isoforms is differentially controlled in human neuroblastoma cell lines M17D and SH-SY5Y. Several microRNAs were computationally...

  10. High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain.

    Directory of Open Access Journals (Sweden)

    Martin C Herzig

    Full Text Available The G2019S mutation in the multidomain protein leucine-rich repeat kinase 2 (LRRK2 is one of the most frequently identified genetic causes of Parkinson's disease (PD. Clinically, LRRK2(G2019S carriers with PD and idiopathic PD patients have a very similar disease with brainstem and cortical Lewy pathology (α-synucleinopathy as histopathological hallmarks. Some patients have Tau pathology. Enhanced kinase function of the LRRK2(G2019S mutant protein is a prime suspect mechanism for carriers to develop PD but observations in LRRK2 knock-out, G2019S knock-in and kinase-dead mutant mice suggest that LRRK2 steady-state abundance of the protein also plays a determining role. One critical question concerning the molecular pathogenesis in LRRK2(G2019S PD patients is whether α-synuclein (aSN has a contributory role. To this end we generated mice with high expression of either wildtype or G2019S mutant LRRK2 in brainstem and cortical neurons. High levels of these LRRK2 variants left endogenous aSN and Tau levels unaltered and did not exacerbate or otherwise modify α-synucleinopathy in mice that co-expressed high levels of LRRK2 and aSN in brain neurons. On the contrary, in some lines high LRRK2 levels improved motor skills in the presence and absence of aSN-transgene-induced disease. Therefore, in many neurons high LRRK2 levels are well tolerated and not sufficient to drive or exacerbate neuronal α-synucleinopathy.

  11. Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity.

    Directory of Open Access Journals (Sweden)

    Cristina d'Abramo

    Full Text Available The use of antibodies to treat neurodegenerative diseases has undergone rapid development in the past decade. To date, immunotherapeutic approaches to Alzheimer's disease have mostly targeted amyloid beta as it is a secreted protein that can be found in plasma and CSF and is consequently accessible to circulating antibodies. Few recent publications have suggested the utility of treatment of tau pathology with monoclonal antibodies to tau. Our laboratory has begun a systematic study of different classes of tau monoclonal antibodies using mutant P301L mice. Three or seven months old mutant tau mice were inoculated weekly with tau monoclonal antibodies at a dose of 10 mg/Kg, until seven or ten months of age were reached respectively. Our data strongly support the notion that in P301L animals treated with MC1, a conformational monoclonal antibody specific for PHF-tau, the rate of development of tau pathology is effectively reduced, while injecting DA31, a high affinity tau sequence antibody, does not exert such benefit. MC1 appears superior to DA31 in overall effects, suggesting that specificity is more important than affinity in therapeutic applications. Unfortunately the survival rate of the P301L treated mice was not improved when immunizing either with MC1 or PHF1, a high affinity phospho-tau antibody previously reported to be efficacious in reducing pathological tau. These data demonstrate that passive immunotherapy in mutant tau models may be efficacious in reducing the development of tau pathology, but a great deal of work remains to be done to carefully select the tau epitopes to target.

  12. Lysine-Directed Post-translational Modifications of Tau Protein in Alzheimer's Disease and Related Tauopathies

    Directory of Open Access Journals (Sweden)

    Christiana Kontaxi

    2017-08-01

    Full Text Available Tau is a microtubule-associated protein responsible mainly for stabilizing the neuronal microtubule network in the brain. Under normal conditions, tau is highly soluble and adopts an “unfolded” conformation. However, it undergoes conformational changes resulting in a less soluble form with weakened microtubule stabilizing properties. Altered tau forms characteristic pathogenic inclusions in Alzheimer's disease and related tauopathies. Although, tau hyperphosphorylation is widely considered to be the major trigger of tau malfunction, tau undergoes several post-translational modifications at lysine residues including acetylation, methylation, ubiquitylation, SUMOylation, and glycation. We are only beginning to define the site-specific impact of each type of lysine modification on tau biology as well as the possible interplay between them, but, like phosphorylation, these modifications are likely to play critical roles in tau's normal and pathobiology. This review summarizes the latest findings focusing on lysine post-translational modifications that occur at both endogenous tau protein and pathological tau forms in AD and other tauopathies. In addition, it highlights the significance of a site-dependent approach of studying tau post-translational modifications under normal and pathological conditions.

  13. Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor ?4 via activating calpain-2

    OpenAIRE

    Yaling Yin; Yali Wang; Di Gao; Jinwang Ye; Xin Wang; Lin Fang; Dongqin Wu; Guilin Pi; Chengbiao Lu; Xin-Wen Zhou; Ying Yang; Jian-Zhi Wang

    2016-01-01

    Cholinergic impairments and tau accumulation are hallmark pathologies in sporadic Alzheimer?s disease (AD), however, the intrinsic link between tau accumulation and cholinergic deficits is missing. Here, we found that overexpression of human wild-type full-length tau (termed hTau) induced a significant reduction of ?4 subunit of nicotinic acetylcholine receptors (nAChRs) with an increased cleavage of the receptor producing a ~55kDa fragment in primary hippocampal neurons and in the rat brains...

  14. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies.

    Science.gov (United States)

    Caccamo, Antonella; Magrì, Andrea; Medina, David X; Wisely, Elena V; López-Aranda, Manuel F; Silva, Alcino J; Oddo, Salvatore

    2013-06-01

    Accumulation of tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies, which include Alzheimer's disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and aggregates to form neurofibrillary tangles. The molecular mechanisms leading to tau accumulation remain unclear and more needs to be done to elucidate them. Age is a major risk factor for all tauopathies, suggesting that molecular changes contributing to the aging process may facilitate tau accumulation and represent common mechanisms across different tauopathies. Here, we use multiple animal models and complementary genetic and pharmacological approaches to show that the mammalian target of rapamycin (mTOR) regulates tau phosphorylation and degradation. Specifically, we show that genetically increasing mTOR activity elevates endogenous mouse tau levels and phosphorylation. Complementary to it, we further demonstrate that pharmacologically reducing mTOR signaling with rapamycin ameliorates tau pathology and the associated behavioral deficits in a mouse model overexpressing mutant human tau. Mechanistically, we provide compelling evidence that the association between mTOR and tau is linked to GSK3β and autophagy function. In summary, we show that increasing mTOR signaling facilitates tau pathology, while reducing mTOR signaling ameliorates tau pathology. Given the overwhelming evidence that reducing mTOR signaling increases lifespan and healthspan, the data presented here have profound clinical implications for aging and tauopathies and provide the molecular basis for how aging may contribute to tau pathology. Additionally, these results provide preclinical data indicating that reducing mTOR signaling may be a valid therapeutic approach for tauopathies. © 2013 John Wiley & Sons Ltd and the Anatomical Society.

  15. The ATLAS Tau Trigger

    CERN Document Server

    Rados, PK; The ATLAS collaboration

    2013-01-01

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

  16. The ATLAS Tau Trigger

    CERN Document Server

    Rados, PK; The ATLAS collaboration

    2013-01-01

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

  17. Measuring CP Violation in $h \\to \\tau^+ \\tau^-$ at Colliders

    CERN Document Server

    Harnik, Roni; Okui, Takemichi; Primulando, Reinard; Yu, Felix

    2013-01-01

    We investigate the LHC and Higgs Factory prospects for measuring the CP phase in the Higgs-tau-tau coupling. Currently this phase can be anywhere between 0 degrees (CP even) and 90 degrees (CP odd). A new, ideal observable is identified from an analytic calculation for the $\\tau^\\pm \\to \\rho^\\pm\

  18. Intracellular and extracellular microtubule associated protein tau as a therapeutic target in Alzheimer disease and other tauopathies.

    Science.gov (United States)

    Avila, Jesús; Pallas, Noemí; Bolós, Marta; Sayas, C Laura; Hernandez, Felix

    2016-06-01

    Microtubule associated protein tau, a protein mainly expressed in neurons, plays an important role in several diseases related to dementia, named tauopathies. Alzheimer disease is the most relevant tauopathy. The role of tau protein in dementia is now a topic under discussion, and is the focus of this review. We have covered two major areas: tau pathology and tau as a therapeutic target. Tau pathology is mainly related to a gain of toxic function due to an abnormal accumulation, aberrant modifications (such as hyperphosphorylation and truncation, among others) and self-aggregation of tau into oligomers or larger structures. Also, tau can be found extracellularly in a toxic form. Tau-based therapy is mainly centered on avoiding the gain of these toxic functions of tau. Tau therapies are focused on lowering tau levels, mainly of modified tau species that could be toxic for neurons (phosphorylated, truncated or aggregated tau), in intracellular or extracellular form. Decreasing the levels of those toxic species is a possible therapeutic strategy.

  19. Extracellular Tau Paired Helical Filaments Differentially Affect Tau Pathogenic Mechanisms in Mitotic and Post-Mitotic Cells: Implications for Mechanisms of Tau Propagation in the Brain.

    Science.gov (United States)

    Varghese, Merina; Santa-Maria, Ismael; Ho, Lap; Ward, Libby; Yemul, Shrishailam; Dubner, Lauren; Księżak-Reding, Hanna; Pasinetti, Giulio Maria

    2016-09-06

    The release of paired helical filaments (PHFs) from neurons into the extracellular space may contribute to the propagation of tau pathology across brain regions in Alzheimer's disease (AD) and other tauopathies. The majority of available mechanistic studies exploring the pathologic role of extracellular PHFs are conducted in proliferating cell lines. Here, we compare how extracellular PHFs induce tauopathy in mitotic cells and in post-mitotic brain neurons. In a mitotic cell line (HEK 293T), extracellular exposure to AD PHFs leads to an intracellular "aggresomal" type deposition of tau, coincidental with redistribution of dynein, a retrograde motor protein. We also observed that PHFs impaired proteasome degradation, but not autophagy. Exposure of cells to proteasome inhibitors was sufficient to induce intracellular tau aggregate formation as well as reorganization of dynein and the intermediate filament protein, vimentin. Thus, in mitotic cells, extracellular PHFs promote cellular tau aggregation, in part, by interfering with cellular proteasome degradation processes. In contrast with our observations with proliferating cells, exposure of post-mitotic primary neuronal cultures to AD PHFs did not promote "aggresomal" tau deposition, but instead resulted in a widespread accumulation of phosphorylated tau-immunoreactive swellings in neuritic processes, characterized by disturbed cytoskeletal organization of dynein and vimentin. Collectively, our observations suggest that extracellular PHFs may contribute to the propagation of tau pathology by independent mechanisms in post-mitotic and mitotic brain cells. These outcomes indicate that in addition to post-mitotic brain neurons, mitotic brain cells should also be considered as targets for therapeutic interventions to attenuate propagation of tauopathy.

  20. 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...

  1. Measurement of $\\tau$ Polarisation in $Z/\\gamma^*\\rightarrow\\tau\\tau$ Decays with the ATLAS Detector

    CERN Document Server

    Winter, Benedict Tobias; The ATLAS collaboration

    2017-01-01

    A measurement of the $\\tau$ polarisation in $Z/\\gamma^*\\rightarrow\\tau\\tau$ decays is presented. The analysis is based on the $20.2$ fb$^{-1}$ of proton$-$proton collision data collected at a centre-of-mass energy of $\\sqrt{s}=8$ TeV by the ATLAS experiment at the CERN Large Hadron Collider in 2012. Events with one leptonic $\\tau$ decay and one hadronic $\\tau$ decay with a single charged particle in the final state are selected. The $\\tau$ polarisation is measured using the kinematic configuration of the hadronic decay. A polarisation of $P_\\tau~=-0.14\\;\\pm~0.02\\;(\\textrm{stat})\\;\\pm~0.04\\;(\\textrm{syst})$ is measured in the mass range $66 < m_{Z/\\gamma^*} < 116$ GeV. It agrees with the Standard Model prediction of $P_\\tau~=-0.1517\\pm0.0014\\;(\\textrm{stat})\\pm0.0013\\;(\\textrm{syst})$.

  2. Measurements of the decays tau/sup -/. -->. rho/sup -/. nu. /sub tau/, tau/sup -/. -->. pi. /sup -/. nu. /sub tau/ and tau/sup -/. -->. K*-(892). nu. /sub tau/ using the MARK II detector at SPEAR

    Energy Technology Data Exchange (ETDEWEB)

    Dorfan, J.

    1981-04-01

    Measurements of the branching fractions for the Cabibbo favored decays tau/sup -/ ..-->.. rho/sup -/ ..-->.. ..pi../sup -/..nu../sub tau/ and the Cabibbo suppressed decay mode tau/sup -/ ..-->.. K*/sup -/ (892)..nu../sub tau/ are presented. The energy dependence of the tau/sup +/tau/sup -/ production cross section is obtained for the decays tau/sup -/ ..-->.. rho/sup -/..nu../sub tau/ and these spectra agree well with the classification of the tau/sup -/ as a spin-1/2 point particle. Fits to the production cross section yield a measurement of M/sub tau/ = (1787 +- 10) MeV/c/sup 2/ for the tau mass. Ninety-five percent confidence upper limits for the forbidden decay tau/sup -/ ..-->.. K*/sup -/(1430)..nu../sub tau/ and the tau neutrino mass are presented.

  3. Extracellular Vesicles Isolated from the Brains of rTg4510 Mice Seed Tau Protein Aggregation in a Threshold-dependent Manner.

    Science.gov (United States)

    Polanco, Juan Carlos; Scicluna, Benjamin James; Hill, Andrew Francis; Götz, Jürgen

    2016-06-10

    The microtubule-associated protein tau has a critical role in Alzheimer disease and related tauopathies. There is accumulating evidence that tau aggregates spread and replicate in a prion-like manner, with the uptake of pathological tau seeds causing misfolding and aggregation of monomeric tau in recipient cells. Here we focused on small extracellular vesicles enriched for exosomes that were isolated from the brains of tau transgenic rTg4510 and control mice. We found that these extracellular vesicles contained tau, although the levels were significantly higher in transgenic mice that have a pronounced tau pathology. Tau in the vesicles was differentially phosphorylated, although to a lower degree than in the brain cells from which they were derived. Several phospho-epitopes (AT8, AT100, and AT180) thought to be critical for tau pathology were undetected in extracellular vesicles. Despite this, when assayed with FRET tau biosensor cells, extracellular vesicles derived from transgenic mice were capable of seeding tau aggregation in a threshold-dependent manner. We also observed that the dye used to label extracellular vesicle membranes was still present during nucleation and formation of tau inclusions, suggesting either a role for membranes in the seeding or in the process of degradation. Together, we clearly demonstrate that extracellular vesicles can transmit tau pathology. This indicates a role for extracellular vesicles in the transmission and spreading of tau pathology. The characteristics of tau in extracellular vesicles and the seeding threshold we identified may explain why tau pathology develops very slowly in neurodegenerative diseases such as Alzheimer disease. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes.

    Science.gov (United States)

    Lasagna-Reeves, Cristian A; Sengupta, Urmi; Castillo-Carranza, Diana; Gerson, Julia E; Guerrero-Munoz, Marcos; Troncoso, Juan C; Jackson, George R; Kayed, Rakez

    2014-05-29

    Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood. An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins. The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.

  5. Long-Term Dietary Supplementation with Selenium-Enriched Yeast Improves Cognitive Impairment, Reverses Synaptic Deficits, and Mitigates Tau Pathology in a Triple Transgenic Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Zhang, Zhong-Hao; Wen, Lei; Wu, Qiu-Yan; Chen, Chen; Zheng, Rui; Liu, Qiong; Ni, Jia-Zuan; Song, Guo-Li

    2017-06-21

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multiple histopathological changes in the brain and by impairments in memory and cognitive function. Currently, there is no effective treatment that can halt or reverse the progression of this disease. Here, we explored the effects of 3 months of treatment with selenium-enriched yeast (Se-yeast), which is commonly used as a source of organic selenium (Se) for nutrition, on cognitive dysfunction and neuropathology in the triple transgenic mouse model of AD (3×Tg-AD mice). As the results revealed that Se-yeast significantly improved the spatial learning and memory retention of 3×Tg-AD mice, promoted neuronal activity, attenuated the activation of astrocytes and microglia, mitigated synaptic deficits, and reduced the levels of total tau and phosphorylated tau though inhibiting the activity of GSK-3β, dietary supplementation with Se-yeast exerted multiple beneficial effects on the prevention or treatment of AD. These findings provide evidence of a potentially viable compound for AD treatment.

  6. Microtubule binding and clustering of human Tau-4R and Tau-P301L proteins isolated from yeast deficient in orthologues of glycogen synthase kinase-3beta or cdk5.

    Science.gov (United States)

    Vandebroek, Tom; Terwel, Dick; Vanhelmont, Thomas; Gysemans, Maarten; Van Haesendonck, Chris; Engelborghs, Yves; Winderickx, Joris; Van Leuven, Fred

    2006-09-01

    Phosphorylation of Tau protein and binding to microtubules is complex in neurons and was therefore studied in the less complicated model of humanized yeast. Human Tau was readily phosphorylated at pathological epitopes, but in opposite directions regulated by kinases Mds1 and Pho85, orthologues of glycogen synthase kinase-3beta and cdk5, respectively (1). We isolated recombinant Tau-4R and mutant Tau-P301L from wild type, Delta mds1 and Delta pho85 yeast strains and measured binding to Taxol-stabilized mammalian microtubules in relation to their phosphorylation patterns. Tau-4R isolated from yeast lacking mds1 was less phosphorylated and bound more to microtubules than Tau-4R isolated from wild type yeast. Paradoxically, phosphorylation of Tau-4R isolated from kinase Pho85-deficient yeast was dramatically increased resulting in very poor binding to microtubules. Dephosphorylation promoted binding to microtubules to uniform high levels, excluding other modifications. Isolated hyperphosphorylated, conformationally altered Tau-4R completely failed to bind microtubules. In parallel to Tau-4R, we expressed, isolated, and analyzed mutant Tau-P301L. Total dephosphorylated Tau-4R and Tau-P301L bound to microtubules very similarly. Surprisingly, Tau-P301L isolated from all yeast strains bound to microtubules more extensively than Tau-4R. Atomic force microscopy demonstrated, however, that the high apparent binding of Tau-P301L was due to aggregation on the microtubules, causing their deformation and bundling. Our data explain the pathological presence of granular Tau aggregates in neuronal processes in tauopathies.

  7. Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy.

    Directory of Open Access Journals (Sweden)

    Katherine J Kopeikina

    Full Text Available Neurofibrillary tangles (NFTs of tau are one of the defining hallmarks of Alzheimer's disease (AD, and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.

  8. Prevention of COPD exacerbations

    DEFF Research Database (Denmark)

    Vestbo, Jørgen; Lange, Peter

    2015-01-01

    Exacerbations have significant impact on the morbidity and mortality of patients with chronic obstructive pulmonary disease. Most guidelines emphasise prevention of exacerbations by treatment with long-acting bronchodilators and/or anti-inflammatory drugs. Whereas most of this treatment is eviden...

  9. 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...

  10. 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...

  11. $\\tau$ 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.

  12. tau. - e and. tau. -. mu. universality from. tau. r arrow. pi. nu. decays

    Energy Technology Data Exchange (ETDEWEB)

    Bryman, D.A. (TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia, V6T 2A3 (Canada))

    1992-08-01

    It is pointed out that a comparison of measurements of {tau}{r arrow}{pi}{nu} decays with {pi}{r arrow}{mu}{nu} and {pi}{r arrow}{ital e}{nu} decays can be used to obtain accurate measures of {tau}-{mu} and {tau}-{ital e} universality. From current data on these processes it is found that the ratios of the electroweak charged-current couplings of the {tau} to those of the muon and electron are {ital g}{sub {tau}}/{ital g}{sub {mu}}=0.983{plus minus}0.025 and {ital g}{sub {tau}}/{ital g}{sub {ital e}}=0.986{plus minus}0.026, in agreement with the hypothesis of universality.

  13. UX Tau A

    Science.gov (United States)

    2007-01-01

    This is an artist's rendition of the one-million-year-old star system called UX Tau A, located approximately 450 light-years away. Observations from NASA's Spitzer Space Telescope showed a gap in the dusty planet-forming disk swirling around the system's central sun-like star. Spitzer saw a gap in UX Tau A's disk that extends from 0.2 to 56 astronomical units (an astronomical unit is the distance between the sun and Earth). The gap extends from the equivalent of Mercury to Pluto in our solar system, and is sandwiched between thick inner and outer disks on either side. Astronomers suspect that the gap was carved out by one or more forming planets. Such dusty disks are where planets are thought to be born. Dust grains clump together like snowballs to form larger rocks, and then the bigger rocks collide to form the cores of planets. When rocks revolve around their central star, they act like cosmic vacuum cleaners, picking up all the gas and dust in their path and creating gaps. Although gaps have been detected in disks swirling around young stars before, UX Tau A is special because the gap is sandwiched between two thick disks of dust. An inner thick dusty disk hugs the central star, then, moving outward, there is a gap, followed by another thick doughnut-shaped disk. Other systems with gaps contain very little to no dust near the central star. In other words, those gaps are more like big holes in the centers of disks. Some scientists suspect that these holes could have been carved out by a process called photoevaporation. Photoevaporation occurs when radiation from the central star heats up the gas and dust around it to the point where it evaporates away. The fact that there is thick disk swirling extremely close to UX Tau A's central star rules out the photoevaporation scenario. If photoevaporation from the star played a role, then large amounts of dust would not be floating so close to the star.

  14. 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.

  15. Bacterial co-expression of human Tau protein with protein kinase A and 14-3-3 for studies of 14-3-3/phospho-Tau interaction.

    Science.gov (United States)

    Tugaeva, Kristina V; Tsvetkov, Philipp O; Sluchanko, Nikolai N

    2017-01-01

    Abundant regulatory 14-3-3 proteins have an extremely wide interactome and coordinate multiple cellular events via interaction with specifically phosphorylated partner proteins. Notwithstanding the key role of 14-3-3/phosphotarget interactions in many physiological and pathological processes, they are dramatically underexplored. Here, we focused on the 14-3-3 interaction with human Tau protein associated with the development of several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Among many known phosphorylation sites within Tau, protein kinase A (PKA) phosphorylates several key residues of Tau and induces its tight interaction with 14-3-3 proteins. However, the stoichiometry and mechanism of 14-3-3 interaction with phosphorylated Tau (pTau) are not clearly elucidated. In this work, we describe a simple bacterial co-expression system aimed to facilitate biochemical and structural studies on the 14-3-3/pTau interaction. We show that dual co-expression of human fetal Tau with PKA in Escherichia coli results in multisite Tau phosphorylation including also naturally occurring sites which were not previously considered in the context of 14-3-3 binding. Tau protein co-expressed with PKA displays tight functional interaction with 14-3-3 isoforms of a different type. Upon triple co-expression with 14-3-3 and PKA, Tau protein could be co-purified with 14-3-3 and demonstrates complex which is similar to that formed in vitro between individual 14-3-3 and pTau obtained from dual co-expression. Although used in this study for the specific case of the previously known 14-3-3/pTau interaction, our co-expression system may be useful to study of other selected 14-3-3/phosphotarget interactions and for validations of 14-3-3 complexes identified by other methods.

  16. Escitalopram attenuates ?-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3? pathway

    OpenAIRE

    Wang, Yan-Juan; Ren, Qing-Guo; Gong, Wei-Gang; Wu, Di; Tang, Xiang; Li, Xiao-Li; Wu, Fang-Fang; Bai, Feng; Xu, Lin; Zhang, Zhi-Jun

    2016-01-01

    Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-? (A?)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with A?1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased A?1?42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3? pathway, and t...

  17. mTOR REGULATES TAU PHOSPHORYLATION AND DEGRADATION: IMPLICATIONS FOR ALZHEIMER’S DISEASE AND OTHER TAUOPATHIES

    Science.gov (United States)

    Caccamo, Antonella; Magrì, Andrea; Medina, David X.; Wisely, Elena V.; López-Aranda, Manuel F.; Silva, Alcino J.; Oddo, Salvatore

    2013-01-01

    SUMMARY Accumulation of tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies, which include Alzheimer’s disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and aggregates to form neurofibrillary tangles. The molecular mechanisms leading to tau accumulation remain unclear and more needs to be done to elucidate them. Age is a major risk factor for all tauopathies, suggesting that molecular changes contributing to the aging process may facilitate tau accumulation and represent common mechanisms across different tauopathies. Here, we use multiple animal models and complementary genetic and pharmacological approaches to show that the mammalian target of rapamycin (mTOR) regulates tau phosphorylation and degradation. Specifically, we show that genetically increasing mTOR activity elevates endogenous mouse tau levels and phosphorylation. Complementary to it, we further demonstrate that pharmacologically reducing mTOR signaling with rapamycin ameliorates tau pathology and the associated behavioral deficits in a mouse model overexpressing mutant human tau. Mechanistically, we provide compelling evidence that the association between mTOR and tau is linked to GSK3β and autophagy function. In summary, we show that increasing mTOR signaling facilitates tau pathology while reducing mTOR signaling ameliorates tau pathology. Given the overwhelming evidence showing that reducing mTOR signaling increases lifespan and health span, the data presented here have profound clinical implications for aging and tauopathies and provide the molecular basis for how aging may contribute to tau pathology. Additionally, these results provide pre-clinical data indicating that reducing mTOR signaling may be a valid therapeutic approach for tauopathies. PMID:23425014

  18. 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.

  19. Tau-positive nuclear indentations in P301S tauopathy mice.

    Science.gov (United States)

    Fernández-Nogales, Marta; Santos-Galindo, María; Merchán-Rubira, Jesús; Hoozemans, Jeroen J M; Rábano, Alberto; Ferrer, Isidro; Avila, Jesús; Hernández, Félix; Lucas, José J

    2017-05-01

    Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term "tau nuclear rods (TNRs)." Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an

  20. 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.

  1. Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Maass, Anne [Univ. of California, Berkeley, CA (United States); German Center for Neurodegenerative Diseases, Magdeburg (Germany); Landau, Susan [Univ. of California, Berkeley, CA (United States); Baker, Suzanne L. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Horng, Andy [Univ. of California, Berkeley, CA (United States); Lockhart, Samuel N. [Univ. of California, Berkeley, CA (United States); La Joie, Renaud [Univ. of California, San Francisco, CA (United States); Rabinovici, Gil D. [Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, San Francisco, CA (United States); Jagust, William J. [Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, San Francisco, CA (United States)

    2017-06-03

    The recent development of tau-specific positron emission tomography (PET) tracers enables in vivo quantification of regional tau pathology, one of the key lesions in Alzheimer's disease (AD). Tau PET imaging may become a useful biomarker for clinical diagnosis and tracking of disease progression but there is no consensus yet on how tau PET signal is best quantified. The goal of the current paper was to evaluate multiple whole-brain and region-specific approaches to detect clinically relevant tau PET signal. Two independent cohorts of cognitively normal adults and amyloid-positive (Aβ+) patients with mild cognitive impairment (MCI) or AD-dementia underwent [18F]AV-1451 PET. Methods for tau tracer quantification included: (i) in vivo Braak staging, (ii) regional uptake in Braak composite regions, (iii) several whole-brain measures of tracer uptake, (iv) regional uptake in AD-vulnerable voxels, and (v) uptake in a priori defined regions. Receiver operating curves characterized accuracy in distinguishing Aβ- controls from AD/MCI patients and yielded tau positivity cutoffs. Clinical relevance of tau PET measures was assessed by regressions against cognition and MR imaging measures. Key tracer uptake patterns were identified by a factor analysis and voxel-wise contrasts. Braak staging, global and region-specific tau measures yielded similar diagnostic accuracies, which differed between cohorts. While all tau measures were related to amyloid and global cognition, memory and hippocampal/entorhinal volume/thickness were associated with regional tracer retention in the medial temporal lobe. Key regions of tau accumulation included medial temporal and inferior/middle temporal regions, retrosplenial cortex, and banks of the superior temporal sulcus. Finally, our data indicate that whole-brain tau PET measures might be adequate biomarkers to detect AD-related tau pathology. However, regional measures covering AD-vulnerable regions may

  2. Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain.

    Directory of Open Access Journals (Sweden)

    Matthew Furgerson

    Full Text Available The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58 enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration.

  3. Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain.

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    Furgerson, Matthew; Fechheimer, Marcus; Furukawa, Ruth

    2012-01-01

    The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP) and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58) enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration.

  4. Effects of lysine residues on structural characteristics and stability of tau proteins

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    Lee, Myeongsang; Baek, Inchul; Choi, Hyunsung; Kim, Jae In; Na, Sungsoo, E-mail: nass@korea.ac.kr

    2015-10-23

    Pathological amyloid proteins have been implicated in neuro-degenerative diseases, specifically Alzheimer's, Parkinson's, Lewy-body diseases and prion related diseases. In prion related diseases, functional tau proteins can be transformed into pathological agents by environmental factors, including oxidative stress, inflammation, Aβ-mediated toxicity and covalent modification. These pathological agents are stable under physiological conditions and are not easily degraded. This un-degradable characteristic of tau proteins enables their utilization as functional materials to capturing the carbon dioxides. For the proper utilization of amyloid proteins as functional materials efficiently, a basic study regarding their structural characteristic is necessary. Here, we investigated the basic tau protein structure of wild-type (WT) and tau proteins with lysine residues mutation at glutamic residue (Q2K) on tau protein at atomistic scale. We also reported the size effect of both the WT and Q2K structures, which allowed us to identify the stability of those amyloid structures. - Highlights: • Lysine mutation effect alters the structure conformation and characteristic of tau. • Over the 15 layers both WT and Q2K models, both tau proteins undergo fractions. • Lysine mutation causes the increment of non-bonded energy and solvent accessible surface area. • Structural instability of Q2K model was proved by the number of hydrogen bonds analysis.

  5. Changes in tau phosphorylation levels in the hippocampus and frontal cortex following chronic stress

    Energy Technology Data Exchange (ETDEWEB)

    Yang, C.; Guo, X. [Wuhan University, Renmin Hospital, Department of Psychiatry, Wuhan, China, Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan (China); Wang, G.H. [Wuhan University, Renmin Hospital, Department of Psychiatry, Wuhan, China, Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan (China); Wuhan University, Institute of Neuropsychiatry, Wuhan, China, Institute of Neuropsychiatry, Wuhan University, Wuhan (China); Wang, H.L.; Liu, Z.C.; Liu, H.; Zhu, Z.X.; Li, Y. [Wuhan University, Renmin Hospital, Department of Psychiatry, Wuhan, China, Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan (China)

    2014-03-03

    Studies have indicated that early-life or early-onset depression is associated with a 2- to 4-fold increased risk of developing Alzheimers disease (AD). In AD, aggregation of an abnormally phosphorylated form of the tau protein may be a key pathological event. Tau is known to play a major role in promoting microtubule assembly and stabilization, and in maintaining the normal morphology of neurons. Several studies have reported that stress may induce tau phosphorylation. The main aim of the present study was to investigate possible alterations in the tau protein in the hippocampus and frontal cortex of 32 male Sprague-Dawley rats exposed to chronic unpredictable mild stress (CUMS) and then re-exposed to CUMS to mimic depression and the recurrence of depression, respectively, in humans. We evaluated the effects of CUMS, fluoxetine, and CUMS re-exposure on tau and phospho-tau. Our results showed that a single exposure to CUMS caused a significant reduction in sucrose preference, indicating a state of anhedonia. The change in behavior was accompanied by specific alterations in phospho-tau protein levels, but fluoxetine treatment reversed the CUMS-induced impairments. Moreover, changes in sucrose preference and phospho-tau were more pronounced in rats re-exposed to CUMS than in those subjected to a single exposure. Our results suggest that changes in tau phosphorylation may contribute to the link between depression and AD.

  6. Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy.

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    Javidnia, Monica; Hebron, Michaeline L; Xin, Yue; Kinney, Nikolas G; Moussa, Charbel E-H

    2017-01-01

    Hyperphosphorylation and aggregation of tau protein is a critical factor in many neurodegenerative diseases. These diseases are increasing in prevalence, and there are currently no cures. Previous work from our group and others has shown that tyrosine kinase inhibitors (TKIs) can stimulate autophagy, decrease pathological proteins, and improve symptoms in models of neurodegeneration. Here we examined the role of pazopanib in mouse models that express either human mutant P301L tau (TauP301L) or triple mutant amyloid precursor protein (3x-AβPP). The TauP301L mouse expresses P301L tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of some human tauopathies. Pazopanib crosses the blood-brain barrier with no detectable peripheral off-side effects, and decreases p-tau in TauP301L mice. Pazopanib reaches a brain concentration sufficient for inhibition of several tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs). Further, pazopanib does not affect microglia but reduces astrocyte levels toward nontransgenic controls in TauP301L mice. Pazopanib does not alter amyloid beta levels or astrocytes in 3x-AβPP mice but modulates a number of inflammatory markers (IP-10, MIP-1α, MIP-1β, and RANTES). These data suggest that pazopanib may be involved in p-tau clearance and modulation of astrocytic activity in models of tauopathies.

  7. Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons.

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    Bolós, M; Pallas-Bazarra, N; Terreros-Roncal, J; Perea, J R; Jurado-Arjona, J; Ávila, J; Llorens-Martín, M

    2017-12-08

    Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice. At the ultrastructural level, soluble Tau reduced the number of afferent synapses and caused a dramatic depletion of synaptic vesicles both in afferent and efferent synapses. Furthermore, the use of an RFP-expressing retrovirus revealed that soluble Tau altered the morphology of newborn granule neurons and reduced their afferent (dendritic spines) and efferent (mossy fiber terminals) connectivity. Finally, soluble Tau caused specific impairment of behavioral pattern separation capacity. Our results thus demonstrate for the first time that soluble Tau causes long-term detrimental effects on the morphology and connectivity of newborn granule neurons and that these effects correlate with impaired behavioral pattern separation skills. These data might be relevant for the field of neurodegenerative disorders, since they contribute to reinforcing the pathological roles played by distinct Tau species in vivo.

  8. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy.

    Science.gov (United States)

    Yanamandra, Kiran; Patel, Tirth K; Jiang, Hong; Schindler, Suzanne; Ulrich, Jason D; Boxer, Adam L; Miller, Bruce L; Kerwin, Diana R; Gallardo, Gilbert; Stewart, Floy; Finn, Mary Beth; Cairns, Nigel J; Verghese, Philip B; Fogelman, Ilana; West, Tim; Braunstein, Joel; Robinson, Grace; Keyser, Jennifer; Roh, Joseph; Knapik, Stephanie S; Hu, Yan; Holtzman, David M

    2017-04-19

    Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain. Copyright © 2017, American Association for the Advancement of Science.

  9. Photometric and spectroscopic monitoring of AA Tau, DN Tau, UX Tau A, T Tau, RY Tau, Lk Ca 4, and Lk Ca 7

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    Vrba, F. J.; Chugainov, P. F.; Weaver, W. B.; Stauffer, J. S.

    1993-01-01

    We report the results of a UBVRI photometric monitoring campaign for three classical T Tauri stars (AA Tau, DN Tau, and UX Tau A) and two weak emission line T Tauri stars (Lk Ca 4 and Lk Ca 7). Observations were obtained at three sites during a core observing period spanning UT 1985 October 14 through UT 1985 December 25, with additional observations continuing until UT 1986 April 6. Concurrent spectrophotometric observations were obtained for all main program stars except Lk Ca 7 and additionally for T Tau, RW Aur, and RY Tau. Periodic photometric variability, assumed to be the stars' rotation periods, were found for AA Tau, DN Tau, Lk Ca 4, and Lk Ca 7, respectively, as 8.2, 6.3, 3.4, and 5.7 days. Several U-filter flares were observed for Lk Ca 4 and Lk Ca 7, which are strongly concentrated toward phases of minimum light. Correlations are found between H-alpha line strengths and V magnitudes for AA Tau and RY Tau. An analysis of absolute color variations of classical T Tauri stars confirms that hot spots are the predominant cause of these stars' variability. Our overall results are consistent with earlier findings that long-lived cool spots are responsible for most of the variability found for weak-emission T Tauri stars, while temporal hot spots are primarily responsible for the observed variability found in classical T Tauri stars.

  10. An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.

    Science.gov (United States)

    Carlomagno, Yari; Chung, Dah-Eun Chloe; Yue, Mei; Castanedes-Casey, Monica; Madden, Benjamin J; Dunmore, Judy; Tong, Jimei; DeTure, Michael; Dickson, Dennis W; Petrucelli, Leonard; Cook, Casey

    2017-09-15

    The aberrant accumulation of tau protein is a pathological hallmark of a class of neurodegenerative diseases known as tauopathies, including Alzheimer's disease and related dementias. On the basis of previous observations that tau is a direct substrate of histone deacetylase 6 (HDAC6), we sought to map all HDAC6-responsive sites in tau and determine how acetylation in a site-specific manner affects tau's biophysical properties in vitro Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. To determine the functional consequence of this HDAC6-regulated phosphorylation event, we examined tau's ability to promote microtubule assembly and found that phosphorylation of Ser-324 interferes with the normal microtubule-stabilizing function of tau. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function. Because the disease relevance of this finding is evident, additional studies are needed to examine the role of pSer-324 in tau pathobiology and to determine whether therapeutically modulating this acetylation-phosphorylation switch affects disease progression in vivo. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Characteristics of TBS-extractable hyperphosphorylated tau species: Aggregation intermediates in rTg4510 mouse brain

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    Sahara, Naruhiko; DeTure, Michael; Ren, Yan; Ebrahim, Abdul-Shukkur; Kang, Dongcheul; Knight, Joshua; Volbracht, Christiane; Pedersen, Jan Torleif; Dickson, Dennis W.; Yen, Shu-Hui; Lewis, Jada

    2012-01-01

    Conditional overexpression of four-repeat human tau containing the P301L missense mutation in the rTg4510 mouse model of tauopathy leads to progressive accumulation of neurofibrillary tangles and hyperphosphorylated, sarkosyl-insoluble tau species, which are biochemically comparable to abnormal tau characteristic of hereditary tauopathies termed FTDP-17. To fully understand the impact of tau species at different stages of self-assembly on neurodegeneration, we fractionated rTg4510 brain representing several stages of tauopathy to obtain TBS-extractable (S1), high salt/sarkosyl-extractable (S3), and sarkosyl-insoluble (P3) fractions. Under reducing condition, the S1 fraction was demonstrated by Western blotting to contain both 50–60 kDa normally-sized and 64 kDa tau. Both are thermo-stable, but the 64 kDa tau showed a higher degree of phosphorylation. Under non-reducing condition, nearly all TBS-extractable 64 kDa tau were detected as ~130 kDa species consistent with the size of dimer. Quantitative analysis showed ~80 times more 64 kDa tau in S1 than P3 fraction. Immunoelectron microscopy revealed tau-positive granules/short filaments in S1 fraction. These structures displayed MC1 immunoreactivities indicative of conformational/pathological change of tau. MC1 immunoreactivity was detected by dot blotting in samples from 2.5 month-old mice, whereas Ab39 immunoreactivity indicative of late stages of tau assembly was detected only in P3 fraction. Quantitative analysis also demonstrated a significant inverse correlation between brain weight and 64 kDa tau, but the level of TBS-extractable 64 kDa tau reflects neurodegeneration better than that of sarkosyl-insoluble 64 kDa tau. Together, the findings suggest that TBS-extractable 64 kDa tau production is a potential target for therapeutic intervention of tauopathies. PMID:22941973

  12. A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function.

    Directory of Open Access Journals (Sweden)

    Abhinaya Iyer

    Full Text Available Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD, PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment.

  13. Tau and Caspase 3 as Targets for Neuroprotection

    Directory of Open Access Journals (Sweden)

    Anat Idan-Feldman

    2012-01-01

    Full Text Available The peptide drug candidate NAP (davunetide has demonstrated protective effects in various in vivo and in vitro models of neurodegeneration. NAP was shown to reduce tau hyperphosphorylation as well as to prevent caspase-3 activation and cytochrome-3 release from mitochondria, both characteristic of apoptotic cell death. Recent studies suggest that caspases may play a role in tau pathology. The purpose of this study was to evaluate the effect of NAP on tau hyperphosphorylation and caspase activity in the same biological system. Our experimental setup used primary neuronal cultures subjected to oxygen-glucose deprivation (OGD, with and without NAP or caspase inhibitor. Cell viability was assessed by measuring mitochondrial activity (MTS assay, and immunoblots were used for analyzing protein level. It was shown that apoptosis was responsible for all cell death occurring following ischemia, and NAP treatment showed a concentration-dependent protection from cell death. Ischemia caused an increase in the levels of active caspase-3 and hyperphosphorylated tau, both of which were prevented by either NAP or caspase-inhibitor treatment. Our data suggest that, in this model system, caspase activation may be an upstream event to tau hyperphosphorylation, although additional studies will be required to fully elucidate the cascade of events.

  14. Involvement of tau phosphorylation in traumatic brain injury patients.

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    Yang, W-J; Chen, W; Chen, L; Guo, Y-J; Zeng, J-S; Li, G-Y; Tong, W-S

    2017-06-01

    Traumatic brain injury (TBI) results in significant morbidity and mortality throughout the world. In TBI patients suffering cognitive, emotional, and behavioral deficits, the leading cause derives from the physical injury to the central nervous system (CNS) that impairs brain function. Here, we applied a targeted approach to understand the potential mechanisms of neuron damage after TBI. Tau protein phosphorylation was compared in the brain tissues collected from patients underwent brain surgery based on the assessment of brain injury extent by Glasgow Coma Scale (GCS). The results indicated that the levels of phosphorylated tau were significantly higher in the severe and extremely severe TBI groups, compared to the moderate group of patients. Phosphorylated, but not the total tau protein was uniquely correlated with the GCS score (R2 =.7849, P<.01) in 142 TBI patients. Consistently, the activities of key players associated with tau hyperphosphorylation GSK-3β and PP2A showed parallel correlations with the severity of TBI as well. These data suggest that the enhanced tau protein phosphorylation occurs upon severe neuron injures and may contribute to the pathological structural changes of CNS leading to brain damage of TBI. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Generation and characterization of new monoclonal antibodies targeting the PHF1 and AT8 epitopes on human tau.

    Science.gov (United States)

    Strang, Kevin H; Goodwin, Marshall S; Riffe, Cara; Moore, Brenda D; Chakrabarty, Paramita; Levites, Yona; Golde, Todd E; Giasson, Benoit I

    2017-07-31

    Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease, defined by the presence of brain pathological inclusions comprised of abnormally aggregated and highly phosphorylated tau protein. The abundance of brain tau aggregates correlates with disease severity and select phospho-tau epitopes increase at early stages of disease. We generated and characterized a series of novel monoclonal antibodies directed to tau phosphorylated at several of these phospho-epitopes, including Ser396/Ser404, Ser404 and Thr205. We also generated phosphorylation independent antibodies against amino acid residues 193-211. We show that most of these antibodies are highly specific for tau and strongly recognize pathological inclusions in human brains and in a transgenic mouse model of tauopathy. They also reveal epitope-specific differences in the biochemical properties of Alzheimer's disease sarkosyl-insoluble tau. These new reagents will be useful for investigating the progression of tau pathology and further as tools to target the cellular transmission of tau pathology.

  16. Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy

    Science.gov (United States)

    Puvenna, Vikram; Engeler, Madeline; Banjara, Manoj; Brennan, Chanda; Schreiber, Peter; Dadas, Aaron; Bahrami, Ashkon; Solanki, Jesal; Bandyopadhyay, Anasua; Morris, Jacqueline K.; Bernick, Charles; Ghosh, Chaitali; Bazarian, Jeffrey J.; Janigro, Damir

    2016-01-01

    Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six post mortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE. PMID:26556772

  17. Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy.

    Science.gov (United States)

    Puvenna, Vikram; Engeler, Madeline; Banjara, Manoj; Brennan, Chanda; Schreiber, Peter; Dadas, Aaron; Bahrami, Ashkon; Solanki, Jesal; Bandyopadhyay, Anasua; Morris, Jacqueline K; Bernick, Charles; Ghosh, Chaitali; Rapp, Edward; Bazarian, Jeffrey J; Janigro, Damir

    2016-01-01

    Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six postmortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (PCTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Tau PET in Alzheimer disease and mild cognitive impairment.

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    Cho, Hanna; Choi, Jae Yong; Hwang, Mi Song; Lee, Jae Hoon; Kim, You Jin; Lee, Hye Mi; Lyoo, Chul Hyoung; Ryu, Young Hoon; Lee, Myung Sik

    2016-07-26

    To investigate the topographical distribution of tau pathology and its effect on functional and structural changes in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) by using (18)F-AV-1451 PET. We included 20 patients with AD, 15 patients with MCI, and 20 healthy controls, and performed neuropsychological function tests, MRI, as well as (18)F-florbetaben (for amyloid) and (18)F-AV-1451 (for tau) PET scans. By using the regional volume-of-interest masks extracted from MRIs, regional binding values of standardized uptake value ratios and volumes were measured. We compared regional binding values among 3 diagnostic groups and identified correlations among the regional binding values, performance in each cognitive function test, and regional atrophy. (18)F-AV-1451 binding was increased only in the entorhinal cortex in patients with MCI, while patients with AD exhibited greater binding in most cortical regions. In the 35 patients with MCI and AD, (18)F-AV-1451 binding in most of the neocortex increased with a worsening of global cognitive function. The visual and verbal memory functions were associated with the extent of (18)F-AV-1451 binding, especially in the medial temporal regions. The (18)F-AV-1451 binding also correlated with the severity of regional atrophy of the cerebral cortex. Tau PET imaging with (18)F-AV-1451 could serve as an in vivo biomarker for the evaluation of AD-related tau pathology and monitoring disease progression. The accumulation of pathologic tau is more closely related to functional and structural deterioration in the AD spectrum than β-amyloid. © 2016 American Academy of Neurology.

  19. Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG).

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    Kovacs, Gabor G; Xie, Sharon X; Lee, Edward B; Robinson, John L; Caswell, Carrie; Irwin, David J; Toledo, Jon B; Johnson, Victoria E; Smith, Douglas H; Alafuzoff, Irina; Attems, Johannes; Bencze, Janos; Bieniek, Kevin F; Bigio, Eileen H; Bodi, Istvan; Budka, Herbert; Dickson, Dennis W; Dugger, Brittany N; Duyckaerts, Charles; Ferrer, Isidro; Forrest, Shelley L; Gelpi, Ellen; Gentleman, Stephen M; Giaccone, Giorgio; Grinberg, Lea T; Halliday, Glenda M; Hatanpaa, Kimmo J; Hof, Patrick R; Hofer, Monika; Hortobágyi, Tibor; Ironside, James W; King, Andrew; Kofler, Julia; Kövari, Enikö; Kril, Jillian J; Love, Seth; Mackenzie, Ian R; Mao, Qinwen; Matej, Radoslav; McLean, Catriona; Munoz, David G; Murray, Melissa E; Neltner, Janna; Nelson, Peter T; Ritchie, Diane; Rodriguez, Roberta D; Rohan, Zdenek; Rozemuller, Annemieke; Sakai, Kenji; Schultz, Christian; Seilhean, Danielle; Smith, Vanessa; Tacik, Pawel; Takahashi, Hitoshi; Takao, Masaki; Rudolf Thal, Dietmar; Weis, Serge; Wharton, Stephen B; White, Charles L; Woulfe, John M; Yamada, Masahito; Trojanowski, John Q

    2017-07-01

    Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  20. $K^{0}_{S}$ 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^-\

  1. Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Lambracht-Washington D

    2013-08-01

    Full Text Available Doris Lambracht-Washington, Roger N Rosenberg Department of Neurology and Neurotherapeutics, Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA Abstract: Immunotherapy might provide an effective treatment for Alzheimer's disease (AD. A unique feature of AD immunotherapies is that an immune response against a self-antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focused on two possible targets in this regard. One is the inhibition of accumulation and deposition of amyloid beta 1–42 (Aβ42, which is one of the major peptides found in senile plaques, and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting Aβ42 as well as tau with the respective anti-Aβ or anti-tau antibodies can provide significant improvements in these mice. While anti-Aβ immunotherapy (active and passive immunizations is already in several stages of clinical trials, tau-based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phosphorylated tau have been found, high interest has again focused on further development of tau-based therapies. While Aβ immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. Last but not least, targeting Aβ and tau simultaneously with immunotherapy might provide additional therapeutic effects, as these two pathologies are likely synergistic; this is an approach that has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about Aβ42 and tau biology, and present an overview on halted, ongoing, and upcoming clinical trials together with ongoing preclinical studies targeting tau

  2. Local Somatodendritic Translation and Hyperphosphorylation of Tau Protein Triggered by AMPA and NMDA Receptor Stimulation

    Directory of Open Access Journals (Sweden)

    Shunsuke Kobayashi

    2017-06-01

    Full Text Available Tau is a major component of the neurofibrillary tangles (NFT that represent a pathological hallmark of Alzheimer's disease (AD. Although generally considered an axonal protein, Tau is found in the somato-dendritic compartment of degenerating neurons and this redistribution is thought to be a trigger of neurodegeneration in AD. Here, we show the presence of tau mRNA in a dendritic ribonucleoprotein (RNP complex that includes Ca2+-calmodulin dependent protein kinase (CaMKIIα mRNA and that is translated locally in response to glutamate stimulation. Further, we show that Tau mRNA is a component of mRNP granules that contain RNA-binding proteins, and that it interacts with Myosin Va, a postsynaptic motor protein; these findings suggest that tau mRNA is transported into dendritic spines. We also report that tau mRNA localized in the somato-dendritic component of primary hippocampal cells and that a sub-toxic concentration of glutamate enhances local translation and hyperphosphorylation of tau, effects that are blocked by the gluatamatergic antagonists MK801 and NBQX. These data thus demonstrate that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA and N-methyl-d-aspartate (NMDA stimulation redistributes tau to the somato-dendritic region of neurons where it may trigger neurodegeneration.

  3. Hyperosmotic Stress Induces Tau Proteolysis by Caspase-3 Activation in SH-SY5Y Cells.

    Science.gov (United States)

    Olivera-Santa Catalina, Marta; Caballero-Bermejo, Montaña; Argent, Ricardo; Alonso, Juan C; Cuenda, Ana; Lorenzo, María J; Centeno, Francisco

    2016-12-01

    Tau is a microtubule-associated protein implicated in the pathogenesis of Alzheimer's disease and other related tauopathies. In this subset of neurodegenerative disorders, Tau auto-assembles into insoluble fibrils that accumulate in neurons as paired helical filaments (PHFs), promoting cellular dysfunction and cytotoxic effects. Growing evidence suggests that abnormal post-translational regulation, mainly hyperphosphorylation and aberrant cleavage, drives Tau to this pathological state. In this work we show that sorbitol-induced hyperosmotic stress promotes Tau proteolysis in SH-SY5Y neuroblastoma cells. The appearance of cleaved Tau was preceded by the activation of μ-calpain, the proteasome system and caspase-3. Tau proteolysis was completely prevented by caspase-3 inhibition but unaffected by neither the proteasome system nor μ-calpain activity blockade. Concomitantly, hyperosmotic stress induced apoptosis in SH-SY5Y cells, which was efficiently avoided by the inhibition of caspase-3 activity. Altogether, our results provide the first evidence that Tau protein is susceptible to caspase-3 proteolysis under hyperosmotic stress and suggest a positive relationship between Tau proteolysis and apoptosis in SH-SY5Y cells. J. Cell. Biochem. 117: 2781-2790, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  4. Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells.

    Science.gov (United States)

    Su, Bo; Wang, Xinglong; Lee, Hyoung-Gon; Tabaton, Massimo; Perry, George; Smith, Mark A; Zhu, Xiongwei

    2010-01-14

    Tau hyperphosphorylation appears to be a critical event leading to abnormal aggregation and disrupted function of tau in affected neurons in Alzheimer's disease (AD). As a prominent early event during AD pathogenesis, oxidative stress is believed to contribute to tau phosphorylation and the formation of neurofibrillary lesions. However, acute oxidative stress has disparate effects on tau phosphorylation. Given the chronic nature of AD, in this study, we aimed to determine the long-term effect of oxidative stress on tau phosphorylation. In this regard, we established a novel in vitro model of chronic oxidative stress through inhibition of glutathione (GSH) synthesis with BSO. We confirmed that these cells were under a chronic mild oxidative stress by looking at oxidative response, the induction of heme oxygenase 1 (HO-1) without neuronal death. Chronic oxidative stress increased levels of tau phosphorylated at PHF-1 epitope (serine 399/404) in a time-dependent manner. Our data further suggest that increased activity of JNK and p38 and decreased activity of PP2A are likely involved in chronic oxidative stress-induced tau phosphorylation. In conclusion we suggest that chronic oxidative stress contributes to increased tau phosphorylation in vitro and could play a critical role in neurofibrillary pathology in vivo. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  5. Dark chocolate exacerbates acne.

    Science.gov (United States)

    Vongraviopap, Saivaree; Asawanonda, Pravit

    2016-05-01

    The effects of chocolate on acne exacerbations have recently been reevaluated. For so many years, it was thought that it had no role in worsening acne. To investigate whether 99% dark chocolate, when consumed in regular daily amounts, would cause acne to worsen in acne-prone male subjects, twenty-five acne prone male subjects were asked to consume 25 g of 99% dark chocolate daily for 4 weeks. Assessments which included Leeds revised acne scores as well as lesion counts took place weekly. Food frequency questionnaire was used, and daily activities were recorded. Statistically significant changes of acne scores and numbers of comedones and inflammatory papules were detected as early as 2 weeks into the study. At 4 weeks, the changes remained statistically significant compared to baseline. Dark chocolate when consumed in normal amounts for 4 weeks can exacerbate acne in male subjects with acne-prone skin. © 2015 The International Society of Dermatology.

  6. Olfactory Dysfunctions and Decreased Nitric Oxide Production in the Brain of Human P301L Tau Transgenic Mice.

    Science.gov (United States)

    Hu, Yang; Ding, Wenting; Zhu, Xiaonan; Chen, Ruzhu; Wang, Xuelan

    2016-04-01

    Different patterns of olfactory dysfunction have been found in both patients and mouse models of Alzheimer's Disease. However, the underlying mechanism of the dysfunction remained unknown. Deficits of nitric oxide production in brain can cause olfactory dysfunction by preventing the formation of olfactory memory. The aim of this study was to investigate the behavioral changes in olfaction and alterations in metabolites of nitric oxide, nitrate/nitrite concentration, in the brain of human P301L tau transgenic mice. The tau mice showed impairments in olfaction and increased abnormal phosphorylation of Tau protein at AT8 in different brain areas, especially in olfactory bulb. We now report that these olfactory deficits and Tau pathological changes were accompanied by decreased nitrate/nitrite concentration in the brain, especially in the olfactory bulb, and reduced expression of nNOS in the brain of tau mice. These findings provided evidence of olfactory dysfunctions correlated with decreased nitric oxide production in the brain of tau mice.

  7. 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.

  8. Aspirin-Exacerbated Asthma

    OpenAIRE

    Varghese, Mathew; Lockey, Richard F

    2008-01-01

    This review focuses on aspirin-exacerbated asthma (AEA). The review includes historical perspective of aspirin, prevalence, pathogenesis, clinical features and treatment of AEA. The pathogenesis of AEA involves the cyclooxygenase and lipooxygenase pathway. Aspirin affects both of these pathways by inhibiting the enzyme cycooxygenase-1 (COX-1). Inhibition of COX-1 leads to a decrease in prostaglandin E2 (PGE2). The decrease in PGE2 results in an increase in cysteinyl leukotrienes by the lipoo...

  9. Acute exacerbation of airspace enlargement with fibrosis

    Directory of Open Access Journals (Sweden)

    Tomoyuki Kakugawa

    2014-01-01

    Full Text Available In 2008, Kawabata et al. described a lesion which they termed “airspace enlargement with fibrosis” that could be included on the spectrum of smoking-related interstitial lung diseases. This group also reported that patients with airspace enlargement with fibrosis but without coexisting interstitial pneumonia of another type had no acute exacerbations and favorable prognoses on clinical follow-up. Here we describe the first case, to our knowledge, of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of another type. An 82-year-old man was referred to our department for worsening dyspnea and new alveolar opacities on chest radiograph following left pulmonary segmentectomy (S6 for cancer. A diagnosis of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of other types was made, based on pathological evidence of airspace enlargement with fibrosis and organizing diffuse alveolar damage. Treatment with high-dose methylprednisolone followed by tapered oral prednisolone resulted in gradual improvement of the clinical condition and chest radiographic findings. Clinicians should be aware that patients with airspace enlargement with fibrosis may experience acute exacerbation.

  10. 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; Pan, Yibin; Panagiotopoulou, Evgenia; Pandini, Carlo Enrico; Panduro Vazquez, William; Pani, Priscilla; Panitkin, Sergey; Pantea, Dan; Paolozzi, Lorenzo; Papadopoulou, Theodora; Papageorgiou, Konstantinos; Paramonov, Alexander; Paredes Hernandez, Daniela; Parker, Michael Andrew; Parker, Kerry Ann; Parodi, Fabrizio; Parsons, John; Parzefall, Ulrich; Pasqualucci, Enrico; Passaggio, Stefano; Pastore, Fernanda; Pastore, Francesca; Pásztor, Gabriella; Pataraia, Sophio; Patel, Nikhul; Pater, Joleen; Pauly, Thilo; Pearce, James; Pearson, Benjamin; Pedersen, Lars Egholm; Pedersen, Maiken; Pedraza Lopez, Sebastian; Pedro, Rute; Peleganchuk, Sergey; Pelikan, Daniel; Penc, Ondrej; Peng, Cong; Peng, Haiping; Penning, Bjoern; Penwell, John; Perepelitsa, Dennis; Perez Codina, Estel; Pérez García-Estañ, María Teresa; Perini, Laura; Pernegger, Heinz; Perrella, Sabrina; Peschke, Richard; Peshekhonov, Vladimir; Peters, Krisztian; Peters, Yvonne; Petersen, Brian; Petersen, Troels; Petit, Elisabeth; Petridis, Andreas; Petridou, Chariclia; Petroff, Pierre; Petrolo, Emilio; Petrucci, Fabrizio; Pettersson, Nora Emilia; Pezoa, Raquel; Phillips, Peter William; Piacquadio, Giacinto; Pianori, Elisabetta; Picazio, Attilio; Piccaro, Elisa; Piccinini, Maurizio; Pickering, Mark Andrew; Piegaia, Ricardo; Pignotti, David; Pilcher, James; Pilkington, Andrew; Pina, João Antonio; Pinamonti, Michele; Pinfold, James; Pingel, Almut; Pinto, Belmiro; Pires, Sylvestre; Pirumov, Hayk; Pitt, Michael; Pizio, Caterina; Plazak, Lukas; Pleier, Marc-Andre; Pleskot, Vojtech; Plotnikova, Elena; Plucinski, Pawel; Pluth, Daniel; Poettgen, Ruth; Poggioli, Luc; Pohl, David-leon; Polesello, Giacomo; Poley, Anne-luise; Policicchio, Antonio; Polifka, Richard; Polini, Alessandro; Pollard, Christopher Samuel; Polychronakos, Venetios; Pommès, Kathy; Pontecorvo, Ludovico; Pope, Bernard; Popeneciu, Gabriel Alexandru; Popovic, Dragan; Poppleton, Alan; Pospisil, Stanislav; Potamianos, Karolos; Potrap, Igor; Potter, Christina; Potter, Christopher; Poulard, Gilbert; Poveda, Joaquin; Pozdnyakov, Valery; Pralavorio, Pascal; Pranko, Aliaksandr; Prasad, Srivas; Prell, Soeren; Price, Darren; Price, Lawrence; Primavera, Margherita; Prince, Sebastien; Proissl, Manuel; Prokofiev, Kirill; Prokoshin, Fedor; Protopapadaki, Eftychia-sofia; Protopopescu, Serban; Proudfoot, James; Przybycien, Mariusz; Ptacek, Elizabeth; Puddu, Daniele; Pueschel, Elisa; Puldon, David; Purohit, Milind; Puzo, Patrick; Qian, Jianming; Qin, Gang; Qin, Yang; Quadt, Arnulf; Quarrie, David; Quayle, William; Queitsch-Maitland, Michaela; Quilty, Donnchadha; Raddum, Silje; Radeka, Veljko; Radescu, Voica; Radhakrishnan, Sooraj Krishnan; Radloff, Peter; Rados, Pere; Ragusa, Francesco; Rahal, Ghita; Rajagopalan, Srinivasan; Rammensee, Michael; Rangel-Smith, Camila; Rauscher, Felix; Rave, Stefan; Ravenscroft, Thomas; Raymond, Michel; Read, Alexander Lincoln; Readioff, Nathan Peter; Rebuzzi, Daniela; Redelbach, Andreas; Redlinger, George; Reece, Ryan; Reeves, Kendall; Rehnisch, Laura; Reisin, Hernan; Relich, Matthew; Rembser, Christoph; Ren, Huan; Renaud, Adrien; Rescigno, Marco; Resconi, Silvia; Rezanova, Olga; Reznicek, Pavel; Rezvani, Reyhaneh; Richter, Robert; Richter, Stefan; Richter-Was, Elzbieta; Ricken, Oliver; Ridel, Melissa; Rieck, Patrick; Riegel, Christian Johann; Rieger, Julia; Rijssenbeek, Michael; Rimoldi, Adele; Rinaldi, Lorenzo; Ristić, Branislav; Ritsch, Elmar; Riu, Imma; Rizatdinova, Flera; Rizvi, Eram; Robertson, Steven; Robichaud-Veronneau, Andree; Robinson, Dave; Robinson, James; Robson, Aidan; Roda, Chiara; Roe, Shaun; Røhne, Ole; Rolli, Simona; Romaniouk, Anatoli; Romano, Marino; Romano Saez, Silvestre Marino; Romero Adam, Elena; Rompotis, Nikolaos; Ronzani, Manfredi; Roos, Lydia; Ros, Eduardo; Rosati, Stefano; Rosbach, Kilian; Rose, Peyton; Rosendahl, Peter Lundgaard; Rosenthal, Oliver; Rossetti, Valerio; Rossi, Elvira; Rossi, Leonardo Paolo; Rosten, Rachel; Rotaru, Marina; Roth, Itamar; Rothberg, Joseph; Rousseau, David; Royon, Christophe; Rozanov, Alexandre; Rozen, Yoram; Ruan, Xifeng; Rubbo, Francesco; Rubinskiy, Igor; Rud, Viacheslav; Rudolph, Christian; Rudolph, Matthew Scott; Rühr, Frederik; Ruiz-Martinez, Aranzazu; Rurikova, Zuzana; Rusakovich, Nikolai; Ruschke, Alexander; Russell, Heather; Rutherfoord, John; Ruthmann, Nils; Ryabov, Yury; Rybar, Martin; Rybkin, Grigori; Ryder, Nick; Saavedra, Aldo; Sabato, Gabriele; Sacerdoti, Sabrina; Saddique, Asif; Sadrozinski, Hartmut; Sadykov, Renat; Safai Tehrani, Francesco; Saimpert, Matthias; Saito, Tomoyuki; Sakamoto, Hiroshi; Sakurai, Yuki; Salamanna, Giuseppe; Salamon, Andrea; Saleem, Muhammad; Salek, David; Sales De Bruin, Pedro Henrique; Salihagic, Denis; Salnikov, Andrei; Salt, José; Salvatore, Daniela; Salvatore, Pasquale Fabrizio; Salvucci, Antonio; Salzburger, Andreas; Sammel, Dirk; Sampsonidis, Dimitrios; Sanchez, Arturo; Sánchez, Javier; Sanchez Martinez, Victoria; Sandaker, Heidi; Sandbach, Ruth Laura; Sander, Heinz Georg; Sanders, Michiel; Sandhoff, Marisa; Sandoval, Carlos; Sandstroem, Rikard; Sankey, Dave; Sannino, Mario; Sansoni, Andrea; Santoni, Claudio; Santonico, Rinaldo; Santos, Helena; Santoyo Castillo, Itzebelt; Sapp, Kevin; Sapronov, Andrey; Saraiva, João; Sarrazin, Bjorn; Sasaki, Osamu; Sasaki, Yuichi; Sato, Koji; Sauvage, Gilles; Sauvan, Emmanuel; Savage, Graham; Savard, Pierre; Sawyer, Craig; Sawyer, Lee; Saxon, James; Sbarra, Carla; Sbrizzi, Antonio; Scanlon, Tim; Scannicchio, Diana; Scarcella, Mark; Scarfone, Valerio; Schaarschmidt, Jana; Schacht, Peter; Schaefer, Douglas; Schaefer, Ralph; Schaeffer, Jan; Schaepe, Steffen; Schaetzel, Sebastian; Schäfer, Uli; Schaffer, Arthur; Schaile, Dorothee; Schamberger, R Dean; Scharf, Veit; Schegelsky, Valery; Scheirich, Daniel; Schernau, Michael; Schiavi, Carlo; Schillo, Christian; Schioppa, Marco; Schlenker, Stefan; Schmidt, Evelyn; Schmieden, Kristof; Schmitt, Christian; Schmitt, Sebastian; Schmitt, Stefan; Schneider, Basil; Schnellbach, Yan Jie; Schnoor, Ulrike; Schoeffel, Laurent; Schoening, Andre; Schoenrock, Bradley Daniel; Schopf, Elisabeth; Schorlemmer, Andre Lukas; Schott, Matthias; Schouten, Doug; Schovancova, Jaroslava; Schramm, Steven; Schreyer, Manuel; Schroeder, Christian; Schuh, Natascha; Schultens, Martin Johannes; Schultz-Coulon, Hans-Christian; Schulz, Holger; Schumacher, Markus; Schumm, Bruce; Schune, Philippe; Schwanenberger, Christian; Schwartzman, Ariel; Schwarz, Thomas Andrew; Schwegler, Philipp; Schweiger, Hansdieter; Schwemling, Philippe; Schwienhorst, Reinhard; Schwindling, Jerome; Schwindt, Thomas; Sciacca, Gianfranco; Scifo, Estelle; Sciolla, Gabriella; Scuri, Fabrizio; Scutti, Federico; Searcy, Jacob; Sedov, George; Sedykh, Evgeny; Seema, Pienpen; Seidel, Sally; Seiden, Abraham; Seifert, Frank; Seixas, José; Sekhniaidze, Givi; Sekhon, Karishma; Sekula, Stephen; Seliverstov, Dmitry; Semprini-Cesari, Nicola; Serfon, Cedric; Serin, Laurent; Serkin, Leonid; Serre, Thomas; Sessa, Marco; Seuster, Rolf; Severini, Horst; Sfiligoj, Tina; Sforza, Federico; Sfyrla, Anna; Shabalina, Elizaveta; Shamim, Mansoora; Shan, Lianyou; Shang, Ruo-yu; Shank, James; Shapiro, Marjorie; Shatalov, Pavel; Shaw, Kate; Shaw, Savanna Marie; Shcherbakova, Anna; Shehu, Ciwake Yusufu; Sherwood, Peter; Shi, Liaoshan; Shimizu, Shima; Shimmin, Chase Owen; Shimojima, Makoto; Shiyakova, Mariya; Shmeleva, Alevtina; Shoaleh Saadi, Diane; Shochet, Mel; Shojaii, Seyedruhollah; Shrestha, Suyog; Shulga, Evgeny; Shupe, Michael; Shushkevich, Stanislav; Sicho, Petr; Sidebo, Per Edvin; Sidiropoulou, Ourania; Sidorov, Dmitri; Sidoti, Antonio; Siegert, Frank; Sijacki, Djordje; Silva, José; Silver, Yiftah; Silverstein, Samuel; Simak, Vladislav; Simard, Olivier; Simic, Ljiljana; Simion, Stefan; Simioni, Eduard; Simmons, Brinick; Simon, Dorian; Simoniello, Rosa; Sinervo, Pekka; Sinev, Nikolai; Sioli, Maximiliano; Siragusa, Giovanni; Sisakyan, Alexei; Sivoklokov, Serguei; Sjölin, Jörgen; Sjursen, Therese; Skinner, Malcolm Bruce; Skottowe, Hugh Philip; Skubic, Patrick; Slater, Mark; Slavicek, Tomas; Slawinska, Magdalena; Sliwa, Krzysztof; Smakhtin, Vladimir; Smart, Ben; Smestad, Lillian; Smirnov, Sergei; Smirnov, Yury; Smirnova, Lidia; Smirnova, Oxana; Smith, Matthew; Smith, Russell; Smizanska, Maria; Smolek, Karel; Snesarev, Andrei; Snidero, Giacomo; Snyder, Scott; Sobie, Randall; Socher, Felix; Soffer, Abner; Soh, Dart-yin; Solans, Carlos; Solar, Michael; Solc, Jaroslav; Soldatov, Evgeny; Soldevila, Urmila; Solodkov, Alexander; Soloshenko, Alexei; Solovyanov, Oleg; Solovyev, Victor; Sommer, Philip; Song, Hong Ye; Soni, Nitesh; Sood, Alexander; Sopczak, Andre; Sopko, Bruno; Sopko, Vit; Sorin, Veronica; Sosa, David; Sosebee, Mark; Sotiropoulou, Calliope Louisa; Soualah, Rachik; Soukharev, Andrey; South, David; Sowden, Benjamin; Spagnolo, Stefania; Spalla, Margherita; Spanò, Francesco; Spearman, William Robert; Sperlich, Dennis; Spettel, Fabian; Spighi, Roberto; Spigo, Giancarlo; Spiller, Laurence Anthony; Spousta, Martin; Spreitzer, Teresa; St Denis, Richard Dante; Staerz, Steffen; Stahlman, Jonathan; Stamen, Rainer; Stamm, Soren; Stanecka, Ewa; Stanescu, Cristian; Stanescu-Bellu, Madalina; Stanitzki, Marcel Michael; Stapnes, Steinar; Starchenko, Evgeny; Stark, Jan; Staroba, Pavel; Starovoitov, Pavel; Staszewski, Rafal; Stavina, Pavel; Steinberg, Peter; Stelzer, Bernd; Stelzer, Harald Joerg; Stelzer-Chilton, Oliver; Stenzel, Hasko; Stewart, Graeme; Stillings, Jan Andre; Stockton, Mark; Stoebe, Michael; Stoicea, Gabriel; Stolte, Philipp; Stonjek, Stefan; Stradling, Alden; Straessner, Arno; Stramaglia, Maria Elena; Strandberg, Jonas; Strandberg, Sara; Strandlie, Are; Strauss, Emanuel; Strauss, Michael; Strizenec, Pavol; Ströhmer, Raimund; Strom, David; Stroynowski, Ryszard; Strubig, Antonia; Stucci, Stefania Antonia; Stugu, Bjarne; Styles, Nicholas Adam; Su, Dong; Su, Jun; Subramaniam, Rajivalochan; Succurro, Antonella; Sugaya, Yorihito; Suhr, Chad; Suk, Michal; Sulin, Vladimir; Sultansoy, Saleh; Sumida, Toshi; Sun, Siyuan; Sun, Xiaohu; Sundermann, Jan Erik; Suruliz, Kerim; Susinno, Giancarlo; Sutton, Mark; Suzuki, Shota; Svatos, Michal; Swedish, Stephen; Swiatlowski, Maximilian; Sykora, Ivan; Sykora, Tomas; Ta, Duc; Taccini, Cecilia; Tackmann, Kerstin; Taenzer, Joe; Taffard, Anyes; Tafirout, Reda; Taiblum, Nimrod; Takai, Helio; Takashima, Ryuichi; Takeda, Hiroshi; Takeshita, Tohru; Takubo, Yosuke; Talby, Mossadek; Talyshev, Alexey; Tam, Jason; Tan, Kong Guan; Tanaka, Junichi; Tanaka, Reisaburo; Tanaka, Shuji; Tannenwald, Benjamin Bordy; Tannoury, Nancy; Tapprogge, Stefan; Tarem, Shlomit; Tarrade, Fabien; Tartarelli, Giuseppe Francesco; Tas, Petr; Tasevsky, Marek; Tashiro, Takuya; Tassi, Enrico; Tavares Delgado, Ademar; Tayalati, Yahya; Taylor, Frank; Taylor, Geoffrey; Taylor, Wendy; Teischinger, Florian Alfred; Teixeira Dias Castanheira, Matilde; Teixeira-Dias, Pedro; Temming, Kim Katrin; Ten Kate, Herman; Teng, Ping-Kun; Teoh, Jia Jian; Tepel, Fabian-Phillipp; Terada, Susumu; Terashi, Koji; Terron, Juan; Terzo, Stefano; Testa, Marianna; Teuscher, Richard; Theveneaux-Pelzer, Timothée; Thomas, Juergen; Thomas-Wilsker, Joshuha; Thompson, Emily; Thompson, Paul; Thompson, Ray; Thompson, Stan; Thomsen, Lotte Ansgaard; Thomson, Evelyn; Thomson, Mark; Thun, Rudolf; Tibbetts, Mark James; Ticse Torres, Royer Edson; Tikhomirov, Vladimir; Tikhonov, Yury; Timoshenko, Sergey; Tiouchichine, Elodie; Tipton, Paul; Tisserant, Sylvain; Todome, Kazuki; Todorov, Theodore; Todorova-Nova, Sharka; Tojo, Junji; Tokár, Stanislav; Tokushuku, Katsuo; Tollefson, Kirsten; Tolley, Emma; Tomlinson, Lee; Tomoto, Makoto; Tompkins, Lauren; Toms, Konstantin; Torrence, Eric; Torres, Heberth; Torró Pastor, Emma; Toth, Jozsef; Touchard, Francois; Tovey, Daniel; Trefzger, Thomas; Tremblet, Louis; Tricoli, Alessandro; Trigger, Isabel Marian; Trincaz-Duvoid, Sophie; Tripiana, Martin; Trischuk, William; Trocmé, Benjamin; Troncon, Clara; Trottier-McDonald, Michel; Trovatelli, Monica; True, Patrick; Truong, Loan; Trzebinski, Maciej; Trzupek, Adam; Tsarouchas, Charilaos; Tseng, Jeffrey; Tsiareshka, Pavel; Tsionou, Dimitra; Tsipolitis, Georgios; Tsirintanis, Nikolaos; Tsiskaridze, Shota; Tsiskaridze, Vakhtang; Tskhadadze, Edisher; Tsukerman, Ilya; Tsulaia, Vakhtang; Tsuno, Soshi; Tsybychev, Dmitri; Tudorache, Alexandra; Tudorache, Valentina; Tuna, Alexander Naip; Tupputi, Salvatore; Turchikhin, Semen; Turecek, Daniel; Turra, Ruggero; Turvey, Andrew John; Tuts, Michael; Tykhonov, Andrii; Tylmad, Maja; Tyndel, Mike; Ueda, Ikuo; Ueno, Ryuichi; Ughetto, Michael; Ugland, Maren; Uhlenbrock, Mathias; Ukegawa, Fumihiko; Unal, Guillaume; Undrus, Alexander; Unel, Gokhan; Ungaro, Francesca; Unno, Yoshinobu; Unverdorben, Christopher; Urban, Jozef; Urquijo, Phillip; Urrejola, Pedro; Usai, Giulio; Usanova, Anna; Vacavant, Laurent; Vacek, Vaclav; Vachon, Brigitte; Valderanis, Chrysostomos; Valencic, Nika; Valentinetti, Sara; Valero, Alberto; Valery, Loic; Valkar, Stefan; Valladolid Gallego, Eva; Vallecorsa, Sofia; Valls Ferrer, Juan Antonio; Van Den Wollenberg, Wouter; Van Der Deijl, Pieter; van der Geer, Rogier; van der Graaf, Harry; Van Der Leeuw, Robin; van Eldik, Niels; van Gemmeren, Peter; Van Nieuwkoop, Jacobus; van Vulpen, Ivo; van Woerden, Marius Cornelis; Vanadia, Marco; Vandelli, Wainer; Vanguri, Rami; Vaniachine, Alexandre; Vannucci, Francois; Vardanyan, Gagik; Vari, Riccardo; Varnes, Erich; Varol, Tulin; Varouchas, Dimitris; Vartapetian, Armen; Varvell, Kevin; Vazeille, Francois; Vazquez Schroeder, Tamara; Veatch, Jason; Veloce, Laurelle Maria; Veloso, Filipe; Velz, Thomas; Veneziano, Stefano; Ventura, Andrea; Ventura, Daniel; Venturi, Manuela; Venturi, Nicola; Venturini, Alessio; Vercesi, Valerio; Verducci, Monica; Verkerke, Wouter; Vermeulen, Jos; Vest, Anja; Vetterli, Michel; Viazlo, Oleksandr; Vichou, Irene; Vickey, Trevor; Vickey Boeriu, Oana Elena; Viehhauser, Georg; Viel, Simon; Vigne, Ralph; Villa, Mauro; Villaplana Perez, Miguel; Vilucchi, Elisabetta; Vincter, Manuella; Vinogradov, Vladimir; Vivarelli, Iacopo; Vives Vaque, Francesc; Vlachos, Sotirios; Vladoiu, Dan; Vlasak, Michal; Vogel, Marcelo; Vokac, Petr; Volpi, Guido; Volpi, Matteo; von der Schmitt, Hans; von Radziewski, Holger; von Toerne, Eckhard; Vorobel, Vit; Vorobev, Konstantin; Vos, Marcel; Voss, Rudiger; Vossebeld, Joost; Vranjes, Nenad; Vranjes Milosavljevic, Marija; Vrba, Vaclav; Vreeswijk, Marcel; Vuillermet, Raphael; Vukotic, Ilija; Vykydal, Zdenek; Wagner, Peter; Wagner, Wolfgang; Wahlberg, Hernan; Wahrmund, Sebastian; Wakabayashi, Jun; Walder, James; Walker, Rodney; Walkowiak, Wolfgang; Wang, Chao; Wang, Fuquan; Wang, Haichen; Wang, Hulin; Wang, Jike; Wang, Jin; Wang, Kuhan; Wang, Rui; Wang, Song-Ming; Wang, Tan; Wang, Xiaoxiao; Wanotayaroj, Chaowaroj; Warburton, Andreas; Ward, Patricia; Wardrope, David Robert; Warsinsky, Markus; Washbrook, Andrew; Wasicki, Christoph; Watkins, Peter; Watson, Alan; Watson, Ian; Watson, Miriam; Watts, Gordon; Watts, Stephen; Waugh, Ben; Webb, Samuel; Weber, Michele; Weber, Stefan Wolf; Webster, Jordan S; Weidberg, Anthony; Weinert, Benjamin; Weingarten, Jens; Weiser, Christian; Weits, Hartger; Wells, Phillippa; Wenaus, Torre; Wengler, Thorsten; Wenig, Siegfried; Wermes, Norbert; Werner, Matthias; Werner, Per; Wessels, Martin; Wetter, Jeffrey; Whalen, Kathleen; Wharton, Andrew Mark; White, Andrew; White, Martin; White, Ryan; White, Sebastian; Whiteson, Daniel; Wickens, Fred; Wiedenmann, Werner; Wielers, Monika; Wienemann, Peter; Wiglesworth, Craig; Wiik-Fuchs, Liv Antje Mari; Wildauer, Andreas; Wilkens, Henric George; Williams, Hugh; Williams, Sarah; Willis, Christopher; Willocq, Stephane; Wilson, Alan; Wilson, John; Wingerter-Seez, Isabelle; Winklmeier, Frank; Winter, Benedict Tobias; Wittgen, Matthias; Wittkowski, Josephine; Wollstadt, Simon Jakob; Wolter, Marcin Wladyslaw; Wolters, Helmut; Wosiek, Barbara; Wotschack, Jorg; Woudstra, Martin; Wozniak, Krzysztof; Wu, Mengqing; Wu, Miles; Wu, Sau Lan; Wu, Xin; Wu, Yusheng; Wyatt, Terry Richard; Wynne, Benjamin; Xella, Stefania; Xu, Da; Xu, Lailin; Yabsley, Bruce; Yacoob, Sahal; Yakabe, Ryota; Yamada, Miho; Yamaguchi, Yohei; Yamamoto, Akira; Yamamoto, Shimpei; Yamanaka, Takashi; Yamauchi, Katsuya; Yamazaki, Yuji; Yan, Zhen; Yang, Haijun; Yang, Hongtao; Yang, Yi; Yao, Weiming; Yasu, Yoshiji; Yatsenko, Elena; Yau Wong, Kaven Henry; Ye, Jingbo; Ye, Shuwei; Yeletskikh, Ivan; Yen, Andy L; Yildirim, Eda; Yorita, Kohei; Yoshida, Rikutaro; Yoshihara, Keisuke; Young, Charles; Young, Christopher John; Youssef, Saul; Yu, David Ren-Hwa; Yu, Jaehoon; Yu, Jiaming; Yu, Jie; Yuan, Li; Yuen, Stephanie P; Yurkewicz, Adam; Yusuff, Imran; Zabinski, Bartlomiej; Zaidan, Remi; Zaitsev, Alexander; Zalieckas, Justas; Zaman, Aungshuman; Zambito, Stefano; Zanello, Lucia; Zanzi, Daniele; Zeitnitz, Christian; Zeman, Martin; Zemla, Andrzej; Zengel, Keith; Zenin, Oleg; Ženiš, Tibor; Zerwas, Dirk; Zhang, Dongliang; Zhang, Fangzhou; Zhang, Huijun; Zhang, Jinlong; Zhang, Lei; Zhang, Ruiqi; Zhang, Xueyao; Zhang, Zhiqing; Zhao, Xiandong; Zhao, Yongke; Zhao, Zhengguo; Zhemchugov, Alexey; Zhong, Jiahang; Zhou, Bing; Zhou, Chen; Zhou, Lei; Zhou, Li; Zhou, Ning; Zhu, Cheng Guang; Zhu, Hongbo; Zhu, Junjie; Zhu, Yingchun; Zhuang, Xuai; Zhukov, Konstantin; Zibell, Andre; Zieminska, Daria; Zimine, Nikolai; Zimmermann, Christoph; Zimmermann, Stephanie; Zinonos, Zinonas; Zinser, Markus; Ziolkowski, Michael; Živković, Lidija; Zobernig, Georg; Zoccoli, Antonio; zur Nedden, Martin; Zurzolo, Giovanni; Zwalinski, Lukasz

    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...

  11. Identification of hadronic tau decays in ATLAS

    Energy Technology Data Exchange (ETDEWEB)

    Coadou, Y.; Hinchliffe, I.; Lozano-Bahilo, J.; Loveridge, L.C.; Shapiro, M.D.

    1998-09-01

    Taus can be an important signature for Supersymmetry at the LHC. They can be produced copiously in the decays of supersymmetric particles. Measurement of their momentum and of the tau-tau invariant mass distribution, would provide detailed information regarding the masses of supersymmetric particles. It is demonstrated using full simulation that it will be possible for ATLAS to make a cut on the reconstructed tau invariant mass using information from the tracking and the electromagnetic calorimeter. The measured energy and momentum of tau's that pass this selection can then be used to infer information about the tau-tau invariant mass.

  12. In vivo tau PET imaging in dementia: Pathophysiology, radiotracer quantification, and a systematic review of clinical findings.

    Science.gov (United States)

    Hall, Benjamin; Mak, Elijah; Cervenka, Simon; Aigbirhio, Franklin I; Rowe, James B; O'Brien, John T

    2017-07-01

    In addition to the deposition of β-amyloid plaques, neurofibrillary tangles composed of aggregated hyperphosphorylated tau are one of the pathological hallmarks of Alzheimer's disease and other neurodegenerative disorders. Until now, our understanding about the natural history and topography of tau deposition has only been based on post-mortem and cerebrospinal fluid studies, and evidence continues to implicate tau as a central driver of downstream neurodegenerative processes and cognitive decline. Recently, it has become possible to assess the regional distribution and severity of tau burden in vivo with the development of novel radiotracers for positron emission tomography (PET) imaging. In this article, we provide a comprehensive discussion of tau pathophysiology, its quantification with novel PET radiotracers, as well as a systematic review of tau PET imaging in normal aging and various dementia conditions: mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and Lewy body dementia. We discuss the main findings in relation to group differences, clinical-cognitive correlations of tau PET, and multi-modal relationships among tau PET and other pathological markers. Collectively, the small but growing literature of tau PET has yielded consistent anatomical patterns of tau accumulation that recapitulate post-mortem distribution of neurofibrillary tangles which correlate with cognitive functions and other markers of pathology. In general, AD is characterised by increased tracer retention in the inferior temporal lobe, extending into the frontal and parietal regions in more severe cases. It is also noted that the spatial topography of tau accumulation is markedly distinct to that of amyloid burden in aging and AD. Tau PET imaging has also revealed characteristic spatial patterns among various non-AD tauopathies, supporting its potential role for differential diagnosis. Finally, we propose novel directions for future

  13. Analisi del decadimento $W -> \\tau \

    CERN Document Server

    Coscetti, Simone

    Questo lavoro di tesi si e' svolto nell'ambito dell'esperimento CMS a LHC, ed in particolare verte sullo studio delle strategie di identificazione off-line del leptone tau, atteso tra i prodotti di decadimento del bosone di Higgs, cosi' come di altre particelle previste in altri modelli teorici. Il canale utilizzato per testare la procedura di identificazione del tau e' il decadimento semileptonico del bosone vettore W. Infine, sulla base dei risultati ottenuti viene presentata una stima quantitativa della sezione d'urto di produzione pp-> W + X

  14. 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.

  15. Dietary Salt Exacerbates Experimental Colitis.

    Science.gov (United States)

    Tubbs, Alan L; Liu, Bo; Rogers, Troy D; Sartor, R Balfour; Miao, Edward A

    2017-08-01

    The Western diet is characterized by high protein, sugar, fat, and low fiber intake, and is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel disease (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet. We demonstrate that an HSD exacerbates inflammatory pathology in the IL-10-deficient murine model of colitis relative to mice fed a low salt diet. This was correlated with enhanced expression of numerous proinflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10-deficient model, an HSD also enhanced cytokine expression during infection by Salmonella typhimurium This occurred in the first 3 d of infection, suggesting that an HSD potentiates an innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate, was hopelessly confounded by the high sodium content of the dextran sodium sulfate. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD. Copyright © 2017 by The American Association of Immunologists, Inc.

  16. Vitamin B12 Inhibits Tau Fibrillization via Binding to Cysteine Residues of Tau.

    Science.gov (United States)

    Rafiee, Saharnaz; Asadollahi, Kazem; Riazi, Gholamhossein; Ahmadian, Shahin; Saboury, Ali Akbar

    2017-12-20

    Two mechanisms underlie the inhibitory/acceleratory action of chemical compounds on tau aggregation including the regulation of cellular kinases and phosphatases activity and direct binding to tau protein. Vitamin B12 is one of the tau polymerization inhibitors, and its deficiency is linked to inactivation of protein phosphatase 2A and subsequently hyperphosphorylation and aggregation of tau protein. Regarding the structure and function of vitamin B12 and tau protein, we assumed that vitamin B12 is also able to directly bind to tau protein. Hence, we investigated the interaction of vitamin B12 with tau protein in vitro using fluorometry and circular dichrosim. Interaction studies was followed by investigation into the effect of vitamin B12 on tau aggregation using ThT fluorescence, circular dichroism, transmission electron microscopy, and SDS-PAGE. The results indicated that vitamin B12 interacts with tau protein and prevents fibrillization of tau protein. Blocking the cysteine residues of tau confirmed the cysteine-mediated binding of vitamin B12 to tau and showed that binding to cysteine is essential for inhibitory effect of vitamin B12 on tau aggregation. SDS-PAGE analysis indicated that vitamin B12 inhibits tau aggregation and that tau oligomers formed in the presence of vitamin B12 are mostly SDS-soluble. We propose that direct binding of vitamin B12 is another mechanism underlying the inhibitory role of vitamin B12 on tau aggregation and neurodegeneration.

  17. 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\

  18. 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.

  19. Tau isolation study for CMS run2

    CERN Document Server

    Stefko, Marcel

    2015-01-01

    Final report on study of hadronic tau fake rate behavior for $H\\rightarrow \\tau \\tau$ analysis of CMS run2 data. Differences between same-sign and opposite-sign events were studied, and Monte Carlo simulation was compared with experimental data.

  20. Observation of Tau Neutrino Interactions

    CERN Document Server

    Kodama, K; Andreopoulos, C; Saoulidou, N; Tzanakos, G S; Yager, P M; Baller, B R; Böhnlein, D J; Freeman, W; Lundberg, B; Mor, J; Rameika, R; Yun, J C; Song, J S; Yoon, C S; Chung, S H; Berghaus, P; Kubantsev, M A; Reay, N W; Sidwell, R A; Stanton, N; Yoshida, S; Aoki, S; Hara, T; Rhee, J T; Ciampa, D; Erickson, C; Graham, M; Heller, K; Rusack, R W; Schwienhorst, R; Siela, J; Trammell, J; Wilcox, J; Hoshino, K; Jiko, H; Miyanishi, M; Komatsu, M; Nakamura, M; Nakano, T; Niwa, K; Nonaka, N; Okada, K; Sato, O; Akdogan, T; Paolone, V; Rosenfeld, C; Kulik, A V; Kafka, T; Oliver, W; Patzak, T; Schneps, J

    2001-01-01

    The DONUT experiment has analyzed 203 neutrino interactions recorded in nuclear emulsion targets. A decay search has found evidence of four tau neutrino interactions with an estimated background of 0.34 events. This number is consistent with the Standard Model expectation.

  1. COPD exacerbation: Lost in translation

    Directory of Open Access Journals (Sweden)

    Bouros Demosthenes

    2009-01-01

    Full Text Available Abstract The introduction and acceptance of a standard definition for exacerbations of COPD can be helpful in prompt diagnosis and management of these events. The latest GOLD executive committee recognised this necessity and it has now included a definition of exacerbation in the guidelines for COPD which is an important step forward in the management of the disease. This definition is pragmatic and compromises the different approaches for exacerbation. However, the inclusion of the "healthcare utilisation" approach (".. may warrant a change in regular medication" in the definition may introduce in the diagnosis of exacerbation factors related to the access to health care services which may not be related to the underlying pathophysiologal process which characterizes exacerbations. It should be also noted that the aetiology of COPD exacerbations has not yet been included in the current definition. In this respect, the definition does not acknowledge the fact that many patients with COPD may suffer from additional conditions (i.e. congestive cardiac failure or pulmonary embolism that can masquerade as exacerbations but they should not be considered as causes of them. The authors therefore suggest that an inclusion of the etiologic factors of COPD exacerbations in the definition. Moreover, COPD exacerbations are characterized by increased airway and systemic inflammation and significant deterioration in lung fuction. These fundamental aspects should be accounted in diagnosis/definition of exacerbations. This could be done by the introduction of a "laboratory" marker in the diagnosis of these acute events. The authors acknowledge that the use of a test or a biomarker in the diagnosis of exacerbations meets certain difficulties related to performing lung function tests or to sampling during exacerbations. However, the introduction of a test that reflects airway or systemic inflammation in the diagnosis of exacerbations might be another step forward

  2. Neuroglobin attenuates Alzheimer-like tau hyperphosphorylation by activating Akt signaling.

    Science.gov (United States)

    Chen, Li-Ming; Xiong, Yan-Si; Kong, Fan-Li; Qu, Min; Wang, Qun; Chen, Xiao-Qian; Wang, Jian-Zhi; Zhu, Ling-Qiang

    2012-01-01

    Neuroglobin (Ngb) is a recently identified member of hemoglobin family, distributed mainly in central and peripheral nervous systems. Recent studies suggest that Ngb can protect neural cells from β-amyloid-induced toxicity in Alzheimer disease (AD). Hyperphosphorylation of tau is another characterized pathological hallmark in the AD brains; however, it is not reported whether Ngb also affects tau phosphorylation. In this study, we found that the level of Ngb was significantly reduced in Tg2576 mice (a recognized mouse model of AD) and TgMAPt mice, and the level of Ngb was negatively correlated with tau phosphorylation. Over-expression of Ngb attenuates tau hyperphosphorylation at multiple AD-related sites induced by up-regulation of glycogen synthase kinase-3β (GSK-3β), a crucial tau kinase. While Ngb activates Akt and thus inhibits GSK-3β, simultaneously inhibition of Akt abolishes the effects of Ngb on GSK-3β inhibition and tau hyperphosphorylation. Our data indicate that Ngb may attenuate tau hyperphosphorylation through activating Akt signaling pathway, implying a therapeutic target for AD. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  3. The physiological phosphorylation of tau is critically changed in fetal brains of individuals with Down syndrome.

    Science.gov (United States)

    Milenkovic, I; Jarc, J; Dassler, E; Aronica, E; Iyer, A; Adle-Biassette, H; Scharrer, A; Reischer, T; Hainfellner, J A; Kovacs, G G

    2017-04-28

    Down syndrome (DS) is a common cause of mental retardation accompanied by cognitive impairment. Comprehensive studies suggested a link between development and ageing, as nearly all individuals with DS develop Alzheimer disease (AD)-like pathology. However, there is still a paucity of data on tau in early DS to support this notion. Using morphometric immunohistochemistry we compared tau phosphorylation in normal brains and in brains of individuals with DS from early development until early postnatal life. We observed in DS a critical loss of physiological phosphorylation of tau. Rhombencephalic structures showed prominent differences between controls and DS using antibodies AT8 (Ser-202/Thr-205) and AT180 (Thr-231). In contrast, in the subiculum only a small portion of controls deviated from DS using antibodies AT100 (Thr-212/Ser-214) and AT270 (Thr-181). With exception of the subiculum, phosphorylation-independent tau did not differ between groups, as confirmed by immunostaining for the HT-7 antibody (epitope between 159 and 163 of the human tau) as well. Our observations suggest functional tau disturbance in DS brains during development, rather than axonal loss. This supports the role of tau as a further important player in the pathophysiology of cognitive impairment in DS and related AD. © 2017 British Neuropathological Society.

  4. Hyperphosphorylation of intrinsically disordered tau protein induces an amyloidogenic shift in its conformational ensemble.

    Directory of Open Access Journals (Sweden)

    Shaolong Zhu

    Full Text Available Tau is an intrinsically disordered protein (IDP whose primary physiological role is to stabilize microtubules in neuronal axons at all stages of development. In Alzheimer's and other tauopathies, tau forms intracellular insoluble amyloid aggregates known as neurofibrillary tangles, a process that appears in many cases to be preceded by hyperphosphorylation of tau monomers. Understanding the shift in conformational bias induced by hyperphosphorylation is key to elucidating the structural factors that drive tau pathology, however, as an IDP, tau is not amenable to conventional structural characterization. In this work, we employ a straightforward technique based on Time-Resolved ElectroSpray Ionization Mass Spectrometry (TRESI-MS and Hydrogen/Deuterium Exchange (HDX to provide a detailed picture of residual structure in tau, and the shifts in conformational bias induced by hyperphosphorylation. By comparing the native and hyperphosphorylated ensembles, we are able to define specific conformational biases that can easily be rationalized as enhancing amyloidogenic propensity. Representative structures for the native and hyperphosphorylated tau ensembles were generated by refinement of a broad sample of conformations generated by low-computational complexity modeling, based on agreement with the TRESI-HDX profiles.

  5. Probing Conformational Dynamics of Tau Protein by Hydrogen/Deuterium Exchange Mass Spectrometry

    Science.gov (United States)

    Huang, Richard Y.-C.; Iacob, Roxana E.; Sankaranarayanan, Sethu; Yang, Ling; Ahlijanian, Michael; Tao, Li; Tymiak, Adrienne A.; Chen, Guodong

    2017-10-01

    Fibrillization of the microtubule-associated protein tau has been recognized as one of the signature pathologies of the nervous system in Alzheimer's disease, progressive supranuclear palsy, and other tauopathies. The conformational transition of tau in the fibrillization process, tau monomer to soluble aggregates to fibrils in particular, remains unclear. Here we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) in combination with other biochemical approaches, including Thioflavin S fluorescence measurements, enzyme-linked immunosorbent assay (ELISA), and Western blotting to understand the heparin-induced tau's fibrillization. HDX-MS studies including anti-tau antibody epitope mapping experiments provided molecular level details of the full-length tau's conformational dynamics and its regional solvent accessibility upon soluble aggregates formation. The results demonstrate that R3 region in the full-length tau's microtubule binding repeat region (MTBR) is stabilized in the aggregation process, leaving both N and C terminal regions to be solvent exposed in the soluble aggregates and fibrils. The findings also illustrate the practical utility of orthogonal analytical methodologies for the characterization of protein higher order structure. [Figure not available: see fulltext.

  6. Model Hirano Bodies Protect against Tau-Independent and Tau-Dependent Cell Death Initiated by the Amyloid Precursor Protein Intracellular Domain

    OpenAIRE

    Furgerson, Matthew; Fechheimer, Marcus; Furukawa, Ruth

    2012-01-01

    The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP) and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has ...

  7. Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice.

    Directory of Open Access Journals (Sweden)

    Peter Borghgraef

    Full Text Available The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.

  8. RNA Interference Silencing of Glycogen Synthase Kinase 3β Inhibites Tau Phosphorylation in Mice with Alzheimer Disease.

    Science.gov (United States)

    Bian, Hong; Bian, Wei; Lin, Xiaoying; Ma, Zhaoyin; Chen, Wen; Pu, Ying

    2016-09-01

    To explore the effect of glycogen synthase kinase 3β (GSK-3β) silencing on Tau-5 phosphorylation in mice suffering Alzheimer disease (AD). GSK-3β was firstly silenced in human neuroblastoma SH-SY5Y cells using special lentivirus (LV) and the content of Tau (A-12), p-Tau (Ser396) and p-Tau (PHF-6) proteins. GSK-3β was also silenced in APP/PS1 mouse model of AD mice, which were divided into three groups (n = 10): AD, vehicle, and LV group. Ten C57 mice were used as control. The memory ability of mice was tested by square water maze, and the morphological changes of hippocampus and neuron death were analyzed by haematoxylin-eosin staining. Moreover, the levels of Tau and phosphorylated Tau (p-Tau) were detected by western blotting and immunohistochemistry, respectively. The lentivirus-mediated GSK-3β silencing system was successfully developed and silencing GSK-3β at the cellular level reduced Tau phosphorylation obviously. Moreover, GSK-3β silence significantly improved the memory ability of AD mice in LV group compared with AD group (P silence. Silencing GSK-3β may have a positive effect on inhibiting the pathologic progression of AD through down-regulating the level of p-Tau.

  9. 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.

  10. Exacerbations of asthma during pregnancy

    DEFF Research Database (Denmark)

    Ali, Z; Hansen, A V; Ulrik, C S

    2016-01-01

    that asthma exacerbations during pregnancy increase the risk of pre-eclampsia, gestational diabetes, placental abruption and placenta praevia. Furthermore, these women also have higher risk for breech presentation, haemorrhage, pulmonary embolism, caesarean delivery, maternal admission to the intensive care...... to these outcomes. In conclusion, asthma exacerbations during pregnancy are associated with complications of pregnancy, labour and delivery. Prevention of exacerbations is essential to reduce the risk of complications and poor outcome....

  11. Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections.

    Science.gov (United States)

    Tai, Xin You; Koepp, Matthias; Duncan, John S; Fox, Nick; Thompson, Pamela; Baxendale, Sallie; Liu, Joan Y W; Reeves, Cheryl; Michalak, Zuzanna; Thom, Maria

    2016-09-01

    SEE BERNASCONI DOI101093/AWW202 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Temporal lobe epilepsy, the most prevalent form of chronic focal epilepsy, is associated with a high prevalence of cognitive impairment but the responsible underlying pathological mechanisms are unknown. Tau, the microtubule-associated protein, is a hallmark of several neurodegenerative diseases including Alzheimer's disease and chronic traumatic encephalopathy. We hypothesized that hyperphosphorylated tau pathology is associated with cognitive decline in temporal lobe epilepsy and explored this through clinico-pathological study. We first performed pathological examination on tissue from 33 patients who had undergone temporal lobe resection between ages 50 and 65 years to treat drug-refractory temporal lobe epilepsy. We identified hyperphosphorylated tau protein using AT8 immunohistochemistry and compared this distribution to Braak patterns of Alzheimer's disease and patterns of chronic traumatic encephalopathy. We quantified tau pathology using a modified tau score created specifically for analysis of temporal lobectomy tissue and the Braak staging, which was limited without extra-temporal brain areas available. Next, we correlated tau pathology with pre- and postoperative cognitive test scores and clinical risk factors including age at time of surgery, duration of epilepsy, history of secondary generalized seizures, history of head injury, handedness and side of surgery. Thirty-one of 33 cases (94%) showed hyperphosphorylated tau pathology in the form of neuropil threads and neurofibrillary tangles and pre-tangles. Braak stage analysis showed 12% of our epilepsy cohort had a Braak staging III-IV compared to an age-matched non-epilepsy control group from the literature (8%). We identified a mixture of tau pathology patterns characteristic of Alzheimer's disease and chronic traumatic encephalopathy. We also found unusual patterns of subpial tau deposition, sparing of the hippocampus and

  12. Exacerbations of asthma - A descriptive study of 425 severe exacerbations

    NARCIS (Netherlands)

    Tattersfield, AE; Postma, DS; Barnes, PJ; Svensson, K; Bauer, CA; O'Byrne, PM; Lofdahl, CG; Pauwels, RA; Ullman, A

    The identification, prevention, and prompt treatment of exacerbations are major objectives of asthma management. We looked at change in PEF, symptoms, and use of rescue p-agonists during the 425 severe exacerbations that occurred during a 12-mo parallel group study (FACET) in which low and high

  13. TTBK2: A Tau Protein Kinase beyond Tau Phosphorylation

    Directory of Open Access Journals (Sweden)

    Jung-Chi Liao

    2015-01-01

    Full Text Available Tau tubulin kinase 2 (TTBK2 is a kinase known to phosphorylate tau and tubulin. It has recently drawn much attention due to its involvement in multiple important cellular processes. Here, we review the current understanding of TTBK2, including its sequence, structure, binding sites, phosphorylation substrates, and cellular processes involved. TTBK2 possesses a casein kinase 1 (CK1 kinase domain followed by a ~900 amino acid segment, potentially responsible for its localization and substrate recruitment. It is known to bind to CEP164, a centriolar protein, and EB1, a microtubule plus-end tracking protein. In addition to autophosphorylation, known phosphorylation substrates of TTBK2 include tau, tubulin, CEP164, CEP97, and TDP-43, a neurodegeneration-associated protein. Mutations of TTBK2 are associated with spinocerebellar ataxia type 11. In addition, TTBK2 is essential for regulating the growth of axonemal microtubules in ciliogenesis. It also plays roles in resistance of cancer target therapies and in regulating glucose and GABA transport. Reported sites of TTBK2 localization include the centriole/basal body, the midbody, and possibly the mitotic spindles. Together, TTBK2 is a multifunctional kinase involved in important cellular processes and demands augmented efforts in investigating its functions.

  14. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice.

    Directory of Open Access Journals (Sweden)

    Carlo Corona

    Full Text Available BACKGROUND: The pathogenic road map leading to Alzheimer's disease (AD is still not completely understood; however, a large body of studies in the last few years supports the idea that beside the classic hallmarks of the disease, namely the accumulation of amyloid-β (Aβ and neurofibrillary tangles, other factors significantly contribute to the initiation and the progression of the disease. Among them, mitochondria failure, an unbalanced neuronal redox state, and the dyshomeostasis of endogenous metals like copper, iron, and zinc have all been reported to play an important role in exacerbating AD pathology. Given these factors, the endogenous peptide carnosine may be potentially beneficial in the treatment of AD because of its free-radical scavenger and metal chelating properties. METHODOLOGY: In this study, we explored the effect of L-carnosine supplementation in the 3xTg-AD mouse, an animal model of AD that shows both Aβ- and tau-dependent pathology. PRINCIPAL FINDINGS: We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits. CONCLUSIONS AND SIGNIFICANCE: Our data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD.

  15. Phosphorylated human tau associates with mouse prion protein amyloid in scrapie-infected mice but does not increase progression of clinical disease.

    Science.gov (United States)

    Race, Brent; Phillips, Katie; Kraus, Allison; Chesebro, Bruce

    2016-07-03

    Tauopathies are a family of neurodegenerative diseases in which fibrils of human hyperphosphorylated tau (P-tau) are believed to cause neuropathology. In Alzheimer disease, P-tau associates with A-beta amyloid and contributes to disease pathogenesis. In familial human prion diseases and variant CJD, P-tau often co-associates with prion protein amyloid, and might also accelerate disease progression. To test this latter possibility, here we compared progression of amyloid prion disease in vivo after scrapie infection of mice with and without expression of human tau. The mice used expressed both anchorless prion protein (PrP) and membrane-anchored PrP, that generate disease associated amyloid and non-amyloid PrP (PrPSc) after scrapie infection. Human P-tau induced by scrapie infection was only rarely associated with non-amyloid PrPSc, but abundant human P-tau was detected at extracellular, perivascular and axonal deposits associated with amyloid PrPSc. This pathology was quite similar to that seen in familial prion diseases. However, association of human and mouse P-tau with amyloid PrPSc did not diminish survival time following prion infection in these mice. By analogy, human P-tau may not affect prion disease progression in humans. Alternatively, these results might be due to other factors, including rapidity of disease, blocking effects by mouse tau, or low toxicity of human P-tau in this model.

  16. Tau accumulation in the nucleus accumbens in tangle-predominant dementia

    Science.gov (United States)

    2014-01-01

    Background Tangle-predominant dementia (TPD) is characterized neuropathologically by numerous neurofibrillary tangles in the limbic areas with no or occasional senile plaques throughout the brain. TPD is an under-recognized disease, while it is a common cause of dementia in those over 80 years of age. In the present study, we describe hyperphosphorylated tau (tau) accumulation in the nucleus accumbens (Acb) in patients with TPD. Results We investigated immunohistochemically the brain tissues from 7 patients with TPD, 22 with Alzheimer disease (AD) and 11 non-demented aged subjects. In the Acb of all 7 TPD patients, a considerable number of tau positive neurons were found together with many neuropil threads. The tau deposits in the Acb were labeled with all the anti-tau antibodies used in the present study. They included conformational change-specific, phosphorylation-specific and phosphorylation-independent antibodies. The Acb consists of the predominant medium-sized neurons with a small number of large neurons. Both the cell types were affected by tau pathology in TPD. Tau accumulation in the majority of such neurons appeared to be pretangle-like, diffuse deposits with only occasional paired helical filament formation. Tau positive neurons were also found in the Acb in some AD and non-demented aged subjects but much fewer in the majority of cases. The immunoblot analyses of fresh frozen samples of the Acb and parahippocampal cortex from 3 TPD and 3 AD patients revealed that the insoluble tau in the Acb was a mixture of the 3- and 4-repeat isoforms. Conclusions To our knowledge, this is the first report on the occurrence of tau accumulation in the Acb in TPD. The Acb receives direct and massive projections from the hippocampal CA1 and subiculum where neurofibrillary tangles are known to occur more frequently in TPD than in AD. The prevalence of abnormal tau accumulation in the Acb in TPD may support the idea that abnormal tau aggregation propagates via neural

  17. Tau reconstruction and identification algorithm

    Indian Academy of Sciences (India)

    2012-11-15

    Nov 15, 2012 ... 13.35.Dx. 1. Introduction. Tau is the heaviest known lepton (Mτ = 1.78 GeV) which decays into lighter leptons. (BR ∼ 35%) or hadrons τh (BR ∼ 65%) in the presence of up to two neutrinos. The τ reconstruction algorithms are using decay mode identification techniques which allow one to reconstruct τh with ...

  18. Hadronic {tau} decays and QCD

    Energy Technology Data Exchange (ETDEWEB)

    Davier, M

    1999-12-01

    Hadronic decays of the {tau} lepton provide a clean source to study hadron dynamics in an energy regime dominated by resonances, with the interesting information captured in the spectral functions. Recent results on exclusive channels are reviewed. Inclusive spectral functions are the basis for QCD analyses, delivering an accurate determination of the strong coupling constant and quantitative information on nonperturbative contributions. Strange decays yield a determination of the strange quark mass. (author)

  19. Isoflurane anesthesia exacerbates learning and memory impairment in zinc-deficient APP/PS1 transgenic mice.

    Science.gov (United States)

    Feng, Chunsheng; Liu, Ya; Yuan, Ye; Cui, Weiwei; Zheng, Feng; Ma, Yuan; Piao, Meihua

    2016-12-01

    Zinc (Zn) is known to play crucial roles in numerous brain functions including learning and memory. Zn deficiency is believed to be widespread throughout the world, particularly in patients with Alzheimer's disease (AD). A number of studies have shown that volatile anesthetics, such as isoflurane, might be potential risk factors for the development of AD. However, whether isoflurane exposure accelerates the process of AD and cognitive impairment in AD patients with Zn deficiency is yet to be documented. The aim of the present study was to explore the effects of 1.4% isoflurane exposure for 2 h on learning and memory function, and neuropathogenesis in 10-month-old Zn-adequate, Zn-deficient, and Zn-treated APP/PS1 mice with the following parameters: behavioral tests, neuronal apoptosis, Aβ, and tau pathology. The results demonstrated that isoflurane exposure showed no impact on learning and memory function, but induced transient elevation of neuroapoptosis in Zn-adequate APP/PS1 mice. Exposure of isoflurane exhibited significant neuroapoptosis, Aβ generation, tau phosphorylation, and learning and memory impairment in APP/PS1 mice in the presence of Zn deficiency. Appropriate Zn treatment improved learning and memory function, and prevented isoflurane-induced neuroapoptosis in APP/PS1 mice. Isoflurane exposure may cause potential neurotoxicity, which is tolerated to some extent in Zn-adequate APP/PS1 mice. When this tolerance is limited, like in AD with Zn deficiency, isoflurane exposure markedly exacerbated learning and memory impairment, and neuropathology, indicating that AD patients with certain conditions such as Zn deficiency may be vulnerable to volatile anesthetic isoflurane. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity

    Science.gov (United States)

    An, Lin; Hu, Xiao-wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-01-01

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. PMID:28225086

  1. Structure-based inhibitors of tau aggregation

    Science.gov (United States)

    Seidler, P. M.; Boyer, D. R.; Rodriguez, J. A.; Sawaya, M. R.; Cascio, D.; Murray, K.; Gonen, T.; Eisenberg, D. S.

    2018-02-01

    Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau.

  2. Neuroinflammation is not a prerequisite for diabetes-induced tau phosphorylation

    Directory of Open Access Journals (Sweden)

    Judith M Van Der Harg

    2015-11-01

    Full Text Available Abnormal phosphorylation and aggregation of tau is a key hallmark of Alzheimer's disease (AD. AD is a multifactorial neurodegenerative disorder for which Diabetes Mellitus (DM is a risk factor. In animal models for DM, the phosphorylation and aggregation of tau is induced or exacerbated, however the underlying mechanism is unknown. In addition to the metabolic dysfunction, DM is characterized by chronic low-grade inflammation. This was reported to be associated with a neuroinflammatory response in the hypothalamus of DM animal models. Neuroinflammation is also implicated in the development and progression of AD. It is unknown whether DM also induces neuroinflammation in brain areas affected in AD, the cortex and hippocampus. Here we investigated whether neuroinflammation could be the mechanistic trigger to induce tau phosphorylation in the brain of DM animals. Two distinct diabetic animal models were used; rats on free-choice high-fat high-sugar (fcHFHS diet that are insulin resistant and streptozotocin-treated rats that are insulin deficient. The streptozotocin-treated animals demonstrated increased tau phosphorylation in the brain as expected, whereas the fcHFHS diet fed animals did not. Remarkably, neither of the diabetic animal models showed reactive microglia or increased GFAP and COX-2 levels in the cortex or hippocampus. From this, we conclude: 1. DM does not induce neuroinflammation in brain regions affected in AD, and 2. Neuroinflammation is not a prerequisite for tau phosphorylation. Neuroinflammation is therefore not the mechanism that explains the close connection between DM and AD.

  3. Aspirin-Exacerbated Asthma

    Directory of Open Access Journals (Sweden)

    Varghese Mathew

    2008-06-01

    Full Text Available This review focuses on aspirin-exacerbated asthma (AEA. The review includes historical perspective of aspirin, prevalence, pathogenesis, clinical features and treatment of AEA. The pathogenesis of AEA involves the cyclooxygenase and lipooxygenase pathway. Aspirin affects both of these pathways by inhibiting the enzyme cycooxygenase-1 (COX-1. Inhibition of COX-1 leads to a decrease in prostaglandin E2 (PGE2. The decrease in PGE2 results in an increase in cysteinyl leukotrienes by the lipooxygenase pathway involving the enzyme 5-lipooxygenase (5-LO. Leukotriene C4 (LTC4 synthase is the enzyme responsible for the production of leukotriene C4, the chief cysteinyl leukotriene responsible for AEA. There have been familial occurences of AEA. An allele of the LTC4 synthase gene in AEA is known as allele C. Allele C has a higher frequency in AEA. Clinical presentation includes a history of asthma after ingestion of aspirin, nasal congestion, watery rhinorrhea and nasal polyposis. Treatment includes leukotriene receptor antagonists, leukotriene inhibitors, aspirin desinsitaztion and surgery. AEA is the most well-defined phenotype of asthma. Although AEA affects adults and children with physician-diagnosed asthma, in some cases there is no history of asthma and AEA often goes unrecognized and underdiagnosed.

  4. Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease

    DEFF Research Database (Denmark)

    Jensen, Camilla Steen; Portelius, Erik; Siersma, Volkert

    2016-01-01

    Background: Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical...... of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients...

  5. 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.

  6. Tau appearance in atmospheric neutrino interactions

    Energy Technology Data Exchange (ETDEWEB)

    Hall, Lawrence J.; Murayama, Hitoshi

    1998-10-24

    If the correct interpretation of the Super-Kamiokande atmospheric neutrino data is {nu}{sub {mu}} {yields} {nu}{sub {tau}} oscillation, the contained data sample should already have more than 10 {tau} appearance events. We study the challenging task of detecting the {tau}, focusing on the decay chain {tau}{sup {+-}} {yields} {rho}{sup {+-}} {yields} {pi}{sup {+-}}{pi}{sup 0} in events with quasi-elastic {tau} production. The background level, which is currently quite uncertain because of a lack of relevant neutral current data, can be measured by the near detector in the K2K experiment. Our estimates of the background suggest that it may be possible to detect {tau} appearance in Super-Kamiokande with 5-10 years of running.

  7. [Modern aspects of using unique natural therapeutic factors of the Iangan-Tau health resort].

    Science.gov (United States)

    Badretdinov, R R; Badretdinova, L M

    2009-01-01

    The authors describe unique natural therapeutic factors of the Yangan-Tau health resort including its climatic features, drinking mineral waters, steam-and-air baths, etc. Modern approaches to the exploitation of these resources for the management of various pathological conditions are discussed.

  8. β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer's disease-related sites.

    Directory of Open Access Journals (Sweden)

    Danielle Frost

    Full Text Available Harmine, a β-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer's disease (AD. Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional β-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope, and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the β-carboline compounds (1 potently reduce the expression of all three phosphorylated forms of tau protein, and (2 inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several β-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.

  9. Tau and β-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging.

    Science.gov (United States)

    Marks, Shawn M; Lockhart, Samuel N; Baker, Suzanne L; Jagust, William J

    2017-03-22

    Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turn associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimer's disease-related protein aggregation as an underlying mechanism of age-related memory impairment. SIGNIFICANCE STATEMENT Alterations in episodic memory and the accumulation of Alzheimer's pathology are common in cognitively normal older adults. However, evidence of pathological effects on episodic memory has largely been limited to β-amyloid (Aβ). Because Aβ and tau often cooccur in older adults, previous research offers an incomplete understanding of the relationship between pathology and episodic memory. With the recent development of in vivo tau PET radiotracers, we show that Aβ and tau are associated with different aspects of memory encoding, leading to aberrant neural activity that is behaviorally detrimental. In addition, our results provide evidence linking Aβ- and tau-associated neural dysfunction to brain atrophy. Copyright © 2017 the authors 0270-6474/17/373192-10$15.00/0.

  10. Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2.

    Science.gov (United States)

    Yin, Yaling; Wang, Yali; Gao, Di; Ye, Jinwang; Wang, Xin; Fang, Lin; Wu, Dongqin; Pi, Guilin; Lu, Chengbiao; Zhou, Xin-Wen; Yang, Ying; Wang, Jian-Zhi

    2016-06-09

    Cholinergic impairments and tau accumulation are hallmark pathologies in sporadic Alzheimer's disease (AD), however, the intrinsic link between tau accumulation and cholinergic deficits is missing. Here, we found that overexpression of human wild-type full-length tau (termed hTau) induced a significant reduction of α4 subunit of nicotinic acetylcholine receptors (nAChRs) with an increased cleavage of the receptor producing a ~55kDa fragment in primary hippocampal neurons and in the rat brains, meanwhile, the α4 nAChR currents decreased. Further studies demonstrated that calpains, including calpain-1 and calpain-2, were remarkably activated with no change of caspase-3, while simultaneous suppression of calpain-2 by selective calpain-2 inhibitor but not calpain-1 attenuated the hTau-induced degradation of α4 nAChR. Finally, we demonstrated that hTau accumulation increased the basal intracellular calcium level in primary hippocampal neurons. We conclude that the hTau accumulation inhibits nAChRs α4 by activating calpain-2. To our best knowledge, this is the first evidence showing that the intracellular accumulation of tau causes cholinergic impairments.

  11. High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation

    Directory of Open Access Journals (Sweden)

    Gwinn Leslie

    2010-01-01

    Full Text Available Abstract Background Neurofibrillary tangles (NFT, a cardinal neuropathological feature of Alzheimer's disease (AD that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments. Results We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 α kinase 2 (EIF2AK2, the dual-specificity tyrosine-(Y-phosphorylation regulated kinase 1A (DYRK1A, and the A-kinase anchor protein 13 (AKAP13 on tau phosphorylation at the 12E8 epitope (serine 262/serine 356. We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways. Conclusions These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.

  12. Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Cardiovascular Links

    Science.gov (United States)

    Laratta, Cheryl R.; van Eeden, Stephan

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a chronic, progressive lung disease resulting from exposure to cigarette smoke, noxious gases, particulate matter, and air pollutants. COPD is exacerbated by acute inflammatory insults such as lung infections (viral and bacterial) and air pollutants which further accelerate the steady decline in lung function. The chronic inflammatory process in the lung contributes to the extrapulmonary manifestations of COPD which are predominantly cardiovascular in nature. Here we review the significant burden of cardiovascular disease in COPD and discuss the clinical and pathological links between acute exacerbations of COPD and cardiovascular disease. PMID:24724085

  13. 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.

  14. A Search for B+ -> tau+ nu

    CERN Document Server

    Aubert, B; Boutigny, D; Karyotakis, Yu; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Graugès-Pous, E; López, L; Palano, A; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes-Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Ronan, M T; Tackmann, K; Wenzel, W A; Del Amo-Sánchez, P; Hawkes, C M; Watson, A T; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Schröder, T; Steinke, M; Walker, D; Asgeirsson, D J; Çuhadar-Dönszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M A; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Williams, D C; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Zeng, Q; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Brandt, T; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, C; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; De Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Nikolich, M B; Panduro-Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Meyer, N T; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Bequilleux, J; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F R; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Menges, W; Sacco, R; Cowan, G; Flächer, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; Mclachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, Gallieno; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; LoSecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Wong, Q K; Blount, N L; Brau, J E; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; La Vaissière, C de; Hamon, O; Leruste, P; Malcles, J; Ocariz, J; Pérez, A; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Haire, M; Biesiada, J; Elmer, P; Lau, Y P; Lü, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; D'Orazio, A; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Ricciardi, S; Röthel, W; Wilson, F F; Aleksan, R; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yéche, C; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Hrynóva, T; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Lüth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Müller, D R; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Vavra, J; Van Bakel, N; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martínez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R V; Nugent, I M; Roney, J M; Sobie, R J; Back, J J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Pappagallo, M; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2007-01-01

    We present a search for the decay B+ -> tau+ nu using 383x10^6 BBbar pairs collected at the Y(4S) resonance with the BABAR detector at the SLAC PEP-II B-Factory. A sample of events with one reconstructed semileptonic B decay (B- -> D0 l nu X)) is selected, and in the recoil a search for B+ -> tau+ nu is performed. The tau is identified in the following channels: tau+ -> e nu nubar, tau+ -> mu nu nubar, tau+ -> pi+ nu, and tau+ -> pi+ pi0 nu. We measure a branching fraction of B(B+ -> tau+ nu)=(0.9 +- 0.6(stat.) +- 0.1(syst.)) x 10^-4. In the absence of a significant signal, we calculate an upper limit at the 90% confidence level of B(B+ -> tau+ nu) < 1.7 x 10^-4. We calculate the product of the B meson decay constant f_B and |V_ub| to be f_B x |V_ub| = (7.2^{+2.0}_{-2.8}(stat.) +- 0.2 (syst.)) x 10^-4 GeV.

  15. Physics with tau leptons at ATLAS

    CERN Document Server

    Morgenstern, M; The ATLAS collaboration

    2012-01-01

    Physics involving tau lepton signatures form an integral part of the ATLAS physics program, and are becoming more prevalent, given the large amounts of data accumulated in 2011 and 2012 LHC running. This talk reviews the increased sensitivity of searches for a Standard Model Higgs boson in the low mass region, as well as searches for neutral and charged supersymmetric Higgs bosons, decaying to tau final states. Other searches involving tau lepton signatures are also reviewed, including searches for heavy gauge bosons, leptoquarks, and supersymmetric decays. Standard Model processes from W, Z, and top pair production involving tau leptons are also investigated.

  16. 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.)

  17. Hybrid chernoff tau-leap

    KAUST Repository

    Moraes, Alvaro

    2014-01-01

    Markovian pure jump processes model a wide range of phenomena, including chemical reactions at the molecular level, dynamics of wireless communication networks, and the spread of epidemic diseases in small populations. There exist algorithms such as Gillespie\\'s stochastic simulation algorithm (SSA) and Anderson\\'s modified next reaction method (MNRM) that simulate a single path with the exact distribution of the process, but this can be time consuming when many reactions take place during a short time interval. Gillespie\\'s approximated tau-leap method, on the other hand, can be used to reduce computational time, but it may lead to nonphysical values due to a positive one-step exit probability, and it also introduces a time discretization error. Here, we present a novel hybrid algorithm for simulating individual paths which adaptively switches between the SSA and the tau-leap method. The switching strategy is based on a comparison of the expected interarrival time of the SSA and an adaptive time step derived from a Chernoff-type bound for the one-step exit probability. Because this bound is nonasymptotic, we do not need to make any distributional approximation for the tau-leap increments. This hybrid method allows us (i) to control the global exit probability of any simulated path and (ii) to obtain accurate and computable estimates of the expected value of any smooth observable of the process with minimal computational work. We present numerical examples that illustrate the performance of the proposed method. © 2014 Society for Industrial and Applied Mathematics.

  18. cis p-tau: early driver of brain injury and tauopathy blocked by antibody

    Science.gov (United States)

    Mannix, Rebekah; Qiu, Jianhua; Moncaster, Juliet; Chen, Chun-Hau; Yao, Yandan; Lin, Yu-Min; Driver, Jane A; Sun, Yan; Wei, Shuo; Luo, Man-Li; Albayram, Onder; Huang, Pengyu; Rotenberg, Alexander; Ryo, Akihide; Goldstein, Lee E; Pascual-Leone, Alvaro; McKee, Ann C.; Meehan, William; Zhou, Xiao Zhen; Lu, Kun Ping

    2015-01-01

    Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. PMID:26176913

  19. Brain alterations and clinical symptoms of dementia in diabetes: Abeta/tau-dependent and independent mechanisms

    Directory of Open Access Journals (Sweden)

    Naoyuki eSato

    2014-09-01

    Full Text Available Emerging evidence suggests that diabetes affects cognitive function and increases the incidence of dementia. However, the mechanisms by which diabetes modifies cognitive function still remains unclear. Morphologically, diabetes is associated with neuronal loss in the frontal and temporal lobes including the hippocampus, and aberrant functional connectivity of the posterior cingulate cortex and medial frontal/temporal gyrus. Clinically, diabetic patients show decreased executive function, information processing, planning, visuospatial construction, and visual memory. Therefore, in comparison with the characteristics of AD brain structure and cognition, diabetes seems to affect cognitive function through not only simple AD pathological feature-dependent mechanisms, but also independent mechanisms. As an Abeta/tau-independent mechanism, diabetes compromises cerebrovascular function, increases subcortical infarction and might alter the blood brain barrier (BBB. Diabetes also affects glucose metabolism, insulin signaling and mitochondrial function in the brain. Diabetes also modifies metabolism of Abeta and tau and causes Abeta/tau-dependent pathological changes. Moreover, there is evidence that suggests an interaction between Abeta/tau-dependent and independent mechanisms. Therefore, diabetes modifies cognitive function through Abeta/tau-dependent and independent mechanisms. Interaction between these two mechanisms forms a vicious cycle.

  20. Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer's disease and Down syndrome.

    Science.gov (United States)

    Mondragón-Rodríguez, S; Perry, G; Luna-Muñoz, J; Acevedo-Aquino, M C; Williams, S

    2014-02-01

    Phosphorylation, conformational changes and cleavage of tau protein have been widely suggested to contribute to abnormal tau processing in the pathogenesis of Alzheimer's disease, as well as in other tauopathies. Consistently, many phosphorylated sites, such as Ser(199-202) -Thr(205) and Ser(396-404) , have been associated with this pathological processing. The present study examined the chronological appearance of phosphorylation during the neurofibrillary tangle (NFT) evolution in Alzheimer disease (AD) and Down syndrome. Immunohistochemistry for modified tau [phosphorylated at Ser(199-202) -Thr(205) (AT8) and Ser(396-404) (PHF-1) or truncated at D(421) (TauC3) and E(391) (MN423)] was performed on paraffin-embedded human brain sections. Double immunofluorescence for phosphorylated and truncated tau was used to detect intensity and distribution of tau immunoreactivity, and provided detailed characterization of NFT pathology. Phosphorylation at sites Ser(396-404) was significantly increased when compared with phosphorylations at sites Ser(199-202) -Thr(205) . Around 50% of the total structures containing phosphorylation at sites Ser(396-404) were found as early phospho-tau aggregates with a well-preserved neuronal soma. Phosphorylation of tau protein at sites Ser(396) coexists with early and late truncation events. Tau abnormal processing in Down syndrome consistently showed similar alterations as observed in AD. Phosphorylation of tau protein at the carboxyl terminus may be among the earliest tau events, and it occurs prior to the apparition of the classical fibrillar structure. Finally, these data validate PHF-1 as an efficient marker for AD cytopathology following the progression of tau aggregation into NFT. © 2013 British Neuropathological Society.

  1. Aminopeptidases do not directly degrade tau protein

    Directory of Open Access Journals (Sweden)

    Hersh Louis B

    2010-11-01

    Full Text Available Abstract Background Tau hyperphosphorylation and aggregation to form intracellular neurofibrillar tangles is prevalent in a number of tauopathies. Thus there is current interest in the mechanisms involved in Tau clearance. It was recently reported that Tau can be degraded by an aminopeptidase known as the puromycin sensitive aminopeptidase (PSA. Until now PSA has been reported to only cleave peptides, with the largest reported substrates having 30-50 amino acids. We have studied this unique PSA cleavage reaction using a number of different PSA preparations. Results An N-terminally His tagged-PSA was expressed and purified from Sf9 insect cells. Although this PSA preparation cleaved Tau, product analysis with N and C terminal Tau antibodies coupled with mass spectrometry showed an endoproteolytic cleavage atypical for an aminopeptidase. Furthermore, the reaction was not blocked by the general aminopeptidase inhibitor bestatin or the specific PSA inhibitor puromycin. In order to test whether Tau hydrolysis might be caused by a protease contaminant the enzyme was expressed in E. coli as glutathione S-transferase and maltose binding protein fusion proteins or in Sf9 cells as a C-terminally His-tagged protein. After purification to near homogeneity none of these other recombinant forms of PSA cleaved Tau. Further, Tau-cleaving activity and aminopeptidase activities derived from the Sf9 cell expression system were separable by molecular sieve chromatography. When tested in a cellular context we again failed to see a PSA dependent cleavage of Tau. A commercial preparation of a related aminopeptidase, aminopeptidase N, also exhibited Tau cleaving activity, but this activity could also be separated from aminopeptidase activity. Conclusion It is concluded that PSA does not directly cleave Tau.

  2. Measurement of the Semileptonic Decays B->D tau nu and B->D* tau nu

    Energy Technology Data Exchange (ETDEWEB)

    Aubert, : B.

    2009-02-23

    The authors present measurements of the semileptonic decays B{sup -} {yields} D{sup 0} {tau}{sup -} {bar {nu}}{sub {tau}}, B{sup -} {yields} D*{sup 0} {tau}{sup -}{bar {nu}}{sub {tau}}, {bar B}{sup 0} {yields} D{sup +} {tau}{sup -} {bar {nu}}{sub {tau}}, and {bar B}{sup 0} {yields} D*{sup +} {tau}{sup -}{bar {nu}}{sub {tau}}, which are sensitive to non-Standard Model amplitudes in certain scenarios. The data sample consists of 232 x 10{sup 6} {Upsilon}(4S) {yields} B{bar B} decays collected with the BABAR detector at the PEP-II e{sup +}e{sup -} collider. They select events with a D or D* meson and a light lepton ({ell} = e or {mu}) recoiling against a fully reconstructed B meson. They perform a fit to the joint distribution of lepton momentum and missing mass squared to distinguish signal B {yields} D{sup (*)}{tau}{sup -} {bar {nu}}{sub {tau}} ({tau}{sup -} {yields} {ell}{sup -} {bar {nu}}{sub {ell}}{nu}{sub {tau}}) events from the backgrounds, predominantly B {yields} D{sup (*)} {ell}{sup -}{bar {nu}}{sub {ell}}. They measure the branching-fraction ratios R(D) {triple_bond} {Beta}(B {yields} D{tau}{sup -} {bar {nu}}{sub {tau}})/{Beta}(B {yields} D{ell}{sup -} {bar {nu}}{sub {ell}}) and R(D*) {triple_bond} {Beta}(B {yields} D*{tau}{sup -} {bar {nu}}{sub {tau}})/{Beta}(B {yields} D* {ell}{sup -} {bar {nu}}{sub {ell}}) and, from a combined fit to B{sup -} and {bar B}{sup 0} channels, obtain the results R(D) = (41.6 {+-} 11.7 {+-} 5.2)% and R(D*) = (29.7 {+-} 5.6 {+-} 1.8)%, where the uncertainties are statistical and systematic. Normalizing to measured B{sup -} {yields} D{sup (*)0} {ell}{sup -} {bar {nu}}{sub {ell}} branching fractions, they obtain {Beta}(B {yields} D{tau}{sup -} {bar {nu}}{sub {tau}}) = (0.86 {+-} 0.24 {+-} 0.11 {+-} 0.06)% and {Beta}(B {yields} D*{tau}{sup -} {bar {nu}}{sub {tau}}) = (1.62 {+-} 0.31 {+-} 0.10 {+-} 0.05)%, where the additional third uncertainty is from the normalization mode. They also present, for the first time, distributions of

  3. Physics with tau leptons at CDF

    Energy Technology Data Exchange (ETDEWEB)

    Hays, C.P.; /Oxford U.

    2007-04-01

    The {radical}s = 1.96 TeV p{bar p} collisions produced by the Tevatron result in many processes with tau leptons in the final state. The CDF Collaboration has studied these final states in Z and t{bar t} production, and has used tau leptons to search for evidence of Higgs, sparticle, and Z{prime} production.

  4. More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases.

    Science.gov (United States)

    Lee, Virginia M-Y; Giasson, Benoit I; Trojanowski, John Q

    2004-03-01

    Intracytoplasmic filamentous aggregates, such as neurofibrillary tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease, are composed of the proteins tau and alpha-synuclein, respectively. These pathological inclusions are linked directly to the etiology and mechanisms of disease in a wide spectrum of neurodegenerative disorders, termed 'tauopathies' and 'synucleinopathies'. Emerging evidence indicates that there is frequent overlap of the pathological and clinical features of patients with tauopathies and synucleinopathies, thereby re-enforcing the notion that these disorders might be linked mechanistically. Indeed, several lines of investigation suggest that tau and alpha-synuclein might constitute a unique class of unstructured proteins that assemble predominantly into homopolymeric (rather than heteropolymeric) fibrils, which deposit mainly in separate amyloid inclusions, but occasionally deposit together. Thus, the ability of tau and alpha-synuclein to affect each other directly or indirectly might contribute to the overlap in the clinical and pathological features of tauopathies and synucleinopathies.

  5. TauSpinner program for studies on spin effect in tau production at the LHC

    CERN Document Server

    Czyczula, Z; Was, Z

    2012-01-01

    Final states involving tau leptons are important components of searches for new particles at the Large Hadron Collider (LHC). A proper treatment of tau spin effects in the Monte Carlo (MC) simulations is important for understanding the detector acceptance as well as for the measurements of tau polarization and tau spin correlations. In this note we present a TauSpinner package designed to simulate the spin effects. It relies on the availability of the four-momenta of the taus and their decay products in the analyzed data. The flavor and the four-momentum of the boson decaying to the tau-tau+ or tau+- nu pair need to be known. In the Z/gamma* case the initial state quark configuration is attributed from the intermediate boson kinematics, and the parton distribution functions (PDF's). TauSpinner is the first algorithm suitable for emulation of tau spin effects in tau-embedded samples. It is also the first tool that offers the user the flexibility to simulate a desired spin effect at the analysis level. An algor...

  6. 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.

  7. Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.

    Science.gov (United States)

    Rodríguez-Martín, Teresa; Pooler, Amy M; Lau, Dawn H W; Mórotz, Gábor M; De Vos, Kurt J; Gilley, Jonathan; Coleman, Michael P; Hanger, Diane P

    2016-01-01

    Expression of the frontotemporal dementia-related tau mutation, P301L, at physiological levels in adult mouse brain (KI-P301L mice) results in overt hypophosphorylation of tau and age-dependent alterations in axonal mitochondrial transport in peripheral nerves. To determine the effects of P301L tau expression in the central nervous system, we examined the kinetics of mitochondrial axonal transport and tau phosphorylation in primary cortical neurons from P301L knock-in (KI-P301L) mice. We observed a significant 50% reduction in the number of mitochondria in the axons of cortical neurons cultured from KI-P301L mice compared to wild-type neurons. Expression of murine P301L tau did not change the speed, direction of travel or likelihood of movement of mitochondria. Notably, the angle that defines the orientation of the mitochondria in the axon, and the volume of individual moving mitochondria, were significantly increased in neurons expressing P301L tau. We found that murine tau phosphorylation in KI-P301L mouse neurons was diminished and the ability of P301L tau to bind to microtubules was also reduced compared to tau in wild-type neurons. The P301L mutation did not influence the ability of murine tau to associate with membranes in cortical neurons or in adult mouse brain. We conclude that P301L tau is associated with mitochondrial changes and causes an early reduction in murine tau phosphorylation in neurons coupled with impaired microtubule binding of tau. These results support the association of mutant tau with detrimental effects on mitochondria and will be of significance for the pathogenesis of tauopathies. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

  8. Caspase-Cleaved Tau Co-Localizes with Early Tangle Markers in the Human Vascular Dementia Brain.

    Science.gov (United States)

    Day, Ryan J; Mason, Maria J; Thomas, Chloe; Poon, Wayne W; Rohn, Troy T

    2015-01-01

    Vascular dementia (VaD) is the second most common form of dementia in the United States and is characterized as a cerebral vessel vascular disease that leads to ischemic episodes. Whereas the relationship between caspase-cleaved tau and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) has been previously described, whether caspase activation and cleavage of tau occurs in VaD is presently unknown. To investigate a potential role for caspase-cleaved tau in VaD, we analyzed seven confirmed cases of VaD by immunohistochemistry utilizing a well-characterized antibody that specifically detects caspase-cleaved tau truncated at Asp421. Application of this antibody (TauC3) revealed consistent labeling within NFTs, dystrophic neurites within plaque-rich regions and corpora amylacea (CA) in the human VaD brain. Labeling of CA by the TauC3 antibody was widespread throughout the hippocampus proper, was significantly higher compared to age matched controls, and co-localized with ubiquitin. Staining of the TauC3 antibody co-localized with MC-1, AT8, and PHF-1 within NFTs. Quantitative analysis indicated that roughly 90% of PHF-1-labeled NFTs contained caspase-cleaved tau. In addition, we documented the presence of active caspase-3 within plaques, blood vessels and pretangle neurons that co-localized with TauC3. Collectively, these data support a role for the activation of caspase-3 and proteolytic cleavage of TauC3 in VaD providing further support for the involvement of this family of proteases in NFT pathology.

  9. 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.

  10. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate tau protein and are activated in tangle-bearing neurons in Alzheimer disease.

    Science.gov (United States)

    Tavares, Ignatius A; Touma, Dona; Lynham, Steven; Troakes, Claire; Schober, Megan; Causevic, Mirsada; Garg, Ritu; Noble, Wendy; Killick, Richard; Bodi, Istvan; Hanger, Diane P; Morris, Jonathan D H

    2013-05-24

    In Alzheimer disease (AD), the microtubule-associated protein tau is highly phosphorylated and aggregates into characteristic neurofibrillary tangles. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) 1 and 2, members of the sterile 20 family of kinases, have been shown to regulate microtubule stability and organization. Here we show that tau is a good substrate for PSK1 and PSK2 phosphorylation with mass spectrometric analysis of phosphorylated tau revealing more than 40 tau residues as targets of these kinases. Notably, phosphorylated residues include motifs located within the microtubule-binding repeat domain on tau (Ser-262, Ser-324, and Ser-356), sites that are known to regulate tau-microtubule interactions. PSK catalytic activity is enhanced in the entorhinal cortex and hippocampus, areas of the brain that are most susceptible to Alzheimer pathology, in comparison with the cerebellum, which is relatively spared. Activated PSK is associated with neurofibrillary tangles, dystrophic neurites surrounding neuritic plaques, neuropil threads, and granulovacuolar degeneration bodies in AD brain. By contrast, activated PSKs and phosphorylated tau are rarely detectible in immunostained control human brain. Our results demonstrate that tau is a substrate for PSK and suggest that this family of kinases could contribute to the development of AD pathology and dementia.

  11. Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein.

    Science.gov (United States)

    Maia, Luis F; Kaeser, Stephan A; Reichwald, Julia; Hruscha, Michael; Martus, Peter; Staufenbiel, Matthias; Jucker, Mathias

    2013-07-17

    Altered concentrations of amyloid-β (Aβ) peptide and Tau protein in the cerebrospinal fluid (CSF) are thought to be predictive markers for Alzheimer's disease (AD). Transgenic mice overexpressing human amyloid precursor protein (APP) have been used to model Aβ pathology, but concomitant changes in Aβ and Tau in CSF have been less well studied. We measured Aβ and Tau in the brains and CSF of two well-characterized transgenic mouse models of AD: one expressing human APP carrying the Swedish mutation (APP23) and the other expressing mutant human APP and mutant human presenilin-1 (APPPS1). Both mouse models exhibit Aβ deposition in the brain, but with different onset and progression trajectories. We found an age-related 50 to 80% decrease in Aβ42 peptide in mouse CSF and a smaller decrease in Aβ40, both inversely correlated with the brain Aβ load. Surprisingly, the same mice showed a threefold increase in total endogenous murine Tau in CSF at the stages when Aβ pathology became prominent. The results mirror the temporal sequence and magnitude of Aβ and Tau changes in the CSF of patients with sporadic and dominantly inherited AD. This observation indicates that APP transgenic mice may be useful as a translational tool for predicting changes in Aβ and Tau markers in the CSF of AD patients. These findings also suggest that APP transgenic mouse models may be useful in the search for new disease markers for AD.

  12. The emerging role of peptidyl-prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer's disease.

    Science.gov (United States)

    Blair, Laura J; Baker, Jeremy D; Sabbagh, Jonathan J; Dickey, Chad A

    2015-04-01

    Peptidyl-prolyl cis/trans isomerases (PPIases), a unique family of molecular chaperones, regulate protein folding at proline residues. These residues are abundant within intrinsically disordered proteins, like the microtubule-associated protein tau. Tau has been shown to become hyperphosphorylated and accumulate as one of the two main pathological hallmarks in Alzheimer's disease, the other being amyloid beta (Ab). PPIases, including Pin1, FK506-binding protein (FKBP) 52, FKBP51, and FKBP12, have been shown to interact with and regulate tau biology. This interaction is particularly important given the numerous proline-directed phosphorylation sites found on tau and the role phosphorylation has been found to play in pathogenesis. This regulation then affects downstream aggregation and oligomerization of tau. However, many PPIases have yet to be explored for their effects on tau biology, despite the high likelihood of interaction based on proline content. Moreover, Pin1, FKBP12, FKBP52, cyclophilin (Cyp) A, CypB, and CypD have been shown to also regulate Ab production or the toxicity associated with Ab pathology. Therefore, PPIases directly and indirectly regulate pathogenic protein multimerization in Alzheimer's disease and represent a family rich in targets for modulating the accumulation and toxicity. © 2015 International Society for Neurochemistry.

  13. Current advances in the treatment of Alzheimer's disease: focused on considerations targeting Aβ and tau

    Directory of Open Access Journals (Sweden)

    Hong-Qi Yang

    2012-10-01

    Full Text Available Abstract Alzheimer’s disease (AD is a neurodegenerative disorder that impairs mainly the memory and cognitive function in elderly. Extracellular beta amyloid deposition and intracellular tau hyperphosphorylation are the two pathological events that are thought to cause neuronal dysfunction in AD. Since the detailed mechanisms that underlie the pathogenesis of AD are still not clear, the current treatments are those drugs that can alleviate the symptoms of AD patients. Recent studies have indicated that these symptom-reliving drugs also have the ability of regulating amyloid precursor protein processing and tau phosphorylation. Thus the pharmacological mechanism of these drugs may be too simply-evaluated. This review summarizes the current status of AD therapy and some potential preclinical considerations that target beta amyloid and tau protein are also discussed.

  14. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

    Science.gov (United States)

    Rodriguez-Rodriguez, Patricia; Sandebring-Matton, Anna; Merino-Serrais, Paula; Parrado-Fernandez, Cristina; Rabano, Alberto; Winblad, Bengt; Ávila, Jesús; Ferrer, Isidre; Cedazo-Minguez, Angel

    2017-12-01

    Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Chronic Traumatic Encephalopathy: Is Latency in Symptom Onset Explained by Tau Propagation?

    Science.gov (United States)

    Kriegel, Joshua; Papadopoulos, Zachary; McKee, Ann C

    2017-01-17

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild brain trauma. CTE, previously termed "dementia pugilistica," has been identified in American football, ice hockey, baseball, rugby and soccer players, boxers, wrestlers, and military personnel exposed to blast and other traumatic brain injuries. There is often a long latency period between an individual's exposure to repetitive brain trauma and the clinical symptoms of CTE. The pathology of CTE is characterized by a progression from isolated focal perivascular hyperphosphorylated tau lesions in the cerebral cortex to a widespread tauopathy that involves diffuse cortical and medial temporal lobe regions. We hypothesize that the spread of tau from focal perivascular lesions to a widespread tauopathy occurs as a result of intraneuronal and intrasynaptic prion-like protein templating, as well as tau secretion and propagation along glymphatic and cerebrospinal fluid pathways. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  16. Acute asthma exacerbations: an overview

    Directory of Open Access Journals (Sweden)

    Domenico Lorenzo Urso

    2014-07-01

    Full Text Available Asthma is a chronic inflammatory disease of the airways. All patient with asthma are at risk of having exacerbations characterized by worsening symptoms, airflow obstruction, and an increased requirement for rescue bronchodilators. Asthma exacerbations can be classified as mild, moderate, severe, or life threatening. The goals of treatment are correction of severe hypoxemia, rapid reversal of airflow obstruction, and reduction of the risk of relapse.http://dx.doi.org/10.7175/rhc.v5i3.932

  17. Disinhibition-like behavior in a P301S mutant tau transgenic mouse model of frontotemporal dementia.

    Science.gov (United States)

    Przybyla, Magdalena; Stevens, Claire H; van der Hoven, Julia; Harasta, Anne; Bi, Mian; Ittner, Arne; van Hummel, Annika; Hodges, John R; Piguet, Olivier; Karl, Tim; Kassiou, Michael; Housley, Gary D; Ke, Yazi D; Ittner, Lars M; Eersel, Janet van

    2016-09-19

    Frontotemporal dementia (FTD) presents clinically with behavioral changes including disinhibition. Mutations in the tau-encoding MAPT gene identified in familial cases of FTD have been used to generate transgenic mouse models of the human condition. Here, we report behavioral changes in a recently developed P301S mutant tau transgenic mouse, including disinhibition-like behavior in the elevated plus maze and hyperactivity in the open field arena. Furthermore, histological analysis revealed the amygdala as a primary and early site of pathological tau deposition in these mice. Taken together, neuropathological and behavioral changes in P301S tau transgenic mice resemble features of human FTD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Tau and β-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging

    Energy Technology Data Exchange (ETDEWEB)

    Marks, Shawn M. [Univ. of California, Berkeley, CA (United States). Helen Wills Neuroscience Inst.; Lockhart, Samuel N. [Univ. of California, Berkeley, CA (United States). Helen Wills Neuroscience Inst.; Baker, Suzanne L. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging; Jagust, William J. [Univ. of California, Berkeley, CA (United States). Helen Wills Neuroscience Inst.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging

    2017-03-22

    Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turn associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimer’s disease-related protein aggregation as an underlying mechanism of age-related memory impairment.

  19. Observation of the Semileptonic Decays B --> D* tau nubar and Evidence for B --> D tau nubar

    CERN Document Server

    Aubert, B; Boutigny, D; Karyotakis, Yu; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Graugès-Pous, E; López, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes-Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabé, T; Wenzel, W A; Del Amo-Sánchez, P; Hawkes, C M; Watson, A T; Koch, H; Schröder, T; Walker, D; Asgeirsson, D J; Çuhadar-Dönszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Gary, J W; Liu, F; Long, O; Shen, B C; Vitug, G M; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, C; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; De Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro-Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Bequilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, L; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Sacco, R; Cowan, G; Flächer, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; Mclachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, Gallieno; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; LoSecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Sekula, S J; Wong, Q K; Blount, N L; Brau, J E; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; De La Vaissière, C; Hamon, O; Leruste, P; Malcles, J; Ocariz, J; Pérez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Biesiada, J; Elmer, P; Lau, Y P; Lü, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Röthel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yéche, C; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Lüth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Müller, D R; Nelson, S; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Vavra, J; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Ziegler, V; Burchat, P R; Edwards, A J; Majewski, S A; Miyashita, T S; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Spanier, S M; Wogsland, B J; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martínez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2007-01-01

    We present measurements of the semileptonic decays B- --> D0 tau- nubar, B- --> D*0 tau- nubar, B0bar --> D+ tau- nubar, and B0bar --> D*+ tau- nubar, which are potentially sensitive to non--Standard Model amplitudes. The data sample comprises 232x10^6 Upsilon(4S) --> BBbar decays collected with the BaBar detector. From a combined fit to B- and B0bar channels, we obtain the branching fractions B(B --> D tau- nubar) = (0.86 +/- 0.24 +/- 0.11 +/- 0.06)% and B(B --> D* tau- nubar) = (1.62 +/- 0.31 +/- 0.10 +/- 0.05)% (normalized for the B0bar), where the uncertainties are statistical, systematic, and normalization-mode-related.

  20. Computational Pathology

    Science.gov (United States)

    Louis, David N.; Feldman, Michael; Carter, Alexis B.; Dighe, Anand S.; Pfeifer, John D.; Bry, Lynn; Almeida, Jonas S.; Saltz, Joel; Braun, Jonathan; Tomaszewski, John E.; Gilbertson, John R.; Sinard, John H.; Gerber, Georg K.; Galli, Stephen J.; Golden, Jeffrey A.; Becich, Michael J.

    2016-01-01

    Context We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. Objective To define the scope and needs of computational pathology. Data Sources A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. Conclusions The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and non-pathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology. PMID:26098131

  1. 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.

  2. Impact of exacerbations on emphysema progression in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Tanabe, Naoya; Muro, Shigeo; Hirai, Toyohiro; Oguma, Tsuyoshi; Terada, Kunihiko; Marumo, Satoshi; Kinose, Daisuke; Ogawa, Emiko; Hoshino, Yuma; Mishima, Michiaki

    2011-06-15

    Low-attenuation areas assessed by computed tomography reflect the extent of pathological emphysema and correlate with airflow limitation and mortality in patients with chronic obstructive pulmonary disease. The cumulative size distribution of low-attenuation area clusters follows a power law characterized by an exponent, D. The values of D reflect the complexity of the terminal airspace geometry and sensitively detect alveolar structural changes. Exacerbations of chronic obstructive pulmonary disease have a negative impact on lung function and prognosis. However, the impact on emphysema progression remains unclear. We investigated the relationship between exacerbation and emphysema progression assessed by computed tomography in patients with chronic obstructive pulmonary disease. Exacerbations were prospectively recorded for 2 years. Annual changes in computed tomography parameters of emphysema were compared between patients with and without a history of exacerbations. In patients with exacerbations, increases in the percentage of low-attenuation areas and decreases in D were greater than in patients without exacerbations. To interpret these results, we established a novel simulation model and found that not only enlargement of preexisting low-attenuation areas but also coalescence of adjoining low-attenuation areas due to alveolar wall destruction caused emphysema progression in patients with exacerbations. This is the first longitudinal study to demonstrate that exacerbations are involved in emphysema progression in patients with chronic obstructive pulmonary disease. Emphysema progression should be evaluated as part of the outcomes of exacerbations in the management of chronic obstructive pulmonary disease.

  3. Administration of a selective β2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Branca, Caterina; Wisely, Elena V; Hartman, Lauren K; Caccamo, Antonella; Oddo, Salvatore

    2014-12-01

    Currently, there are no available approaches to cure or slow down the progression of Alzheimer's disease (AD), which is characterized by the accumulation of extracellular amyloid-β (Aβ) deposits and intraneuronal tangles that comprised hyperphosphorylated tau. The β2 adrenergic receptors (β2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to AD; however, these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent β-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here, we show that administration of ICI 118,551 (ICI), a selective β2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI increased Aβ levels and Aβ plaque burden. Concomitantly, ICI-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic amyloid precursor protein processing. These results suggest that under the conditions used here, selective pharmacologic inhibition of β2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between β2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of β blockers on AD. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Toward antiviral therapy/prophylaxis for rhinovirus-induced exacerbations of chronic obstructive pulmonary disease : challenges, opportunities, and strategies

    NARCIS (Netherlands)

    Thibaut, Hendrik Jan; Lacroix, Céline; De Palma, Armando M; Franco, David; Decramer, Mark; Neyts, Johan

    Chronic obstructive pulmonary disease (COPD) is a life-threatening lung illness characterized by persistent and progressive airflow limitation. Exacerbations of COPD contribute to the severity of this pathology and accelerate disease progression. To date, pharmacological treatment of both stable

  5. 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.

  6. Searches for Lepton Flavor Violation in the Decays tau+- ---> e+- gamma and tau+- ---> mu+- gamma

    Energy Technology Data Exchange (ETDEWEB)

    Aubert, Bernard; Karyotakis, Y.; Lees, J.P.; Poireau, V.; Prencipe, E.; Prudent, X.; Tisserand, V.; /Annecy, LAPP; Garra Tico, J.; Grauges, E.; /Barcelona U., ECM; Martinelli, M.; Palano, A.; Pappagallo, M.; /INFN, Bari /Bari U.; Eigen, G.; Stugu, B.; Sun, L.; /Bergen U.; Battaglia, M.; Brown, David Nathan; Hooberman, B.; Kerth, L.T.; Kolomensky, Yu.G.; Lynch, G.; /LBL, Berkeley /UC, Berkeley /Birmingham U. /Ruhr U., Bochum /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UC, Riverside /UC, San Diego /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /INFN, Ferrara /Ferrara U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /Frascati /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /Harvard U. /Heidelberg U. /Humboldt U., Berlin /Imperial Coll., London /Iowa U. /Iowa State U. /Johns Hopkins U. /Orsay, LAL /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Louisville U. /Mainz U., Inst. Kernphys. /Manchester U. /Maryland U. /Massachusetts U., Amherst /MIT, LNS; /more authors..

    2010-06-11

    Searches for lepton-flavor-violating decays of a {tau} lepton to a lighter mass lepton and a photon have been performed with the entire dataset of (963 {+-} 7) x 10{sup 6} {tau} decays collected by the BABAR detector near the {Upsilon}(4S), {Upsilon}(3S) and {Upsilon}(2S) resonances. The searches yield no evidence of signals and they set upper limits on the branching fractions of {Beta}({tau}{sup {+-}} {yields} e{sup {+-}}{gamma}) < 3.3 x 10{sup -8} and {Beta}({tau}{sup {+-}} {yields} {mu}{sup {+-}}{gamma}) < 4.4 x 10{sup -8} at 90% confidence level.

  7. Measurement of the tau- --> K- pi0 nu_tau Branching Fraction

    CERN Document Server

    Aubert, B; Boutigny, D; Karyotakis, Yu; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Graugès-Pous, E; López, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes-Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabé, T; Wenzel, W A; Del Amo-Sánchez, P; Hawkes, C M; Watson, A T; Held, T; Koch, H; Pelizaeus, M; Schröder, T; Steinke, M; Walker, D; Asgeirsson, D J; Çuhadar-Dönszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, C; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; De Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro-Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Bequilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Menges, W; Sacco, R; Cowan, G; Flächer, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; Mclachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, Gallieno; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; LoSecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Wong, Q K; Blount, N L; Brau, J E; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; De La Vaissière, C; Hamon, O; Leruste, P; Malcles, J; Ocariz, J; Pérez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Haire, M; Biesiada, J; Elmer, P; Lau, Y P; Lü, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Ricciardi, S; Röthel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hame lde Monchenault, G; Kozanecki, W; Vasseur, G; Yéche, C; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Hrynóva, T; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Lüth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Müller, D R; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Vavra, J; Van Bakel, N; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martínez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2007-01-01

    A measurement of the tau- --> K- pi0 nu_tau branching fraction has been made using 230.2 fb-1 of data recorded by the BABAR detector at the PEP-II e+ e- collider, located at the Stanford Linear Accelerator Center (SLAC), at a center of mass energy sqrt{s} close to 10.58 GeV. We measure BF(tau- --> K- pi0 nu_tau) = (0.416 +/- 0.003 (stat) +/- 0.018 (syst)) %.

  8. Measurements of {mu}{mu} and {tau}{tau} by the VENUS detector

    Energy Technology Data Exchange (ETDEWEB)

    Miura, Makoto [Tsukuba Univ., Ibaraki (Japan). Inst. of Physics

    1995-09-01

    We have studied {mu}- and {tau}-pair production at the center of mass energy 57.77 GeV. The data used in this analysis were collected by the VENUS detector from 1990 to 1993 corresponding to 197.59 pb{sup -1}. The observed cross section and asymmetry for {mu}{mu} are {sigma}{sub {mu}{mu}} = 17.09 {+-} 0.32 {+-} 0.17 {+-} 0.13 (pb), A{sub {mu}{mu}} = -0.2515 {+-} 0.0166 {+-} 0.0087, within the acceptance of |cos{theta}| {<=} 0.75, P{sub {mu}+,{mu}-} {>=} E{sub beam}/2, {theta}{sub acoll.} {<=} 10 degrees, and for {tau}{tau} {sigma}{sub {tau}{tau}} = 17.38 {+-} 0.40 {+-} 0.27 {+-} 0.14 (pb), A{sub {tau}{tau}} = -0.2106 {+-} 0.0167 {+-} 0.0098. within the acceptance of |cos{theta}| {<=} 0.70, E{sub {tau}+,{tau}-} {>=} 2/3E{sub beam}, {theta}{sub acoll.} {<=} 30 degrees. These values are presented independently of both experimental methods and theoretical models. (author)

  9. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy.

    Science.gov (United States)

    Cherry, Jonathan D; Tripodis, Yorghos; Alvarez, Victor E; Huber, Bertrand; Kiernan, Patrick T; Daneshvar, Daniel H; Mez, Jesse; Montenigro, Philip H; Solomon, Todd M; Alosco, Michael L; Stern, Robert A; McKee, Ann C; Stein, Thor D

    2016-10-28

    The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran's Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE.

  10. 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.

  11. Measurement of the Tau Polarisation at LEP

    CERN Document Server

    Heister, A.; Barate, R.; De Bonis, I.; Decamp, D.; Ghez, Philippe; Goy, C.; Lees, J.P.; Merle, E.; Minard, M.N.; Pietrzyk, B.; Alemany, R.; Bravo, S.; Casado, M.P.; Chmeissani, M.; Crespo, J.M.; Fernandez, E.; Fernandez-Bosman, M.; Garrido, L.; Grauges, E.; Martinez, M.; Merino, G.; Miquel, R.; Mir, L.M.; Pacheco, A.; Ruiz, H.; Colaleo, A.; Creanza, D.; de Palma, M.; 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.; Azzurri, P.; Boix, G.; Buchmuller, O.; Cattaneo, M.; Cerutti, F.; Clerbaux, B.; Dissertori, G.; Drevermann, H.; Forty, R.W.; Frank, M.; Greening, T.C.; Hansen, J.B.; Harvey, John; Janot, P.; Jost, B.; Kado, M.; Mato, P.; Moutoussi, A.; Ranjard, F.; Rolandi, Gigi; Schlatter, D.; Schmitt, M.; Schneider, O.; Spagnolo, P.; Tejessy, W.; Teubert, F.; Tournefier, E.; Ward, J.; Wright, A.E.; Ajaltouni, Z.; Badaud, F.; Falvard, A.; Gay, P.; 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.; Waananen, A.; Daskalakis, G.; Kyriakis, A.; Markou, C.; Simopoulou, E.; 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.; Antonelli, A.; Antonelli, M.; Bencivenni, G.; Bologna, G.; Bossi, F.; Campana, P.; Capon, G.; Chiarella, V.; Laurelli, P.; Mannocchi, G.; Murtas, F.; Murtas, G.P.; Passalacqua, L.; Pepe-Altarelli, M.; Halley, A.W.; Lynch, J.G.; Negus, P.; O'Shea, V.; Raine, C.; Thompson, A.S.; Wasserbaech, S.; Cavanaugh, R.; 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.; Marinelli, N.; Sedgbeer, J.K.; Thompson, J.C.; Ghete, V.M.; Girtler, P.; Kneringer, E.; Kuhn, D.; Rudolph, G.; Bouhova-Thacker, E.; Bowdery, C.K.; Finch, A.J.; Foster, F.; Hughes, G.; Jones, R.W.L.; Pearson, M.R.; Robertson, N.A.; Giehl, I.; Jakobs, K.; Kleinknecht, K.; Quast, G.; Renk, B.; Rohne, E.; Sander, H.G.; Wachsmuth, H.; Zeintiz, C.; Bonissent, A.; Carr, J.; Coyle, P.; Leroy, O.; Payre, P.; Rousseau, D.; Talby, M.; Aleppo, M.; Ragusa, F.; David, A.; Dietl, H.; Ganis, G.; Huttmann, K.; Lutjens, G.; Mannert, C.; Manner, W.; Moser, H.G.; Settles, R.; Stenzel, H.; Wiedenmann, W.; Wolf, G.; Boucrot, J.; Callot, O.; Chen, S.; Davier, M.; Duflot, L.; Grivaz, J.F.; Heusse, P.; Jacholkowska, A.; Lefrancois, J.; Nikolic, Irina; Veillet, J.J.; Videau, I.; Yuan, C.; Bagliesi, Giuseppe; Boccali, T.; Calderini, G.; Ciulli, V.; Foa, L.; Giassi, A.; Ligabue, F.; Messineo, A.; Palla, F.; Sanguinetti, G.; Sciaba, A.; Sguazzoni, G.; Tenchini, R.; Venturi, A.; Verdini, P.G.; Blair, G.A.; Cowan, G.; Green, M.G.; Medcalf, T.; Strong, J.A.; Teixeira-Dias, P.; von Wimmersperg-Toeller, J.H.; Clifft, R.W.; Edgecock, T.R.; Norton, P.R.; Tomalin, I.R.; 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.; Konstantinidis, N.; Litke, A.M.; Taylor, G.; Booth, C.N.; Cartwright, S.; Combley, F.; Lehto, M.; Thompson, L.F.; Affholderbach, K.; Boehrer, Armin; Brandt, S.; Grupen, C.; Misiejuk, A.; Ngac, A.; Prange, G.; Sieler, U.; Giannini, G.; Rothberg, J.; Armstrong, S.R.; Cranmer, K.; Elmer, P.; Ferguson, D.P.S.; Gao, Y.; Gonzalez, S.; Hayes, O.J.; Hu, H.; Jin, S.; Kile, J.; McNamara, P.A., III; Nielsen, J.; Orejudos, W.; Pan, Y.B.; Saadi, Y.; Scott, I.J.; Walsh, J.; Wu, Sau Lan; Wu, X.; Zobernig, G.

    2001-01-01

    The polarisation of $\\tau$'s produced in Z decay is measured using 160 pb$^{-1}$ of data accumulated at LEP by the ALEPH detector between 1990 and 1995. The variation of the polarisation with polar angle yields the two parameters ${\\cal A}_e = 0.1504 \\pm 0.0068 $ and ${\\cal A}_{\\tau} = 0.1451 \\pm 0.0059$ which are consistent with the hypothesis of $e$-$\\tau$ universality. Assuming universality, the value ${\\cal A}_{e\\mbox{-}\\tau} = 0.1474 \\pm 0.0045$ is obtained from which the effective weak mixing angle $\\sin^2 {\\theta_{\\mathrm{W}}^{\\mathrm{eff}}} =0.23147 \\pm 0.00057 $ is derived.

  12. Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Carsten Merkwirth

    Full Text Available Fusion and fission of mitochondria maintain the functional integrity of mitochondria and protect against neurodegeneration, but how mitochondrial dysfunctions trigger neuronal loss remains ill-defined. Prohibitins form large ring complexes in the inner membrane that are composed of PHB1 and PHB2 subunits and are thought to function as membrane scaffolds. In Caenorhabditis elegans, prohibitin genes affect aging by moderating fat metabolism and energy production. Knockdown experiments in mammalian cells link the function of prohibitins to membrane fusion, as they were found to stabilize the dynamin-like GTPase OPA1 (optic atrophy 1, which mediates mitochondrial inner membrane fusion and cristae morphogenesis. Mutations in OPA1 are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells, highlighting the importance of OPA1 function in neurons. Here, we show that neuron-specific inactivation of Phb2 in the mouse forebrain causes extensive neurodegeneration associated with behavioral impairments and cognitive deficiencies. We observe early onset tau hyperphosphorylation and filament formation in the hippocampus, demonstrating a direct link between mitochondrial defects and tau pathology. Loss of PHB2 impairs the stability of OPA1, affects mitochondrial ultrastructure, and induces the perinuclear clustering of mitochondria in hippocampal neurons. A destabilization of the mitochondrial genome and respiratory deficiencies manifest in aged neurons only, while the appearance of mitochondrial morphology defects correlates with tau hyperphosphorylation in the absence of PHB2. These results establish an essential role of prohibitin complexes for neuronal survival in vivo and demonstrate that OPA1 stability, mitochondrial fusion, and the maintenance of the mitochondrial genome in neurons depend on these scaffolding proteins. Moreover, our findings establish prohibitin-deficient mice as a novel genetic model for

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

    Science.gov (United States)

    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 (306VQIVYK311) 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.

  14. Physics highlights of a tau charm factory

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez-Romero, E.M. (CIEMAT Investigacion Basica, Div. Fisica de Particulas, Madrid (Spain))

    1993-06-07

    After the very recent proposal from the Spanish Government to build a Tau-Charm Factory, in this talk, I give a fast overview of the characteristics and experimental conditions available in such a laboratory. Some of the more relevant measurements unique to this facility are highlighted for the three main fields of experimentation: Tau physics, Charmed mesons physics and the J/[Psi] and [Psi]' resonances. (orig.)

  15. Toward a Consensus Definition for COPD Exacerbations

    National Research Council Canada - National Science Library

    Roberto Rodriguez-Roisin

    2000-01-01

    .... Exacerbations are associated with a significant increase in mortality, hospitalization, and health-care utilization, but there is currently no widely accepted definition of what constitutes an exacerbation of COPD...

  16. Changes of cerebrospinal fluid Aβ42, t-tau, and p-tau in Parkinson's disease patients with cognitive impairment relative to those with normal cognition: a meta-analysis.

    Science.gov (United States)

    Hu, Xiaohui; Yang, Yan; Gong, Daokai

    2017-11-01

    The cerebrospinal fluid (CSF) signature of reduced amyloid beta 1-42 (Aβ42), elevated total tau (t-tau), and phosphorylated tau181 (p-tau) is important for the early diagnosis of Alzheimer's disease (AD). Aβ42, t-tau, and p-tau have been reported in numerous studies to contribute to predicting cognitive impairment in Parkinson's disease (PDCI). However, no consistent conclusion can be drawn so far. Literatures regarding Aβ42, t-tau, and p-tau in CSF were systematically reviewed, and a meta-analysis was thus performed to evaluate the changes of these biomarkers in PDCI patients, including PD with mild cognitive impairment (PDMCI) and PD dementia (PDD) patients, relative to PD with normal cognition (PDNC) patients. Databases of "PubMed," "EBSCO," and "Springer" were retrieved for articles concerning Aβ42, t-tau, and p-tau in PDCI patients relative to those in PDNC patients published from January 1, 2000 to February 1, 2017. The following keywords were set, namely, "dementia" or "cognitive impairment" or "mild cognitive impairment" and "cerebrospinal fluid" and "Parkinson*." Sixteen articles comprising 590 PDCI patients and 1182 PDNC patients were included. The results showed that CSF Aβ42 level in PDCI cohort was lower than that in PDNC cohort (pooled Std.MD = -0.44, 95% CI [-0.61, -0.26], p < 0.00001). Reduced Aβ42 (pooled Std.MD = -0.60, 95% CI [-0.75, -0.45], p < 0.00001) as well as elevated t-tau (pooled Std.MD = 0.21, 95% CI [0.06, 0.35], p = 0.006) and p-tau (pooled Std.MD = 0.36, 95% CI [0.02, 0.69], p = 0.04) could be observed in PDD cohort compared with PDNC cohort. Therefore, amyloid pathology and tauopathy may participate in the development of PDD, which is similar to AD.

  17. Ginsenoside Rd attenuates beta-amyloid-induced tau phosphorylation by altering the functional balance of glycogen synthase kinase 3beta and protein phosphatase 2A.

    Science.gov (United States)

    Li, Ling; Liu, Zhirong; Liu, Juanfang; Tai, Xuhui; Hu, Xinghua; Liu, Xuedong; Wu, Zhongliang; Zhang, Guangyun; Shi, Ming; Zhao, Gang

    2013-06-01

    Neurofibrillary tangles are aggregates of hyperphosphorylated tau that are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by a balance of kinase and phosphatase activities. Our previous study has demonstrated that ginsenoside Rd, one of the principal active ingredients of Pana notoginseng, inhibits okadaic acid-induced tau phosphorylation in vivo and in vitro, but the underlying mechanism(s) is unknown. In this study, we showed that ginsenoside Rd pretreatment inhibited tau phosphorylation at multiple sites in beta-amyloid (Aβ)-treated cultured cortical neurons, and in vivo in both a rat and transgenic mouse model. Ginsenoside Rd not only reduced Aβ-induced increased expression of glycogen synthase kinase 3beta (GSK-3β), the most important kinase involved in tau phosphorylation, but also inhibited its activity by enhancing and attenuating its phosphorylation at Ser9 and Tyr216, respectively. Moreover, ginsenoside Rd enhanced the activity of protein phosphatase 2A (PP-2A), a key phosphatase involved in tau dephosphorylation. Finally, an in vitro biochemical assay revealed that ginsenoside Rd directly affected GSK-3β and PP-2A activities. Thus, our findings provide the first evidence that ginsenoside Rd attenuates Aβ-induced pathological tau phosphorylation by altering the functional balance of GSK-3β and PP-2A. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. The impact of tau hyperphosphorylation at Ser262 on memory and learning after global brain ischaemia in a rat model of reversible cardiac arrest

    Directory of Open Access Journals (Sweden)

    Shohreh Majd

    2017-06-01

    Full Text Available An increase in phosphorylated tau (p-tau is associated with Alzheimer's disease (AD, and brain hypoxia. Investigation of the association of residue-specific tau hyperphosphorylation and changes in cognition, leads to greater understanding of its potential role in the pathology of memory impairment. The aims of this study are to investigate the involvement of the main metabolic kinases, Liver Kinase B1 (LKB1 and Adenosine Monophosphate Kinase Protein Kinase (AMPK, in tau phosphorylation-derived memory impairment, and to study the potential contribution of the other tau kinases and phosphatases including Glycogen Synthase Kinase (GSK-3β, Protein kinase A (PKA and Protein Phosphatase 2A (PP2A. Spatial memory and learning were tested in a rat global brain ischemic model of reversible cardiac arrest (CA. The phosphorylation levels of LKB1, AMPK, GSK-3β, PP2A, PKA and tau-specific phosphorylation were assessed in rats, subjected to ischaemia/reperfusion and in clinically diagnosed AD and normal human brains. LKB1 and AMPK phosphorylation increased 4 weeks after CA as did AMPK related p-tau (Ser262. The animals showed unchanged levels of GSK-3β specific p-tau (Ser202/Thr205, phospho-PP2A (Tyr307, total GSK-3β, PP2A, phospho-cAMP response element-binding protein (CREB which is an indicator of PKA activity, and no memory deficits. AD brains had hyperphosphorylated tau in all the residues of Ser262, Ser202 and Thr205, with increased phosphorylation of both AMPK (Thr172 and GSK-3β (Ser9, and reduced PP2A levels. Our data suggests a crucial role for a combined activation of tau kinases and phosphatases in adversely affecting memory and that hyperphosphorylation of tau in more than one specific site may be required to create memory deficits.

  19. Amyloid β-Exposed Human Astrocytes Overproduce Phospho-Tau and Overrelease It within Exosomes, Effects Suppressed by Calcilytic NPS 2143—Further Implications for Alzheimer's Therapy

    Directory of Open Access Journals (Sweden)

    Anna Chiarini

    2017-04-01

    Full Text Available The two main drivers of Alzheimer's disease (AD, amyloid-β (Aβ and hyperphosphorylated Tau (p-Tau oligomers, cooperatively accelerate AD progression, but a hot debate is still ongoing about which of the two appears first. Here we present preliminary evidence showing that Tau and p-Tau are expressed by untransformed cortical adult human astrocytes in culture and that exposure of such cells to an Aβ42 proxy, Aβ25−35, which binds the calcium-sensing receptor (CaSR and activates its signaling, significantly increases intracellular p-Tau levels, an effect CaSR antagonist (calcilytic NPS 2143 wholly hinders. The astrocytes also release both Tau and p-Tau by means of exosomes into the extracellular medium, an activity that could mediate p-Tau diffusion within the brain. Preliminary data also indicate that exosomal levels of p-Tau increase after Aβ25−35 exposure, but remain unchanged in cells pre-treated for 30-min with NPS 2143 before adding Aβ25−35. Thus, our previous and present findings raise the unifying prospect that Aβ•CaSR signaling plays a crucial role in AD development and progression by simultaneously activating (i the amyloidogenic processing of amyloid precursor holoprotein, whose upshot is a surplus production and secretion of Aβ42 oligomers, and (ii the GSK-3β-mediated increased production of p-Tau oligomers which are next released extracellularly inside exosomes. Therefore, as calcilytics suppress both effects on Aβ42 and p-Tau metabolic handling, these highly selective antagonists of pathological Aβ•CaSR signaling would effectively halt AD's progressive spread preserving patients' cognition and life quality.

  20. Simulated cytoskeletal collapse via tau degradation.

    Directory of Open Access Journals (Sweden)

    Austin Sendek

    Full Text Available We present a coarse-grained two dimensional mechanical model for the microtubule-tau bundles in neuronal axons in which we remove taus, as can happen in various neurodegenerative conditions such as Alzheimers disease, tauopathies, and chronic traumatic encephalopathy. Our simplified model includes (i taus modeled as entropic springs between microtubules, (ii removal of taus from the bundles due to phosphorylation, and (iii a possible depletion force between microtubules due to these dissociated phosphorylated taus. We equilibrate upon tau removal using steepest descent relaxation. In the absence of the depletion force, the transverse rigidity to radial compression of the bundles falls to zero at about 60% tau occupancy, in agreement with standard percolation theory results. However, with the attractive depletion force, spring removal leads to a first order collapse of the bundles over a wide range of tau occupancies for physiologically realizable conditions. While our simplest calculations assume a constant concentration of microtubule intercalants to mediate the depletion force, including a dependence that is linear in the detached taus yields the same collapse. Applying percolation theory to removal of taus at microtubule tips, which are likely to be the protective sites against dynamic instability, we argue that the microtubule instability can only obtain at low tau occupancy, from 0.06-0.30 depending upon the tau coordination at the microtubule tips. Hence, the collapse we discover is likely to be more robust over a wide range of tau occupancies than the dynamic instability. We suggest in vitro tests of our predicted collapse.

  1. Aged chimpanzees exhibit pathologic hallmarks of Alzheimer's disease.

    Science.gov (United States)

    Edler, Melissa K; Sherwood, Chet C; Meindl, Richard S; Hopkins, William D; Ely, John J; Erwin, Joseph M; Mufson, Elliott J; Hof, Patrick R; Raghanti, Mary Ann

    2017-11-01

    Alzheimer's disease (AD) is a uniquely human brain disorder characterized by the accumulation of amyloid-beta protein (Aβ) into extracellular plaques, neurofibrillary tangles (NFT) made from intracellular, abnormally phosphorylated tau, and selective neuronal loss. We analyzed a large group of aged chimpanzees (n = 20, age 37-62 years) for evidence of Aβ and tau lesions in brain regions affected by AD in humans. Aβ was observed in plaques and blood vessels, and tau lesions were found in the form of pretangles, NFT, and tau-immunoreactive neuritic clusters. Aβ deposition was higher in vessels than in plaques and correlated with increases in tau lesions, suggesting that amyloid build-up in the brain's microvasculature precedes plaque formation in chimpanzees. Age was correlated to greater volumes of Aβ plaques and vessels. Tangle pathology was observed in individuals that exhibited plaques and moderate or severe cerebral amyloid angiopathy, a condition in which amyloid accumulates in the brain's vasculature. Amyloid and tau pathology in aged chimpanzees suggests these AD lesions are not specific to the human brain. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Measurement of the $Z \\to \\tau\\tau$ Cross Section with the ATLAS Detector

    CERN Document Server

    Aad, Georges; Abdallah, Jalal; Abdelalim, Ahmed Ali; Abdesselam, Abdelouahab; Abdinov, Ovsat; Abi, Babak; Abolins, Maris; Abramowicz, Halina; Abreu, Henso; Acerbi, Emilio; Acharya, Bobby Samir; Adams, David; Addy, Tetteh; Adelman, Jahred; Aderholz, Michael; Adomeit, Stefanie; Adragna, Paolo; Adye, Tim; Aefsky, Scott; Aguilar-Saavedra, Juan Antonio; Aharrouche, Mohamed; Ahlen, Steven; Ahles, Florian; Ahmad, Ashfaq; Ahsan, Mahsana; Aielli, Giulio; Akdogan, Taylan; Akesson, Torsten Paul; Akimoto, Ginga; Akimov, Andrei; Akiyama, Kunihiro; Alam, Mohammad; Alam, Muhammad Aftab; Albert, Justin; Albrand, Solveig; Aleksa, Martin; Aleksandrov, Igor; Alessandria, Franco; Alexa, Calin; Alexander, Gideon; Alexandre, Gauthier; Alexopoulos, Theodoros; Alhroob, Muhammad; Aliev, Malik; Alimonti, Gianluca; Alison, John; Aliyev, Magsud; Allport, Phillip; Allwood-Spiers, Sarah; Almond, John; Aloisio, Alberto; Alon, Raz; Alonso, Alejandro; Alviggi, Mariagrazia; Amako, Katsuya; Amaral, Pedro; Amelung, Christoph; Ammosov, Vladimir; Amorim, Antonio; Amoros, Gabriel; Amram, Nir; Anastopoulos, Christos; Andari, Nansi; Andeen, Timothy; Anders, Christoph Falk; Anderson, Kelby; Andreazza, Attilio; Andrei, George Victor; Andrieux, Marie-Laure; Anduaga, Xabier; Angerami, Aaron; Anghinolfi, Francis; Anjos, Nuno; Annovi, Alberto; Antonaki, Ariadni; Antonelli, Mario; Antonov, Alexey; Antos, Jaroslav; Anulli, Fabio; Aoun, Sahar; Aperio Bella, Ludovica; Apolle, Rudi; Arabidze, Giorgi; Aracena, Ignacio; Arai, Yasuo; Arce, Ayana; Archambault, John-Paul; Arfaoui, Samir; Arguin, Jean-Francois; Arik, Engin; Arik, Metin; Armbruster, Aaron James; Arnaez, Olivier; Arnault, Christian; Artamonov, Andrei; Artoni, Giacomo; Arutinov, David; Asai, Shoji; Asfandiyarov, Ruslan; Ask, Stefan; Asman, Barbro; Asquith, Lily; Assamagan, Ketevi; Astbury, Alan; Astvatsatourov, Anatoli; Atoian, Grigor; Aubert, Bernard; Auerbach, Benjamin; Auge, Etienne; Augsten, Kamil; Aurousseau, Mathieu; Austin, Nicholas; Avolio, Giuseppe; Avramidou, Rachel Maria; Axen, David; Ay, Cano; Azuelos, Georges; Azuma, Yuya; Baak, Max; Baccaglioni, Giuseppe; Bacci, Cesare; Bach, Andre; Bachacou, Henri; Bachas, Konstantinos; Bachy, Gerard; Backes, Moritz; Backhaus, Malte; Badescu, Elisabeta; Bagnaia, Paolo; Bahinipati, Seema; Bai, Yu; Bailey, David; Bain, Travis; Baines, John; Baker, Oliver Keith; Baker, Mark; Baker, Sarah; Baltasar Dos Santos Pedrosa, Fernando; Banas, Elzbieta; Banerjee, Piyali; Banerjee, Swagato; Banfi, Danilo; Bangert, Andrea Michelle; Bansal, Vikas; Bansil, Hardeep Singh; Barak, Liron; Baranov, Sergei; Barashkou, Andrei; Galtieri, Angela Barbaro; Barber, Tom; Barberio, Elisabetta Luigia; Barberis, Dario; Barbero, Marlon; Bardin, Dmitri; Barillari, Teresa; Barisonzi, Marcello; Barklow, Timothy; Barlow, Nick; Barnett, Bruce; Barnett, Michael; Baroncelli, Antonio; Barone, Gaetano; Barr, Alan; Barreiro, Fernando; Barreiro Guimaraes da Costa, Joao; Barrillon, Pierre; Bartoldus, Rainer; Barton, Adam Edward; Bartsch, Detlef; Bartsch, Valeria; Bates, Richard; Batkova, Lucia; Batley, Richard; Battaglia, Andreas; Battistin, Michele; Battistoni, Giuseppe; Bauer, Florian; Bawa, Harinder Singh; Beare, Brian; Beau, Tristan; Beauchemin, Pierre-Hugues; Beccherle, Roberto; Bechtle, Philip; Beck, Hans Peter; Beckingham, Matthew; Becks, Karl-Heinz; Beddall, Andrew; Beddall, Ayda; Bedikian, Sourpouhi; Bednyakov, Vadim; Bee, Christopher; Begel, Michael; Behar Harpaz, Silvia; Behera, Prafulla; Beimforde, Michael; Belanger-Champagne, Camille; Bell, Paul; Bell, William; Bella, Gideon; Bellagamba, Lorenzo; Bellina, Francesco; Bellomo, Massimiliano; Belloni, Alberto; Beloborodova, Olga; Belotskiy, Konstantin; Beltramello, Olga; Ben Ami, Sagi; Benary, Odette; Benchekroun, Driss; Benchouk, Chafik; Bendel, Markus; Benedict, Brian Hugues; Benekos, Nektarios; Benhammou, Yan; Benjamin, Douglas; Benoit, Mathieu; Bensinger, James; Benslama, Kamal; Bentvelsen, Stan; Berge, David; Bergeaas Kuutmann, Elin; Berger, Nicolas; Berghaus, Frank; Berglund, Elina; Beringer, Jurg; Bernardet, Karim; Bernat, Pauline; Bernhard, Ralf; Bernius, Catrin; Berry, Tracey; Bertin, Antonio; Bertinelli, Francesco; Bertolucci, Federico; Besana, Maria Ilaria; Besson, Nathalie; Bethke, Siegfried; Bhimji, Wahid; Bianchi, Riccardo-Maria; Bianco, Michele; Biebel, Otmar; Bieniek, Stephen Paul; Biesiada, Jed; Biglietti, Michela; Bilokon, Halina; Bindi, Marcello; Binet, Sebastien; Bingul, Ahmet; Bini, Cesare; Biscarat, Catherine; Bitenc, Urban; Black, Kevin; Blair, Robert; Blanchard, Jean-Baptiste; Blanchot, Georges; Blazek, Tomas; Blocker, Craig; Blocki, Jacek; Blondel, Alain; Blum, Walter; Blumenschein, Ulrike; Bobbink, Gerjan; Bobrovnikov, Victor; Bocchetta, Simona Serena; Bocci, Andrea; Boddy, Christopher Richard; Boehler, Michael; Boek, Jennifer; Boelaert, Nele; Boser, Sebastian; Bogaerts, Joannes Andreas; Bogdanchikov, Alexander; Bogouch, Andrei; Bohm, Christian; Boisvert, Veronique; Bold, Tomasz; Boldea, Venera; Bolnet, Nayanka Myriam; Bona, Marcella; Bondarenko, Valery; Boonekamp, Maarten; Boorman, Gary; Booth, Chris; Bordoni, Stefania; Borer, Claudia; Borisov, Anatoly; Borissov, Guennadi; Borjanovic, Iris; Borroni, Sara; Bos, Kors; Boscherini, Davide; Bosman, Martine; Boterenbrood, Hendrik; Botterill, David; Bouchami, Jihene; Boudreau, Joseph; Bouhova-Thacker, Evelina Vassileva; Boulahouache, Chaouki; Bourdarios, Claire; Bousson, Nicolas; Boveia, Antonio; Boyd, James; Boyko, Igor; Bozhko, Nikolay; Bozovic-Jelisavcic, Ivanka; Bracinik, Juraj; Braem, Andre; Branchini, Paolo; Brandenburg, George; Brandt, Andrew; Brandt, Gerhard; Brandt, Oleg; Bratzler, Uwe; Brau, Benjamin; Brau, James; Braun, Helmut; Brelier, Bertrand; Bremer, Johan; Brenner, Richard; Bressler, Shikma; Breton, Dominique; Britton, Dave; Brochu, Frederic; Brock, Ian; Brock, Raymond; Brodbeck, Timothy; Brodet, Eyal; Broggi, Francesco; Bromberg, Carl; Brooijmans, Gustaaf; Brooks, William; Brown, Gareth; Brown, Heather; Bruckman de Renstrom, Pawel; Bruncko, Dusan; Bruneliere, Renaud; Brunet, Sylvie; Bruni, Alessia; Bruni, Graziano; Bruschi, Marco; Buanes, Trygve; Bucci, Francesca; Buchanan, James; Buchanan, Norman; Buchholz, Peter; Buckingham, Ryan; Buckley, Andrew; Buda, Stelian Ioan; Budagov, Ioulian; Budick, Burton; Buscher, Volker; Bugge, Lars; Buira-Clark, Daniel; Bulekov, Oleg; Bunse, Moritz; Buran, Torleiv; Burckhart, Helfried; Burdin, Sergey; Burgess, Thomas; Burke, Stephen; Busato, Emmanuel; Bussey, Peter; Buszello, Claus-Peter; Butin, Francois; Butler, Bart; Butler, John; Buttar, Craig; Butterworth, Jonathan; Buttinger, William; Byatt, Tom; Cabrera Urban, Susana; Caforio, Davide; Cakir, Orhan; Calafiura, Paolo; Calderini, Giovanni; Calfayan, Philippe; Calkins, Robert; Caloba, Luiz; Caloi, Rita; Calvet, David; Calvet, Samuel; Camacho Toro, Reina; Camarri, Paolo; Cambiaghi, Mario; Cameron, David; Campana, Simone; Campanelli, Mario; Canale, Vincenzo; Canelli, Florencia; Canepa, Anadi; Cantero, Josu; Capasso, Luciano; Garrido, Maria Del Mar Capeans; Caprini, Irinel; Caprini, Mihai; Capriotti, Daniele; Capua, Marcella; Caputo, Regina; Caramarcu, Costin; Cardarelli, Roberto; Carli, Tancredi; Carlino, Gianpaolo; Carminati, Leonardo; Caron, Bryan; Caron, Sascha; Montoya, German D.Carrillo; Carter, Antony; Carter, Janet; Carvalho, Joao; Casadei, Diego; Casado, Maria Pilar; Cascella, Michele; Caso, Carlo; Castaneda Hernandez, Alfredo Martin; Castaneda-Miranda, Elizabeth; Castillo Gimenez, Victoria; Castro, Nuno Filipe; Cataldi, Gabriella; Cataneo, Fernando; Catinaccio, Andrea; Catmore, James; Cattai, Ariella; Cattani, Giordano; Caughron, Seth; Cauz, Diego; Cavalleri, Pietro; Cavalli, Donatella; Cavalli-Sforza, Matteo; Cavasinni, Vincenzo; Ceradini, Filippo; Santiago Cerqueira, Augusto; Cerri, Alessandro; Cerrito, Lucio; Cerutti, Fabio; Cetin, Serkant Ali; Cevenini, Francesco; Chafaq, Aziz; Chakraborty, Dhiman; Chan, Kevin; Chapleau, Bertrand; Chapman, John Derek; Chapman, John Wehrley; Chareyre, Eve; Charlton, Dave; Chavda, Vikash; Chavez Barajas, Carlos Alberto; Cheatham, Susan; Chekanov, Sergei; Chekulaev, Sergey; Chelkov, Gueorgui; Chelstowska, Magda Anna; Chen, Chunhui; Chen, Hucheng; Chen, Shenjian; Chen, Tingyang; Chen, Xin; Cheng, Shaochen; Cheplakov, Alexander; Chepurnov, Vladimir; Cherkaoui El Moursli, Rajaa; Chernyatin, Valeriy; Cheu, Elliott; Cheung, Sing-Leung; Chevalier, Laurent; Chiefari, Giovanni; Chikovani, Leila; Childers, John Taylor; Chilingarov, Alexandre; Chiodini, Gabriele; Chizhov, Mihail; Choudalakis, Georgios; Chouridou, Sofia; Christidi, Illectra-Athanasia; Christov, Asen; Chromek-Burckhart, Doris; Chu, Ming-Lee; Chudoba, Jiri; Ciapetti, Guido; Ciba, Krzysztof; Ciftci, Abbas Kenan; Ciftci, Rena; Cinca, Diane; Cindro, Vladimir; Ciobotaru, Matei Dan; Ciocca, Claudia; Ciocio, Alessandra; Cirilli, Manuela; Ciubancan, Mihai; Clark, Allan G.; Clark, Philip James; Cleland, Bill; Clemens, Jean-Claude; Clement, Benoit; Clement, Christophe; Clifft, Roger; Coadou, Yann; Cobal, Marina; Coccaro, Andrea; Cochran, James H.; Coe, Paul; Cogan, Joshua Godfrey; Coggeshall, James; Cogneras, Eric; Cojocaru, Claudiu; Colas, Jacques; Colijn, Auke-Pieter; Collard, Caroline; Collins, Neil; Collins-Tooth, Christopher; Collot, Johann; Colon, German; Conde Muino, Patricia; Coniavitis, Elias; Conidi, Maria Chiara; Consonni, Michele; Consonni, Sofia Maria; Consorti, Valerio; Constantinescu, Serban; Conta, Claudio; Conventi, Francesco; Cook, James; Cooke, Mark; Cooper, Ben; Cooper-Sarkar, Amanda; Cooper-Smith, Neil; Copic, Katherine; Cornelissen, Thijs; Corradi, Massimo; Corriveau, Francois; Cortes-Gonzalez, Arely; Cortiana, Giorgio; Costa, Giuseppe; Costa, Maria Jose; Costanzo, Davide; Costin, Tudor; Cote, David; Coura Torres, Rodrigo; Courneyea, Lorraine; Cowan, Glen; Cowden, Christopher; Cox, Brian; Cranmer, Kyle; Crescioli, Francesco; Cristinziani, Markus; Crosetti, Giovanni; Crupi, Roberto; Crepe-Renaudin, Sabine; Cuciuc, Constantin-Mihai; Cuenca Almenar, Cristobal; Donszelmann, Tulay Cuhadar; Curatolo, Maria; Curtis, Chris; Cwetanski, Peter; Czirr, Hendrik; Czyczula, Zofia; D'Auria, Saverio; D'Onofrio, Monica; D'Orazio, Alessia; Da Silva, Paulo Vitor; Da Via, Cinzia; Dabrowski, Wladyslaw; Dai, Tiesheng; Dallapiccola, Carlo; Dam, Mogens; Dameri, Mauro; Damiani, Daniel; Danielsson, Hans Olof; Dannheim, Dominik; Dao, Valerio; Darbo, Giovanni; Darlea, Georgiana Lavinia; Daum, Cornelis; Dauvergne, Jean-Pierre; Davey, Will; Davidek, Tomas; Davidson, Nadia; Davidson, Ruth; Davies, Eleanor; Davies, Merlin; Davison, Adam; Davygora, Yuriy; Dawe, Edmund; Dawson, Ian; Dawson, John; Daya, Rozmin; De, Kaushik; De Asmundis, Riccardo; De Castro, Stefano; De Castro Faria Salgado, Pedro; De Cecco, Sandro; de Graat, Julien; De Groot, Nicolo; de Jong, Paul; de la Taille, Christophe; de la Torre, Hector; De Lotto, Barbara; De Mora, Lee; De Nooij, Lucie; De Oliveira Branco, Miguel; De Pedis, Daniele; De Salvo, Alessandro; De Sanctis, Umberto; De Santo, Antonella; de Vivie De Regie, Jean-Baptiste; Dean, Simon; Dedovich, Dmitri; Degenhardt, James; Dehchar, Mohamed; del Papa, Carlo; del Peso, Jose; del Prete, Tarcisio; Deliyergiyev, Maksym; Dell'Acqua, Andrea; Dell'Asta, Lidia; Della Pietra, Massimo; della Volpe, Domenico; Delmastro, Marco; Delpierre, Pierre; Delruelle, Nicolas; Delsart, Pierre-Antoine; Deluca, Carolina; Demers, Sarah; Demichev, Mikhail; Demirkoz, Bilge; Deng, Jianrong; Denisov, Sergey; Derendarz, Dominik; Derkaoui, Jamal Eddine; Derue, Frederic; Dervan, Paul; Desch, Klaus Kurt; Devetak, Erik; Deviveiros, Pier-Olivier; Dewhurst, Alastair; DeWilde, Burton; Dhaliwal, Saminder; Dhullipudi, Ramasudhakar; Di Ciaccio, Anna; Di Ciaccio, Lucia; Di Girolamo, Alessandro; Di Girolamo, Beniamino; Di Luise, Silvestro; Di Mattia, Alessandro; Di Micco, Biagio; Di Nardo, Roberto; Di Simone, Andrea; Di Sipio, Riccardo; Diaz, Marco Aurelio; Diblen, Faruk; Diehl, Edward; Dietrich, Janet; Dietzsch, Thorsten; Diglio, Sara; Yagci, Kamile Dindar; Dingfelder, Jochen; Dionisi, Carlo; Dita, Petre; Dita, Sanda; Dittus, Fridolin; Djama, Fares; Djobava, Tamar; Barros do Vale, Maria Aline; Do Valle Wemans, Andre; Doan, Thi Kieu Oanh; Dobbs, Matt; Dobinson, Robert; Dobos, Daniel; Dobson, Ellie; Dobson, Marc; Dodd, Jeremy; Doglioni, Caterina; Doherty, Tom; Doi, Yoshikuni; Dolejsi, Jiri; Dolenc, Irena; Dolezal, Zdenek; Dolgoshein, Boris; Dohmae, Takeshi; Donadelli, Marisilvia; Donega, Mauro; Donini, Julien; Dopke, Jens; Doria, Alessandra; dos Anjos, Andre; Dosil, Mireia; Dotti, Andrea; Dova, Maria-Teresa; Dowell, John; Doxiadis, Alexander; Doyle, Tony; Drasal, Zbynek; Drees, Jurgen; Dressnandt, Nandor; Drevermann, Hans; Driouichi, Chafik; Dris, Manolis; Dubbert, Jorg; Dubbs, Tim; Dube, Sourabh; Duchovni, Ehud; Duckeck, Guenter; Dudarev, Alexey; Dudziak, Fanny; Duhrssen, Michael; Duerdoth, Ian; Duflot, Laurent; Dufour, Marc-Andre; Dunford, Monica; Duran Yildiz, Hatice; Duxfield, Robert; Dwuznik, Michal; Dydak, Friedrich; Dzahini, Daniel; Duren, Michael; Ebenstein, William; Ebke, Johannes; Eckert, Simon; Eckweiler, Sebastian; Edmonds, Keith; Edwards, Clive; Edwards, Nicholas Charles; Ehrenfeld, Wolfgang; Ehrich, Thies; Eifert, Till; Eigen, Gerald; Einsweiler, Kevin; Eisenhandler, Eric; Ekelof, Tord; El Kacimi, Mohamed; Ellert, Mattias; Elles, Sabine; Ellinghaus, Frank; Ellis, Katherine; Ellis, Nicolas; Elmsheuser, Johannes; Elsing, Markus; Ely, Robert; Emeliyanov, Dmitry; Engelmann, Roderich; Engl, Albert; Epp, Brigitte; Eppig, Andrew; Erdmann, Johannes; Ereditato, Antonio; Eriksson, Daniel; Ernst, Jesse; Ernst, Michael; Ernwein, Jean; Errede, Deborah; Errede, Steven; Ertel, Eugen; Escalier, Marc; Escobar, Carlos; Espinal Curull, Xavier; Esposito, Bellisario; Etienne, Francois; Etienvre, Anne-Isabelle; Etzion, Erez; Evangelakou, Despoina; Evans, Hal; Fabbri, Laura; Fabre, Caroline; Fakhrutdinov, Rinat; Falciano, Speranza; Fang, Yaquan; Fanti, Marcello; Farbin, Amir; Farilla, Addolorata; Farley, Jason; Farooque, Trisha; Farrington, Sinead; Farthouat, Philippe; Fassnacht, Patrick; Fassouliotis, Dimitrios; Fatholahzadeh, Baharak; Favareto, Andrea; Fayard, Louis; Fazio, Salvatore; Febbraro, Renato; Federic, Pavol; Fedin, Oleg; Fedorko, Woiciech; Fehling-Kaschek, Mirjam; Feligioni, Lorenzo; Fellmann, Denis; Felzmann, Ulrich; Feng, Cunfeng; Feng, Eric; Fenyuk, Alexander; Ferencei, Jozef; Ferland, Jonathan; Fernando, Waruna; Ferrag, Samir; Ferrando, James; Ferrara, Valentina; Ferrari, Arnaud; Ferrari, Pamela; Ferrari, Roberto; Ferrer, Antonio; Ferrer, Maria Lorenza; Ferrere, Didier; Ferretti, Claudio; Ferretto Parodi, Andrea; Fiascaris, Maria; Fiedler, Frank; Filipcic, Andrej; Filippas, Anastasios; Filthaut, Frank; Fincke-Keeler, Margret; Fiolhais, Miguel; Fiorini, Luca; Firan, Ana; Fischer, Gordon; Fischer, Peter; Fisher, Matthew; Fisher, Steve; Flechl, Martin; Fleck, Ivor; Fleckner, Johanna; Fleischmann, Philipp; Fleischmann, Sebastian; Flick, Tobias; Flores Castillo, Luis; Flowerdew, Michael; Fohlisch, Florian; Fokitis, Manolis; Fonseca Martin, Teresa; Forbush, David Alan; Formica, Andrea; Forti, Alessandra; Fortin, Dominique; Foster, Joe; Fournier, Daniel; Foussat, Arnaud; Fowler, Andrew; Fowler, Ken; Fox, Harald; Francavilla, Paolo; Franchino, Silvia; Francis, David; Frank, Tal; Franklin, Melissa; Franz, Sebastien; Fraternali, Marco; Fratina, Sasa; French, Sky; Froeschl, Robert; Froidevaux, Daniel; Frost, James; Fukunaga, Chikara; Fullana Torregrosa, Esteban; Fuster, Juan; Gabaldon, Carolina; Gabizon, Ofir; Gadfort, Thomas; Gadomski, Szymon; Gagliardi, Guido; Gagnon, Pauline; Galea, Cristina; Gallas, Elizabeth; Gallas, Manuel; Gallo, Valentina Santina; Gallop, Bruce; Gallus, Petr; Galyaev, Eugene; Gan, K.K.; Gao, Yongsheng; Gapienko, Vladimir; Gaponenko, Andrei; Garberson, Ford; Garcia-Sciveres, Maurice; Garcia, Carmen; Garcia Navarro, Jose Enrique; Gardner, Robert; Garelli, Nicoletta; Garitaonandia, Hegoi; Garonne, Vincent; Garvey, John; Gatti, Claudio; Gaudio, Gabriella; Gaumer, Olivier; Gaur, Bakul; Gauthier, Lea; Gavrilenko, Igor; Gay, Colin; Gaycken, Goetz; Gayde, Jean-Christophe; Gazis, Evangelos; Ge, Peng; Gee, Norman; Geerts, Daniel Alphonsus Adrianus; Geich-Gimbel, Christoph; Gellerstedt, Karl; Gemme, Claudia; Gemmell, Alistair; Genest, Marie-Helene; Gentile, Simonetta; George, Matthias; George, Simon; Gerlach, Peter; Gershon, Avi; Geweniger, Christoph; Ghazlane, Hamid; Ghez, Philippe; Ghodbane, Nabil; Giacobbe, Benedetto; Giagu, Stefano; Giakoumopoulou, Victoria; Giangiobbe, Vincent; Gianotti, Fabiola; Gibbard, Bruce; Gibson, Adam; Gibson, Stephen; Gilbert, Laura; Gilchriese, Murdock; Gilewsky, Valentin; Gillberg, Dag; Gillman, Tony; Gingrich, Douglas; Ginzburg, Jonatan; Giokaris, Nikos; Giordano, Raffaele; Giorgi, Francesco Michelangelo; Giovannini, Paola; Giraud, Pierre-Francois; Giugni, Danilo; Giunta, Michele; Giusti, Paolo; Gjelsten, Borge Kile; Gladilin, Leonid; Glasman, Claudia; Glatzer, Julian; Glazov, Alexandre; Glitza, Karl-Walter; Glonti, George; Godfrey, Jennifer; Godlewski, Jan; Goebel, Martin; Gopfert, Thomas; Goeringer, Christian; Gossling, Claus; Gottfert, Tobias; Goldfarb, Steven; Goldin, Daniel; Golling, Tobias; Golovnia, Serguei; Gomes, Agostinho; Gomez Fajardo, Luz Stella; Goncalo, Ricardo; Goncalves Pinto Firmino Da Costa, Joao; Gonella, Laura; Gonidec, Allain; Gonzalez, Saul; Gonzalez de la Hoz, Santiago; Gonzalez Silva, Laura; Gonzalez-Sevilla, Sergio; Goodson, Jeremiah Jet; Goossens, Luc; Gorbounov, Petr Andreevich; Gordon, Howard; Gorelov, Igor; Gorfine, Grant; Gorini, Benedetto; Gorini, Edoardo; Gorisek, Andrej; Gornicki, Edward; Gorokhov, Serguei; Goryachev, Vladimir; Gosdzik, Bjoern; Gosselink, Martijn; Gostkin, Mikhail Ivanovitch; Gouanere, Michel; Gough Eschrich, Ivo; Gouighri, Mohamed; Goujdami, Driss; Goulette, Marc Phillippe; Goussiou, Anna; Goy, Corinne; Grabowska-Bold, Iwona; Grabski, Varlen; Grafstrom, Per; Grah, Christian; Grahn, Karl-Johan; Grancagnolo, Francesco; Grancagnolo, Sergio; Grassi, Valerio; Gratchev, Vadim; Grau, Nathan; Gray, Heather; Gray, Julia Ann; Graziani, Enrico; Grebenyuk, Oleg; Greenfield, Debbie; Greenshaw, Timothy; Greenwood, Zeno Dixon; Gregor, Ingrid-Maria; Grenier, Philippe; Griffiths, Justin; Grigalashvili, Nugzar; Grillo, Alexander; Grinstein, Sebastian; Grishkevich, Yaroslav; Grivaz, Jean-Francois; Grognuz, Joel; Groh, Manfred; Gross, Eilam; Grosse-Knetter, Joern; Groth-Jensen, Jacob; Grybel, Kai; Guarino, Victor; Guest, Daniel; Guicheney, Christophe; Guida, Angelo; Guillemin, Thibault; Guindon, Stefan; Guler, Hulya; Gumpert, Christian; Gunther, Jaroslav; Guo, Bin; Guo, Jun; Gupta, Ambreesh; Gusakov, Yury; Gushchin, Vladimir; Gutierrez, Andrea; Gutierrez, Phillip; Guttman, Nir; Gutzwiller, Olivier; Guyot, Claude; Gwenlan, Claire; Gwilliam, Carl; Haas, Andy; Haas, Stefan; Haber, Carl; Hackenburg, Robert; Hadavand, Haleh Khani; Hadley, David; Haefner, Petra; Hahn, Ferdinand; Haider, Stefan; Hajduk, Zbigniew; Hakobyan, Hrachya; Haller, Johannes; Hamacher, Klaus; Hamal, Petr; Hamilton, Andrew; Hamilton, Samuel; Han, Hongguang; Han, Liang; Hanagaki, Kazunori; Hance, Michael; Handel, Carsten; Hanke, Paul; Hansen, John Renner; Hansen, Jorgen Beck; Hansen, Jorn Dines; Hansen, Peter Henrik; Hansson, Per; Hara, Kazuhiko; Hare, Gabriel; Harenberg, Torsten; Harkusha, Siarhei; Harper, Devin; Harrington, Robert; Harris, Orin; Harrison, Karl; Hartert, Jochen; Hartjes, Fred; Haruyama, Tomiyoshi; Harvey, Alex; Hasegawa, Satoshi; Hasegawa, Yoji; Hassani, Samira; Hatch, Mark; Hauff, Dieter; Haug, Sigve; Hauschild, Michael; Hauser, Reiner; Havranek, Miroslav; Hawes, Brian; Hawkes, Christopher; Hawkings, Richard John; Hawkins, Donovan; Hayakawa, Takashi; Hayden, Daniel; Hayward, Helen; Haywood, Stephen; Hazen, Eric; He, Mao; Head, Simon; Hedberg, Vincent; Heelan, Louise; Heim, Sarah; Heinemann, Beate; Heisterkamp, Simon; Helary, Louis; Heller, Mathieu; Hellman, Sten; Hellmich, Dennis; Helsens, Clement; Henderson, Robert; Henke, Michael; Henrichs, Anna; Henriques Correia, Ana Maria; Henrot-Versille, Sophie; Henry-Couannier, Frederic; Hensel, Carsten; Henss, Tobias; Medina Hernandez, Carlos; Hernandez Jimenez, Yesenia; Herrberg, Ruth; Hershenhorn, Alon David; Herten, Gregor; Hertenberger, Ralf; Hervas, Luis; Hessey, Nigel; Hidvegi, Attila; Higon-Rodriguez, Emilio; Hill, Daniel; Hill, John; Hill, Norman; Hiller, Karl Heinz; Hillert, Sonja; Hillier, Stephen; Hinchliffe, Ian; Hines, Elizabeth; Hirose, Minoru; Hirsch, Florian; Hirschbuehl, Dominic; Hobbs, John; Hod, Noam; Hodgkinson, Mark; Hodgson, Paul; Hoecker, Andreas; Hoeferkamp, Martin; Hoffman, Julia; Hoffmann, Dirk; Hohlfeld, Marc; Holder, Martin; Holmes, Alan; Holmgren, Sven-Olof; Holy, Tomas; Holzbauer, Jenny; Homma, Yasuhiro; Hong, Tae Min; Hooft van Huysduynen, Loek; Horazdovsky, Tomas; Horn, Claus; Horner, Stephan; Horton, Katherine; Hostachy, Jean-Yves; Hou, Suen; Houlden, Michael; Hoummada, Abdeslam; Howarth, James; Howell, David; Hristova, Ivana; Hrivnac, Julius; Hruska, Ivan; Hryn'ova, Tetiana; Hsu, Pai-hsien Jennifer; Hsu, Shih-Chieh; Huang, Guang Shun; Hubacek, Zdenek; Hubaut, Fabrice; Huegging, Fabian; Huffman, Todd Brian; Hughes, Emlyn; Hughes, Gareth; Hughes-Jones, Richard; Huhtinen, Mika; Hurst, Peter; Hurwitz, Martina; Husemann, Ulrich; Huseynov, Nazim; Huston, Joey; Huth, John; Iacobucci, Giuseppe; Iakovidis, Georgios; Ibbotson, Michael; Ibragimov, Iskander; Ichimiya, Ryo; Iconomidou-Fayard, Lydia; Idarraga, John; Idzik, Marek; Iengo, Paolo; Igonkina, Olga; Ikegami, Yoichi; Ikeno, Masahiro; Ilchenko, Yuri; Iliadis, Dimitrios; Imbault, Didier; Imhaeuser, Martin; Imori, Masatoshi; Ince, Tayfun; Inigo-Golfin, Joaquin; Ioannou, Pavlos; Iodice, Mauro; Ionescu, Gelu; Irles Quiles, Adrian; Ishii, Koji; Ishikawa, Akimasa; Ishino, Masaya; Ishmukhametov, Renat; Issever, Cigdem; Istin, Serhat; Itoh, Yuki; Ivashin, Anton; Iwanski, Wieslaw; Iwasaki, Hiroyuki; Izen, Joseph; Izzo, Vincenzo; Jackson, Brett; Jackson, John; Jackson, Paul; Jaekel, Martin; Jain, Vivek; Jakobs, Karl; Jakobsen, Sune; Jakubek, Jan; Jana, Dilip; Jankowski, Ernest; Jansen, Eric; Jantsch, Andreas; Janus, Michel; Jarlskog, Goran; Jeanty, Laura; Jelen, Kazimierz; Jen-La Plante, Imai; Jenni, Peter; Jeremie, Andrea; Jez, Pavel; Jezequel, Stephane; Jha, Manoj Kumar; Ji, Haoshuang; Ji, Weina; Jia, Jiangyong; Jiang, Yi; Jimenez Belenguer, Marcos; Jin, Ge; Jin, Shan; Jinnouchi, Osamu; Joergensen, Morten Dam; Joffe, David; Johansen, Lars; Johansen, Marianne; Johansson, Erik; Johansson, Per; Johnert, Sebastian; Johns, Kenneth; Jon-And, Kerstin; Jones, Graham; Jones, Roger; Jones, Tegid; Jones, Tim; Jonsson, Ove; Joram, Christian; Jorge, Pedro; Joseph, John; Jovin, Tatjana; Ju, Xiangyang; Juranek, Vojtech; Jussel, Patrick; Kabachenko, Vasily; Kabana, Sonja; Kaci, Mohammed; Kaczmarska, Anna; Kadlecik, Peter; Kado, Marumi; Kagan, Harris; Kagan, Michael; Kaiser, Steffen; Kajomovitz, Enrique; Kalinin, Sergey; Kalinovskaya, Lidia; Kama, Sami; Kanaya, Naoko; Kaneda, Michiru; Kanno, Takayuki; Kantserov, Vadim; Kanzaki, Junichi; Kaplan, Benjamin; Kapliy, Anton; Kaplon, Jan; Kar, Deepak; Karagoz, Muge; Karnevskiy, Mikhail; Karr, Kristo; Kartvelishvili, Vakhtang; Karyukhin, Andrey; Kashif, Lashkar; Kasmi, Azzedine; Kass, Richard; Kastanas, Alex; Kataoka, Mayuko; Kataoka, Yousuke; Katsoufis, Elias; Katzy, Judith; Kaushik, Venkatesh; Kawagoe, Kiyotomo; Kawamoto, Tatsuo; Kawamura, Gen; Kayl, Manuel; Kazanin, Vassili; Kazarinov, Makhail; Keates, James Robert; Keeler, Richard; Kehoe, Robert; Keil, Markus; Kekelidze, George; Kelly, Marc; Kennedy, John; Kenney, Christopher John; Kenyon, Mike; Kepka, Oldrich; Kerschen, Nicolas; Kersevan, Borut Paul; Kersten, Susanne; Kessoku, Kohei; Ketterer, Christian; Keung, Justin; Khakzad, Mohsen; Khalil-zada, Farkhad; Khandanyan, Hovhannes; Khanov, Alexander; Kharchenko, Dmitri; Khodinov, Alexander; Kholodenko, Anatoli; Khomich, Andrei; Khoo, Teng Jian; Khoriauli, Gia; Khoroshilov, Andrey; Khovanskiy, Nikolai; Khovanskiy, Valery; Khramov, Evgeniy; Khubua, Jemal; Kim, Hyeon Jin; Kim, Min Suk; Kim, Peter; Kim, Shinhong; Kimura, Naoki; Kind, Oliver; King, Barry; King, Matthew; King, Robert Steven Beaufoy; Kirk, Julie; Kirsch, Guillaume; Kirsch, Lawrence; Kiryunin, Andrey; Kisielewska, Danuta; Kittelmann, Thomas; Kiver, Andrey; Kiyamura, Hironori; Kladiva, Eduard; Klaiber-Lodewigs, Jonas; Klein, Max; Klein, Uta; Kleinknecht, Konrad; Klemetti, Miika; Klier, Amit; Klimentov, Alexei; Klingenberg, Reiner; Klinkby, Esben; Klioutchnikova, Tatiana; Klok, Peter; Klous, Sander; Kluge, Eike-Erik; Kluge, Thomas; Kluit, Peter; Kluth, Stefan; Kneringer, Emmerich; Knobloch, Juergen; Knoops, Edith; Knue, Andrea; Ko, Byeong Rok; Kobayashi, Tomio; Kobel, Michael; Kocian, Martin; Kocnar, Antonin; Kodys, Peter; Koneke, Karsten; Konig, Adriaan; Koenig, Sebastian; Kopke, Lutz; Koetsveld, Folkert; Koevesarki, Peter; Koffas, Thomas; Koffeman, Els; Kohn, Fabian; Kohout, Zdenek; Kohriki, Takashi; Koi, Tatsumi; Kokott, Thomas; Kolachev, Guennady; Kolanoski, Hermann; Kolesnikov, Vladimir; Koletsou, Iro; Koll, James; Kollar, Daniel; Kollefrath, Michael; Kolya, Scott; Komar, Aston; Komaragiri, Jyothsna Rani; Komori, Yuto; Kondo, Takahiko; Kono, Takanori; Kononov, Anatoly; Konoplich, Rostislav; Konstantinidis, Nikolaos; Kootz, Andreas; Koperny, Stefan; Kopikov, Sergey; Korcyl, Krzysztof; Kordas, Kostantinos; Koreshev, Victor; Korn, Andreas; Korol, Aleksandr; Korolkov, Ilya; Korolkova, Elena; Korotkov, Vladislav; Kortner, Oliver; Kortner, Sandra; Kostyukhin, Vadim; Kotamaki, Miikka Juhani; Kotov, Sergey; Kotov, Vladislav; Kotwal, Ashutosh; Kourkoumelis, Christine; Kouskoura, Vasiliki; Koutsman, Alex; Kowalewski, Robert Victor; Kowalski, Tadeusz; Kozanecki, Witold; Kozhin, Anatoly; Kral, Vlastimil; Kramarenko, Viktor; Kramberger, Gregor; Krasny, Mieczyslaw Witold; Krasznahorkay, Attila; Kraus, James; Kreisel, Arik; Krejci, Frantisek; Kretzschmar, Jan; Krieger, Nina; Krieger, Peter; Kroeninger, Kevin; Kroha, Hubert; Kroll, Joe; Kroseberg, Juergen; Krstic, Jelena; Kruchonak, Uladzimir; Kruger, Hans; Kruker, Tobias; Krumshteyn, Zinovii; Kruth, Andre; Kubota, Takashi; Kuehn, Susanne; Kugel, Andreas; Kuhl, Thorsten; Kuhn, Dietmar; Kukhtin, Victor; Kulchitsky, Yuri; Kuleshov, Sergey; Kummer, Christian; Kuna, Marine; Kundu, Nikhil; Kunkle, Joshua; Kupco, Alexander; Kurashige, Hisaya; Kurata, Masakazu; Kurochkin, Yurii; Kus, Vlastimil; Kuykendall, William; Kuze, Masahiro; Kuzhir, Polina; Kvasnicka, Ondrej; Kvita, Jiri; Kwee, Regina; La Rosa, Alessandro; La Rotonda, Laura; Labarga, Luis; Labbe, Julien; Lablak, Said; Lacasta, Carlos; Lacava, Francesco; Lacker, Heiko; Lacour, Didier; Lacuesta, Vicente Ramon; Ladygin, Evgueni; Lafaye, Remi; Laforge, Bertrand; Lagouri, Theodota; Lai, Stanley; Laisne, Emmanuel; Lamanna, Massimo; Lampen, Caleb; Lampl, Walter; Lancon, Eric; Landgraf, Ulrich; Landon, Murrough; Landsman, Hagar; Lane, Jenna; Lange, Clemens; Lankford, Andrew; Lanni, Francesco; Lantzsch, Kerstin; Laplace, Sandrine; Lapoire, Cecile; Laporte, Jean-Francois; Lari, Tommaso; Larionov, Anatoly; Larner, Aimee; Lasseur, Christian; Lassnig, Mario; Laurelli, Paolo; Lavorato, Antonia; Lavrijsen, Wim; Laycock, Paul; Lazarev, Alexandre; Le Dortz, Olivier; Le Guirriec, Emmanuel; Le Maner, Christophe; Le Menedeu, Eve; Lebel, Celine; LeCompte, Thomas; Ledroit-Guillon, Fabienne Agnes Marie; Lee, Hurng-Chun; Lee, Jason; Lee, Shih-Chang; Lee, Lawrence; Lefebvre, Michel; Legendre, Marie; Leger, Annie; LeGeyt, Benjamin; Legger, Federica; Leggett, Charles; Lehmacher, Marc; Lehmann Miotto, Giovanna; Lei, Xiaowen; Leite, Marco Aurelio Lisboa; Leitner, Rupert; Lellouch, Daniel; Lellouch, Jeremie; Leltchouk, Mikhail; Lendermann, Victor; Leney, Katharine; Lenz, Tatiana; Lenzen, Georg; Lenzi, Bruno; Leonhardt, Kathrin; Leontsinis, Stefanos; Leroy, Claude; Lessard, Jean-Raphael; Lesser, Jonas; Lester, Christopher; Leung Fook Cheong, Annabelle; Leveque, Jessica; Levin, Daniel; Levinson, Lorne; Levitski, Mikhail; Lewandowska, Marta; Lewis, Adrian; Lewis, George; Leyko, Agnieszka; Leyton, Michael; Li, Bo; Li, Haifeng; Li, Shu; Li, Xuefei; Liang, Zhihua; Liang, Zhijun; Liberti, Barbara; Lichard, Peter; Lichtnecker, Markus; Lie, Ki; Liebig, Wolfgang; Lifshitz, Ronen; Lilley, Joseph; Limbach, Christian; Limosani, Antonio; Limper, Maaike; Lin, Simon; Linde, Frank; Linnemann, James; Lipeles, Elliot; Lipinsky, Lukas; Lipniacka, Anna; Liss, Tony; Lissauer, David; Lister, Alison; Litke, Alan; Liu, Chuanlei; Liu, Dong; Liu, Hao; Liu, Jianbei; Liu, Minghui; Liu, Shengli; Liu, Yanwen; Livan, Michele; Livermore, Sarah; Lleres, Annick; Llorente Merino, Javier; Lloyd, Stephen; Lobodzinska, Ewelina; Loch, Peter; Lockman, William; Lockwitz, Sarah; Loddenkoetter, Thomas; Loebinger, Fred; Loginov, Andrey; Loh, Chang Wei; Lohse, Thomas; Lohwasser, Kristin; Lokajicek, Milos; Loken, James; Lombardo, Vincenzo Paolo; Long, Robin Eamonn; Lopes, Lourenco; Lopez Mateos, David; Losada, Marta; Loscutoff, Peter; Sterzo, Francesco Lo; Losty, Michael; Lou, Xinchou; Lounis, Abdenour; Loureiro, Karina; Love, Jeremy; Love, Peter; Lowe, Andrew; Lu, Feng; Lubatti, Henry; Luci, Claudio; Lucotte, Arnaud; Ludwig, Andreas; Ludwig, Dorthe; Ludwig, Inga; Ludwig, Jens; Luehring, Frederick; Luijckx, Guy; Lumb, Debra; Luminari, Lamberto; Lund, Esben; Lund-Jensen, Bengt; Lundberg, Bjorn; Lundberg, Johan; Lundquist, Johan; Lungwitz, Matthias; Lupi, Anna; Lutz, Gerhard; Lynn, David; Lys, Jeremy; Lytken, Else; Ma, Hong; Ma, Lian Liang; Macana Goia, Jorge Andres; Maccarrone, Giovanni; Macchiolo, Anna; Macek, Bostjan; Machado Miguens, Joana; Macina, Daniela; Mackeprang, Rasmus; Madaras, Ronald; Mader, Wolfgang; Maenner, Reinhard; Maeno, Tadashi; Mattig, Peter; Mattig, Stefan; Magalhaes Martins, Paulo Jorge; Magnoni, Luca; Magradze, Erekle; Mahalalel, Yair; Mahboubi, Kambiz; Mahout, Gilles; Maiani, Camilla; Maidantchik, Carmen; Maio, Amelia; Majewski, Stephanie; Makida, Yasuhiro; Makovec, Nikola; Mal, Prolay; Malecki, Pawel; Malecki, Piotr; Maleev, Victor; Malek, Fairouz; Mallik, Usha; Malon, David; Maltezos, Stavros; Malyshev, Vladimir; Malyukov, Sergei; Mameghani, Raphael; Mamuzic, Judita; Manabe, Atsushi; Mandelli, Luciano; Mandic, Igor; Mandrysch, Rocco; Maneira, Jose; Mangeard, Pierre-Simon; Manjavidze, Ioseb; Mann, Alexander; Manning, Peter; Manousakis-Katsikakis, Arkadios; Mansoulie, Bruno; Manz, Andreas; Mapelli, Alessandro; Mapelli, Livio; March, Luis; Marchand, Jean-Francois; Marchese, Fabrizio; Marchiori, Giovanni; Marcisovsky, Michal; Marin, Alexandru; Marino, Christopher; Marroquim, Fernando; Marshall, Robin; Marshall, Zach; Martens, Kalen; Marti-Garcia, Salvador; Martin, Andrew; Martin, Brian; Martin, Brian Thomas; Martin, Franck Francois; Martin, Jean-Pierre; Martin, Philippe; Martin, Tim; Martin Dit Latour, Bertrand; Martinez, Mario; Martinez Outschoorn, Verena; Martyniuk, Alex; Marx, Marilyn; Marzano, Francesco; Marzin, Antoine; Masetti, Lucia; Mashimo, Tetsuro; Mashinistov, Ruslan; Masik, Jiri; Maslennikov, Alexey; Massa, Ignazio; Massaro, Graziano; Massol, Nicolas; Mastrandrea, Paolo; Mastroberardino, Anna; Masubuchi, Tatsuya; Mathes, Markus; Matricon, Pierre; Matsumoto, Hiroshi; Matsunaga, Hiroyuki; Matsushita, Takashi; Mattravers, Carly; Maugain, Jean-Marie; Maxfield, Stephen; Maximov, Dmitriy; May, Edward; Mayne, Anna; Mazini, Rachid; Mazur, Michael; Mazzanti, Marcello; Mazzoni, Enrico; Kee, Shawn Patrick Mc; McCarn, Allison; McCarthy, Robert; McCarthy, Tom; McCubbin, Norman; McFarlane, Kenneth; Mcfayden, Josh; McGlone, Helen; Mchedlidze, Gvantsa; McLaren, Robert Andrew; Mclaughlan, Tom; McMahon, Steve; McPherson, Robert; Meade, Andrew; Mechnich, Joerg; Mechtel, Markus; Medinnis, Mike; Meera-Lebbai, Razzak; Meguro, Tatsuma; Mehdiyev, Rashid; Mehlhase, Sascha; Mehta, Andrew; Meier, Karlheinz; Meinhardt, Jens; Meirose, Bernhard; Melachrinos, Constantinos; Mellado Garcia, Bruce Rafael; Mendoza Navas, Luis; Meng, Zhaoxia; Mengarelli, Alberto; Menke, Sven; Menot, Claude; Meoni, Evelin; Mercurio, Kevin Michael; Mermod, Philippe; Merola, Leonardo; Meroni, Chiara; Merritt, Frank; Messina, Andrea; Metcalfe, Jessica; Mete, Alaettin Serhan; Meuser, Stefan; Meyer, Carsten; Meyer, Jean-Pierre; Meyer, Jochen; Meyer, Joerg; Meyer, Thomas Christian; Meyer, W.Thomas; Miao, Jiayuan; Michal, Sebastien; Micu, Liliana; Middleton, Robin; Miele, Paola; Migas, Sylwia; Mijovic, Liza; Mikenberg, Giora; Mikestikova, Marcela; Mikuz, Marko; Miller, David; Miller, Robert; Mills, Bill; Mills, Corrinne; Milov, Alexander; Milstead, David; Milstein, Dmitry; Minaenko, Andrey; Minano, Mercedes; Minashvili, Irakli; Mincer, Allen; Mindur, Bartosz; Mineev, Mikhail; Ming, Yao; Mir, Lluisa-Maria; Mirabelli, Giovanni; Miralles Verge, Lluis; Misiejuk, Andrzej; Mitrevski, Jovan; Mitrofanov, Gennady; Mitsou, Vasiliki A.; Mitsui, Shingo; Miyagawa, Paul; Miyazaki, Kazuki; Mjornmark, Jan-Ulf; Moa, Torbjoern; Mockett, Paul; Moed, Shulamit; Moeller, Victoria; Monig, Klaus; Moser, Nicolas; Mohapatra, Soumya; Mohr, Wolfgang; Mohrdieck-Mock, Susanne; Moisseev, Artemy; Moles-Valls, Regina; Molina-Perez, Jorge; Monk, James; Monnier, Emmanuel; Montesano, Simone; Monticelli, Fernando; Monzani, Simone; Moore, Roger; Moorhead, Gareth; Mora Herrera, Clemencia; Moraes, Arthur; Morais, Antonio; Morange, Nicolas; Morel, Julien; Morello, Gianfranco; Moreno, Deywis; Moreno Llácer, María; Morettini, Paolo; Morii, Masahiro; Morin, Jerome; Morita, Youhei; Morley, Anthony Keith; Mornacchi, Giuseppe; Morone, Maria-Christina; Morozov, Sergey; Morris, John; Morvaj, Ljiljana; Moser, Hans-Guenther; Mosidze, Maia; Moss, Josh; Mount, Richard; Mountricha, Eleni; Mouraviev, Sergei; Moyse, Edward; Mudrinic, Mihajlo; Mueller, Felix; Mueller, James; Mueller, Klemens; Muller, Thomas; Muenstermann, Daniel; Muir, Alex; Munwes, Yonathan; Murakami, Koichi; Murray, Bill; Mussche, Ido; Musto, Elisa; Myagkov, Alexey; Myska, Miroslav; Nadal, Jordi; Nagai, Koichi; Nagano, Kunihiro; Nagasaka, Yasushi; Nairz, Armin Michael; Nakahama, Yu; Nakamura, Koji; Nakano, Itsuo; Nanava, Gizo; Napier, Austin; Nash, Michael; Nation, Nigel; Nattermann, Till; Naumann, Thomas; Navarro, Gabriela; Neal, Homer; Nebot, Eduardo; Nechaeva, Polina; Negri, Andrea; Negri, Guido; Nektarijevic, Snezana; Nelson, Silke; Nelson, Timothy Knight; Nemecek, Stanislav; Nemethy, Peter; Nepomuceno, Andre Asevedo; Nessi, Marzio; Nesterov, Stanislav; Neubauer, Mark; Neusiedl, Andrea; Neves, Ricardo; Nevski, Pavel; Newman, Paul; Hong, Van Nguyen Thi; Nickerson, Richard; Nicolaidou, Rosy; Nicolas, Ludovic; Nicquevert, Bertrand; Niedercorn, Francois; Nielsen, Jason; Niinikoski, Tapio; Nikiforov, Andriy; Nikolaenko, Vladimir; Nikolaev, Kirill; Nikolic-Audit, Irena; Nikolics, Katalin; Nikolopoulos, Konstantinos; Nilsen, Henrik; Nilsson, Paul; Ninomiya, Yoichi; Nisati, Aleandro; Nishiyama, Tomonori; Nisius, Richard; Nodulman, Lawrence; Nomachi, Masaharu; Nomidis, Ioannis; Nordberg, Markus; Nordkvist, Bjoern; Norton, Peter; Novakova, Jana; Nozaki, Mitsuaki; Nozicka, Miroslav; Nozka, Libor; Nugent, Ian Michael; Nuncio-Quiroz, Adriana-Elizabeth; Nunes Hanninger, Guilherme; Nunnemann, Thomas; Nurse, Emily; Nyman, Tommi; O'Brien, Brendan Joseph; O'Neale, Steve; O'Neil, Dugan; O'Shea, Val; Oakham, Gerald; Oberlack, Horst; Ocariz, Jose; Ochi, Atsuhiko; Oda, Susumu; Odaka, Shigeru; Odier, Jerome; Ogren, Harold; Oh, Alexander; Oh, Seog; Ohm, Christian; Ohshima, Takayoshi; Ohshita, Hidetoshi; Ohska, Tokio Kenneth; Ohsugi, Takashi; Okada, Shogo; Okawa, Hideki; Okumura, Yasuyuki; Okuyama, Toyonobu; Olcese, Marco; Olchevski, Alexander; Oliveira, Miguel Alfonso; Oliveira Damazio, Denis; Oliver Garcia, Elena; Olivito, Dominick; Olszewski, Andrzej; Olszowska, Jolanta; Omachi, Chihiro; Onofre, Antonio; Onyisi, Peter; Oram, Christopher; Oreglia, Mark; Oren, Yona; Orestano, Domizia; Orlov, Iliya; Oropeza Barrera, Cristina; Orr, Robert; Osculati, Bianca; Ospanov, Rustem; Osuna, Carlos; Otero y Garzon, Gustavo; Ottersbach, John; Ouchrif, Mohamed; Ould-Saada, Farid; Ouraou, Ahmimed; Ouyang, Qun; Owen, Mark; Owen, Simon; Ozcan, Veysi Erkcan; Ozturk, Nurcan; Pacheco Pages, Andres; Padilla Aranda, Cristobal; Pagan Griso, Simone; Paganis, Efstathios; Paige, Frank; Pajchel, Katarina; Palestini, Sandro; Pallin, Dominique; Palma, Alberto; Palmer, Jody; Pan, Yibin; Panagiotopoulou, Evgenia; Panes, Boris; Panikashvili, Natalia; Panitkin, Sergey; Pantea, Dan; Panuskova, Monika; Paolone, Vittorio; Papadelis, Aras; Papadopoulou, Theodora; Paramonov, Alexander; Park, Woochun; Parker, Andy; Parodi, Fabrizio; Parsons, John; Parzefall, Ulrich; Pasqualucci, Enrico; Passeri, Antonio; Pastore, Fernanda; Pastore, Francesca; Pasztor, Gabriella; Pataraia, Sophio; Patel, Nikhul; Pater, Joleen; Patricelli, Sergio; Pauly, Thilo; Pecsy, Martin; Pedraza Morales, Maria Isabel; Peleganchuk, Sergey; Peng, Haiping; Pengo, Ruggero; Penson, Alexander; Penwell, John; Perantoni, Marcelo; Perez, Kerstin; Cavalcanti, Tiago Perez; Perez Codina, Estel; Perez Garcia-Estan, Maria Teresa; Perez Reale, Valeria; Perini, Laura; Pernegger, Heinz; Perrino, Roberto; Perrodo, Pascal; Persembe, Seda; Peshekhonov, Vladimir; Peters, Onne; Petersen, Brian; Petersen, Jorgen; Petersen, Troels; Petit, Elisabeth; Petridis, Andreas; Petridou, Chariclia; Petrolo, Emilio; Petrucci, Fabrizio; Petschull, Dennis; Petteni, Michele; Pezoa, Raquel; Phan, Anna; Phillips, Alan; Phillips, Peter William; Piacquadio, Giacinto; Piccaro, Elisa; Piccinini, Maurizio; Pickford, Andrew; Piec, Sebastian Marcin; Piegaia, Ricardo; Pilcher, James; Pilkington, Andrew; Pina, Joao Antonio; Pinamonti, Michele; Pinder, Alex; Pinfold, James; Ping, Jialun; Pinto, Belmiro; Pirotte, Olivier; Pizio, Caterina; Placakyte, Ringaile; Plamondon, Mathieu; Plano, Will; Pleier, Marc-Andre; Pleskach, Anatoly; Poblaguev, Andrei; Poddar, Sahill; Podlyski, Fabrice; Poggioli, Luc; Poghosyan, Tatevik; Pohl, Martin; Polci, Francesco; Polesello, Giacomo; Policicchio, Antonio; Polini, Alessandro; Poll, James; Polychronakos, Venetios; Pomarede, Daniel Marc; Pomeroy, Daniel; Pommes, Kathy; Pontecorvo, Ludovico; Pope, Bernard; Popeneciu, Gabriel Alexandru; Popovic, Dragan; Poppleton, Alan; Porter, Robert; Posch, Christoph; Pospelov, Guennady; Pospisil, Stanislav; Potrap, Igor; Potter, Christina; Potter, Christopher; Poulard, Gilbert; Poveda, Joaquin; Prabhu, Robindra; Pralavorio, Pascal; Prasad, Srivas; Pravahan, Rishiraj; Prell, Soeren; Pretzl, Klaus Peter; Pribyl, Lukas; Price, Darren; Price, Lawrence; Price, Michael John; Prichard, Paul; Prieur, Damien; Primavera, Margherita; Prokofiev, Kirill; Prokoshin, Fedor; Protopopescu, Serban; Proudfoot, James; Prudent, Xavier; Przysiezniak, Helenka; Psoroulas, Serena; Ptacek, Elizabeth; Purdham, John; Purohit, Milind; Puzo, Patrick; Pylypchenko, Yuriy; Qian, Jianming; Qian, Zuxuan; Qin, Zhonghua; Quadt, Arnulf; Quarrie, David; Quayle, William; Quinonez, Fernando; Raas, Marcel; Radescu, Voica; Radics, Balint; Rador, Tonguc; Ragusa, Francesco; Rahal, Ghita; Rahimi, Amir; Rahm, David; Rajagopalan, Srinivasan; Rammensee, Michael; Rammes, Marcus; Ramstedt, Magnus; Randrianarivony, Koloina; Ratoff, Peter; Rauscher, Felix; Rauter, Emanuel; Raymond, Michel; Read, Alexander Lincoln; Rebuzzi, Daniela; Redelbach, Andreas; Redlinger, George; Reece, Ryan; Reeves, Kendall; Reichold, Armin; Reinherz-Aronis, Erez; Reinsch, Andreas; Reisinger, Ingo; Reljic, Dusan; Rembser, Christoph; Ren, Zhongliang; Renaud, Adrien; Renkel, Peter; Rescigno, Marco; Resconi, Silvia; Resende, Bernardo; Reznicek, Pavel; Rezvani, Reyhaneh; Richards, Alexander; Richter, Robert; Richter-Was, Elzbieta; Ridel, Melissa; Rieke, Stefan; Rijpstra, Manouk; Rijssenbeek, Michael; Rimoldi, Adele; Rinaldi, Lorenzo; Rios, Ryan Randy; Riu, Imma; Rivoltella, Giancesare; Rizatdinova, Flera; Rizvi, Eram; Robertson, Steven; Robichaud-Veronneau, Andree; Robinson, Dave; Robinson, James; Robinson, Mary; Robson, Aidan; Rocha de Lima, Jose Guilherme; Roda, Chiara; Roda Dos Santos, Denis; Rodier, Stephane; Rodriguez, Diego; Roe, Adam; Roe, Shaun; Rohne, Ole; Rojo, Victoria; Rolli, Simona; Romaniouk, Anatoli; Romanov, Victor; Romeo, Gaston; Romero Maltrana, Diego; Roos, Lydia; Ros, Eduardo; Rosati, Stefano; Rosbach, Kilian; Rose, Matthew; Rosenbaum, Gabriel; Rosenberg, Eli; Rosendahl, Peter Lundgaard; Rosselet, Laurent; Rossetti, Valerio; Rossi, Elvira; Rossi, Leonardo Paolo; Rossi, Lucio; Rotaru, Marina; Roth, Itamar; Rothberg, Joseph; Rousseau, David; Royon, Christophe; Rozanov, Alexander; Rozen, Yoram; Ruan, Xifeng; Rubinskiy, Igor; Ruckert, Benjamin; Ruckstuhl, Nicole; Rud, Viacheslav; Rudolph, Christian; Rudolph, Gerald; Ruhr, Frederik; Ruggieri, Federico; Ruiz-Martinez, Aranzazu; Rulikowska-Zarebska, Elzbieta; Rumiantsev, Viktor; Rumyantsev, Leonid; Runge, Kay; Runolfsson, Ogmundur; Rurikova, Zuzana; Rusakovich, Nikolai; Rust, Dave; Rutherfoord, John; Ruwiedel, Christoph; Ruzicka, Pavel; Ryabov, Yury; Ryadovikov, Vasily; Ryan, Patrick; Rybar, Martin; Rybkin, Grigori; Ryder, Nick; Rzaeva, Sevda; Saavedra, Aldo; Sadeh, Iftach; Sadrozinski, Hartmut; Sadykov, Renat; Safai Tehrani, Francesco; Sakamoto, Hiroshi; Salamanna, Giuseppe; Salamon, Andrea; Saleem, Muhammad; Salihagic, Denis; Salnikov, Andrei; Salt, Jose; Salvachua Ferrando, Belen; Salvatore, Daniela; Salvatore, Pasquale Fabrizio; Salvucci, Antonio; Salzburger, Andreas; Sampsonidis, Dimitrios; Samset, Bjorn Hallvard; Sanchez, Arturo; Sandaker, Heidi; Sander, Heinz Georg; Sanders, Michiel; Sandhoff, Marisa; Sandoval, Tanya; Sandstroem, Rikard; Sandvoss, Stephan; Sankey, Dave; Sansoni, Andrea; Santamarina Rios, Cibran; Santoni, Claudio; Santonico, Rinaldo; Santos, Helena; Saraiva, Joao; Sarangi, Tapas; Sarkisyan-Grinbaum, Edward; Sarri, Francesca; Sartisohn, Georg; Sasaki, Osamu; Sasaki, Takashi; Sasao, Noboru; Satsounkevitch, Igor; Sauvage, Gilles; Sauvan, Emmanuel; Sauvan, Jean-Baptiste; Savard, Pierre; Savinov, Vladimir; Savu, Dan Octavian; Savva, Panagiota; Sawyer, Lee; Saxon, David; Says, Louis-Pierre; Sbarra, Carla; Sbrizzi, Antonio; Scallon, Olivia; Scannicchio, Diana; Schaarschmidt, Jana; Schacht, Peter; Schafer, Uli; Schaepe, Steffen; Schaetzel, Sebastian; Schaffer, Arthur; Schaile, Dorothee; Schamberger, R. Dean; Schamov, Andrey; Scharf, Veit; Schegelsky, Valery; Scheirich, Daniel; Schernau, Michael; Scherzer, Max; Schiavi, Carlo; Schieck, Jochen; Schioppa, Marco; Schlenker, Stefan; Schlereth, James; Schmidt, Evelyn; Schmieden, Kristof; Schmitt, Christian; Schmitt, Sebastian; Schmitz, Martin; Schoning, Andre; Schott, Matthias; Schouten, Doug; Schovancova, Jaroslava; Schram, Malachi; Schroeder, Christian; Schroer, Nicolai; Schuh, Silvia; Schuler, Georges; Schultes, Joachim; Schultz-Coulon, Hans-Christian; Schulz, Holger; Schumacher, Jan; Schumacher, Markus; Schumm, Bruce; Schune, Philippe; Schwanenberger, Christian; Schwartzman, Ariel; Schwemling, Philippe; Schwienhorst, Reinhard; Schwierz, Rainer; Schwindling, Jerome; Schwindt, Thomas; Scott, Bill; Searcy, Jacob; Sedykh, Evgeny; Segura, Ester; Seidel, Sally; Seiden, Abraham; Seifert, Frank; Seixas, Jose; Sekhniaidze, Givi; Seliverstov, Dmitry; Sellden, Bjoern; Sellers, Graham; Seman, Michal; Semprini-Cesari, Nicola; Serfon, Cedric; Serin, Laurent; Seuster, Rolf; Severini, Horst; Sevior, Martin; Sfyrla, Anna; Shabalina, Elizaveta; Shamim, Mansoora; Shan, Lianyou; Shank, James; Shao, Qi Tao; Shapiro, Marjorie; Shatalov, Pavel; Shaver, Leif; Shaw, Christian; Shaw, Kate; Sherman, Daniel; Sherwood, Peter; Shibata, Akira; Shichi, Hideharu; Shimizu, Shima; Shimojima, Makoto; Shin, Taeksu; Shmeleva, Alevtina; Shochet, Mel; Short, Daniel; Shupe, Michael; Sicho, Petr; Sidoti, Antonio; Siebel, Anca-Mirela; Siegert, Frank; Siegrist, James; Sijacki, Djordje; Silbert, Ohad; Silva, Jose; Silver, Yiftah; Silverstein, Daniel; Silverstein, Samuel; Simak, Vladislav; Simard, Olivier; Simic, Ljiljana; Simion, Stefan; Simmons, Brinick; Simonyan, Margar; Sinervo, Pekka; Sinev, Nikolai; Sipica, Valentin; Siragusa, Giovanni; Sisakyan, Alexei; Sivoklokov, Serguei; Sjolin, Jorgen; Sjursen, Therese; Skinnari, Louise Anastasia; Skovpen, Kirill; Skubic, Patrick; Skvorodnev, Nikolai; Slater, Mark; Slavicek, Tomas; Sliwa, Krzysztof; Sloan, Terrence; Sloper, John erik; Smakhtin, Vladimir; Smirnov, Sergei; Smirnova, Lidia; Smirnova, Oxana; Smith, Ben Campbell; Smith, Douglas; Smith, Kenway; Smizanska, Maria; Smolek, Karel; Snesarev, Andrei; Snow, Steve; Snow, Joel; Snuverink, Jochem; Snyder, Scott; Soares, Mara; Sobie, Randall; Sodomka, Jaromir; Soffer, Abner; Solans, Carlos; Solar, Michael; Solc, Jaroslav; Soldatov, Evgeny; Soldevila, Urmila; Solfaroli Camillocci, Elena; Solodkov, Alexander; Solovyanov, Oleg; Sondericker, John; Soni, Nitesh; Sopko, Vit; Sopko, Bruno; Sorbi, Massimo; Sosebee, Mark; Soukharev, Andrey; Spagnolo, Stefania; Spano, Francesco; Spighi, Roberto; Spigo, Giancarlo; Spila, Federico; Spiriti, Eleuterio; Spiwoks, Ralf; Spousta, Martin; Spreitzer, Teresa; Spurlock, Barry; St. Denis, Richard Dante; Stahl, Thorsten; Stahlman, Jonathan; Stamen, Rainer; Stanecka, Ewa; Stanek, Robert; Stanescu, Cristian; Stapnes, Steinar; Starchenko, Evgeny; Stark, Jan; Staroba, Pavel; Starovoitov, Pavel; Staude, Arnold; Stavina, Pavel; Stavropoulos, Georgios; Steele, Genevieve; Steinbach, Peter; Steinberg, Peter; Stekl, Ivan; Stelzer, Bernd; Stelzer, Harald Joerg; Stelzer-Chilton, Oliver; Stenzel, Hasko; Stevenson, Kyle; Stewart, Graeme; Stillings, Jan Andre; Stockmanns, Tobias; Stockton, Mark; Stoerig, Kathrin; Stoicea, Gabriel; Stonjek, Stefan; Strachota, Pavel; Stradling, Alden; Straessner, Arno; Strandberg, Jonas; Strandberg, Sara; Strandlie, Are; Strang, Michael; Strauss, Emanuel; Strauss, Michael; Strizenec, Pavol; Strohmer, Raimund; Strom, David; Strong, John; Stroynowski, Ryszard; Strube, Jan; Stugu, Bjarne; Stumer, Iuliu; Stupak, John; Sturm, Philipp; Soh, Dart-yin; Su, Dong; Subramania, Halasya Siva; Succurro, Antonella; Sugaya, Yorihito; Sugimoto, Takuya; Suhr, Chad; Suita, Koichi; Suk, Michal; Sulin, Vladimir; Sultansoy, Saleh; Sumida, Toshi; Sun, Xiaohu; Sundermann, Jan Erik; Suruliz, Kerim; Sushkov, Serge; Susinno, Giancarlo; Sutton, Mark; Suzuki, Yu; Svatos, Michal; Sviridov, Yuri; Swedish, Stephen; Sykora, Ivan; Sykora, Tomas; Szeless, Balazs; Sanchez, Javier; Ta, Duc; Tackmann, Kerstin; Taffard, Anyes; Tafirout, Reda; Taga, Adrian; Taiblum, Nimrod; Takahashi, Yuta; Takai, Helio; Takashima, Ryuichi; Takeda, Hiroshi; Takeshita, Tohru; Talby, Mossadek; Talyshev, Alexey; Tamsett, Matthew; Tanaka, Junichi; Tanaka, Reisaburo; Tanaka, Satoshi; Tanaka, Shuji; Tanaka, Yoshito; Tani, Kazutoshi; Tannoury, Nancy; Tappern, Geoffrey; Tapprogge, Stefan; Tardif, Dominique; Tarem, Shlomit; Tarrade, Fabien; Tartarelli, Giuseppe Francesco; Tas, Petr; Tasevsky, Marek; Tassi, Enrico; Tatarkhanov, Mous; Taylor, Christopher; Taylor, Frank; Taylor, Geoffrey; Taylor, Wendy; Teixeira Dias Castanheira, Matilde; Teixeira-Dias, Pedro; Temming, Kim Katrin; Ten Kate, Herman; Teng, Ping-Kun; Terada, Susumu; Terashi, Koji; Terron, Juan; Terwort, Mark; Testa, Marianna; Teuscher, Richard; Thadome, Jocelyn; Therhaag, Jan; Theveneaux-Pelzer, Timothee; Thioye, Moustapha; Thoma, Sascha; Thomas, Juergen; Thompson, Emily; Thompson, Paul; Thompson, Peter; Thompson, Stan; Thomson, Evelyn; Thomson, Mark; Thun, Rudolf; Tic, Tom\\'{a}\\v{s}; Tikhomirov, Vladimir; Tikhonov, Yury; Timmermans, Charles; Tipton, Paul; Viegas, Florbela De Jes Tique Aires; Tisserant, Sylvain; Tobias, Jurgen; Toczek, Barbara; Todorov, Theodore; Todorova-Nova, Sharka; Toggerson, Brokk; Tojo, Junji; Tokar, Stanislav; Tokunaga, Kaoru; Tokushuku, Katsuo; Tollefson, Kirsten; Tomoto, Makoto; Tompkins, Lauren; Toms, Konstantin; Tong, Guoliang; Tonoyan, Arshak; Topfel, Cyril; Topilin, Nikolai; Torchiani, Ingo; Torrence, Eric; Torres, Heberth; Torro Pastor, Emma; Toth, Jozsef; Touchard, Francois; Tovey, Daniel; Traynor, Daniel; Trefzger, Thomas; Tremblet, Louis; Tricoli, Alesandro; Trigger, Isabel Marian; Trincaz-Duvoid, Sophie; Trinh, Thi Nguyet; Tripiana, Martin; Trischuk, William; Trivedi, Arjun; Trocme, Benjamin; Troncon, Clara; Trottier-McDonald, Michel; Trzupek, Adam; Tsarouchas, Charilaos; Tseng, Jeffrey; Tsiakiris, Menelaos; Tsiareshka, Pavel; Tsionou, Dimitra; Tsipolitis, Georgios; Tsiskaridze, Vakhtang; Tskhadadze, Edisher; Tsukerman, Ilya; Tsulaia, Vakhtang; Tsung, Jieh-Wen; Tsuno, Soshi; Tsybychev, Dmitri; Tua, Alan; Tuggle, Joseph; Turala, Michal; Turecek, Daniel; Turk Cakir, Ilkay; Turlay, Emmanuel; Turra, Ruggero; Tuts, Michael; Tykhonov, Andrii; Tylmad, Maja; Tyndel, Mike; Tyrvainen, Harri; Tzanakos, George; Uchida, Kirika; Ueda, Ikuo; Ueno, Ryuichi; Ugland, Maren; Uhlenbrock, Mathias; Uhrmacher, Michael; Ukegawa, Fumihiko; Unal, Guillaume; Underwood, David; Undrus, Alexander; Unel, Gokhan; Unno, Yoshinobu; Urbaniec, Dustin; Urkovsky, Evgeny; Urrejola, Pedro; Usai, Giulio; Uslenghi, Massimiliano; Vacavant, Laurent; Vacek, Vaclav; Vachon, Brigitte; Vahsen, Sven; Valenta, Jan; Valente, Paolo; Valentinetti, Sara; Valkar, Stefan; Valladolid Gallego, Eva; Vallecorsa, Sofia; Ferrer, Juan Antonio Valls; Van der Graaf, Harry; van der Kraaij, Erik; van der Leeuw, Robin; van der Poel, Egge; van der Ster, Daniel; Van Eijk, Bob; van Eldik, Niels; Van Gemmeren, Peter; van Kesteren, Zdenko; Van Vulpen, Ivo; Vandelli, Wainer; Vandoni, Giovanna; Vaniachine, Alexandre; Vankov, Peter; Vannucci, Francois; Varela Rodriguez, Fernando; Vari, Riccardo; Varnes, Erich; Varouchas, Dimitris; Vartapetian, Armen; Varvell, Kevin; Vassilakopoulos, Vassilios; Vazeille, Francois; Vegni, Guido; Veillet, Jean-Jacques; Vellidis, Constantine; Veloso, Filipe; Veness, Raymond; Veneziano, Stefano; Ventura, Andrea; Ventura, Daniel; Venturi, Manuela; Venturi, Nicola; Vercesi, Valerio; Verducci, Monica; Verkerke, Wouter; Vermeulen, Jos; Vest, Anja; Vetterli, Michel; Vichou, Irene; Vickey, Trevor; Viehhauser, Georg; Viel, Simon; Villa, Mauro; Villaplana Perez, Miguel; Vilucchi, Elisabetta; Vincter, Manuella; Vinek, Elisabeth; Vinogradov, Vladimir; Virchaux, Marc; Virzi, Joseph; Vitells, Ofer; Viti, Michele; Vivarelli, Iacopo; Vives Vaque, Francesc; Vlachos, Sotirios; Vlasak, Michal; Vlasov, Nikolai; Vogel, Adrian; Vokac, Petr; Volpi, Guido; Volpi, Matteo; Volpini, Giovanni; von der Schmitt, Hans; von Loeben, Joerg; von Radziewski, Holger; von Toerne, Eckhard; Vorobel, Vit; Vorobiev, Alexander; Vorwerk, Volker; Vos, Marcel; Voss, Rudiger; Voss, Thorsten Tobias; Vossebeld, Joost; Vranjes, Nenad; Vranjes Milosavljevic, Marija; Vrba, Vaclav; Vreeswijk, Marcel; Anh, Tuan Vu; Vuillermet, Raphael; Vukotic, Ilija; Wagner, Wolfgang; Wagner, Peter; Wahlen, Helmut; Wakabayashi, Jun; Walbersloh, Jorg; Walch, Shannon; Walder, James; Walker, Rodney; Walkowiak, Wolfgang; Wall, Richard; Waller, Peter; Wang, Chiho; Wang, Haichen; Wang, Hulin; Wang, Jike; Wang, Jin; Wang, Joshua C.; Wang, Rui; Wang, Song-Ming; Warburton, Andreas; Ward, Patricia; Warsinsky, Markus; Watkins, Peter; Watson, Alan; Watson, Miriam; Watts, Gordon; Watts, Stephen; Waugh, Anthony; Waugh, Ben; Weber, Jens; Weber, Marc; Weber, Michele; Weber, Pavel; Weidberg, Anthony; Weigell, Philipp; Weingarten, Jens; Weiser, Christian; Wellenstein, Hermann; Wells, Phillippa; Wen, Mei; Wenaus, Torre; Wendler, Shanti; Weng, Zhili; Wengler, Thorsten; Wenig, Siegfried; Wermes, Norbert; Werner, Matthias; Werner, Per; Werth, Michael; Wessels, Martin; Weydert, Carole; Whalen, Kathleen; Wheeler-Ellis, Sarah Jane; Whitaker, Scott; White, Andrew; White, Martin; White, Sebastian; Whitehead, Samuel Robert; Whiteson, Daniel; Whittington, Denver; Wicek, Francois; Wicke, Daniel; Wickens, Fred; Wiedenmann, Werner; Wielers, Monika; Wienemann, Peter; Wiglesworth, Craig; Wiik, Liv Antje Mari; Wijeratne, Peter Alexander; Wildauer, Andreas; Wildt, Martin Andre; Wilhelm, Ivan; Wilkens, Henric George; Will, Jonas Zacharias; Williams, Eric; Williams, Hugh; Willis, William; Willocq, Stephane; Wilson, John; Wilson, Michael Galante; Wilson, Alan; Wingerter-Seez, Isabelle; Winkelmann, Stefan; Winklmeier, Frank; Wittgen, Matthias; Wolter, Marcin Wladyslaw; Wolters, Helmut; Wooden, Gemma; Wosiek, Barbara; Wotschack, Jorg; Woudstra, Martin; Wraight, Kenneth; Wright, Catherine; Wrona, Bozydar; Wu, Sau Lan; Wu, Xin; Wu, Yusheng; Wulf, Evan; Wunstorf, Renate; Wynne, Benjamin; Xaplanteris, Leonidas; Xella, Stefania; Xie, Song; Xie, Yigang; Xu, Chao; Xu, Da; Xu, Guofa; Yabsley, Bruce; Yacoob, Sahal; Yamada, Miho; Yamamoto, Akira; Yamamoto, Kyoko; Yamamoto, Shimpei; Yamamura, Taiki; Yamaoka, Jared; Yamazaki, Takayuki; Yamazaki, Yuji; Yan, Zhen; Yang, Haijun; Yang, Un-Ki; Yang, Yi; Yang, Yi; Yang, Zhaoyu; Yanush, Serguei; Yao, Weiming; Yao, Yushu; Yasu, Yoshiji; Ybeles Smit, Gabriel Valentijn; Ye, Jingbo; Ye, Shuwei; Yilmaz, Metin; Yoosoofmiya, Reza; Yorita, Kohei; Yoshida, Riktura; Young, Charles; Youssef, Saul; Yu, Dantong; Yu, Jaehoon; Yu, Jie; Yuan, Li; Yurkewicz, Adam; Zaets, Vassilli; Zaidan, Remi; Zaitsev, Alexander; Zajacova, Zuzana; Zalite, Youris; Zanello, Lucia; Zarzhitsky, Pavel; Zaytsev, Alexander; Zeitnitz, Christian; Zeller, Michael; Zemla, Andrzej; Zendler, Carolin; Zenin, Oleg; Zenis, Tibor; Zenonos, Zenonas; Zenz, Seth; Zerwas, Dirk; Zevi Della Porta, Giovanni; Zhan, Zhichao; Zhang, Dongliang; Zhang, Huaqiao; Zhang, Jinlong; Zhang, Xueyao; Zhang, Zhiqing; Zhao, Long; Zhao, Tianchi; Zhao, Zhengguo; Zhemchugov, Alexey; Zheng, Shuchen; Zhong, Jiahang; Zhou, Bing; Zhou, Ning; Zhou, Yue; Zhu, Cheng Guang; Zhu, Hongbo; Zhu, Junjie; Zhu, Yingchun; Zhuang, Xuai; Zhuravlov, Vadym; Zieminska, Daria; Zimmermann, Robert; Zimmermann, Simone; Zimmermann, Stephanie; Ziolkowski, Michael; Zitoun, Robert; Zivkovic, Lidija; Zmouchko, Viatcheslav; Zobernig, Georg; Zoccoli, Antonio; Zolnierowski, Yves; Zsenei, Andras; zur Nedden, Martin; Zutshi, Vishnu; Zwalinski, Lukasz

    2011-01-01

    The Z to tau tau cross section is measured with the ATLAS experiment at the LHC in four different final states determined by the decay modes of the tau leptons: muon-hadron, electron-hadron, electron-muon, and muon-muon. The analysis is based on a data sample corresponding to an integrated luminosity of 36 pb^(-1), at a proton-proton center-of-mass energy of sqrt(s) = 7 TeV. Cross sections are measured separately for each final state in fiducial regions of high detector acceptance, as well as in the full phase space, over the mass region 66 - 116 GeV. The individual cross sections are combined and the product of the total Z production cross section and Z to tau tau branching fraction is measured to be 0.97 +/- 0.07(stat) +/- 0.06(syst) +/- 0.03(lumi), in agreement with NNLO calculations.

  3. Escitalopram attenuates β-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway.

    Science.gov (United States)

    Wang, Yan-Juan; Ren, Qing-Guo; Gong, Wei-Gang; Wu, Di; Tang, Xiang; Li, Xiao-Li; Wu, Fang-Fang; Bai, Feng; Xu, Lin; Zhang, Zhi-Jun

    2016-03-22

    Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-β (Aβ)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with Aβ1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased Aβ1-42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3β pathway, and the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3β pathway and decreased Aβ1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3β pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Aβ1-42 induced impairment of neurite outgrowth and spine density, and reversed Aβ1-42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Aβ1-42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway.

  4. Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition.

    Science.gov (United States)

    Schelle, Juliane; Häsler, Lisa M; Göpfert, Jens C; Joos, Thomas O; Vanderstichele, Hugo; Stoops, Erik; Mandelkow, Eva-Maria; Neumann, Ulf; Shimshek, Derya R; Staufenbiel, Matthias; Jucker, Mathias; Kaeser, Stephan A

    2017-06-01

    The inhibition of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). We previously reported an age-related increase of tau protein in the cerebrospinal fluid (CSF) of amyloid β (Aβ) precursor protein (APP) transgenic mice. APP transgenic mice were treated with a potent BACE1 inhibitor. CSF tau and CSF Aβ levels were assessed. A novel high-sensitivity tau sandwich immunoassay was developed. We demonstrate that long-term BACE1 inhibition prevents CSF tau increase both in early-depositing APP transgenic mice and APP transgenic mice with moderate Aβ pathology. Our results demonstrate that BACE1 inhibition not only reduces Aβ generation but also downstream AD pathophysiology. The tight correlation between Aβ aggregation in brain and CSF tau levels renders CSF tau a valuable marker to predict the effectiveness of BACE1 inhibitors in current clinical trials. Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  5. Regional Overlap of Pathologies in Lewy Body Disorders.

    Science.gov (United States)

    Colom-Cadena, Martí; Grau-Rivera, Oriol; Planellas, Lluís; Cerquera, Catalina; Morenas, Estrella; Helgueta, Sergio; Muñoz, Laia; Kulisevsky, Jaime; Martí, Maria Jose; Tolosa, Eduard; Clarimon, Jordi; Lleó, Alberto; Gelpi, Ellen

    2017-03-01

    Lewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated α-synuclein in Lewy bodies and Lewy neurites in the central and peripheral nervous systems. The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, β-amyloid aggregates, TAR DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain disease (AGD). The incidence and physiological relevance of these concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of α-synuclein, tau, β-amyloid (Aβ), TDP-43, and AGD pathologies in 17 areas in 63 LBD cases (44 with Parkinson disease [PD], 28 with dementia, and 19 with dementia with Lewy bodies). APOE and MAPT genetic variants were also investigated. A majority of LBD cases had 2 or 3 concomitant findings, particularly Alzheimer disease-related pathology. Pathological stages of tau, β-amyloid and α-synuclein pathologies were increased in cases with dementia. Aβ score was the best correlate of the time to dementia in PD. In addition, β-amyloid deposition correlated with α-synuclein load in all groups. MAPT H1 haplotype did not influence any assessed pathology in PD. These results highlight the common concurrence of pathologies in patients with LBD that may have an impact on the clinical expression of the diseases. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  6. Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment.

    Science.gov (United States)

    Smolek, Tomas; Madari, Aladar; Farbakova, Jana; Kandrac, Ondrej; Jadhav, Santosh; Cente, Martin; Brezovakova, Veronika; Novak, Michal; Zilka, Norbert

    2016-03-01

    Canine cognitive impairment syndrome (CDS) represents a group of symptoms related to the aging of the canine brain. These changes ultimately lead to a decline of memory function and learning abilities, alteration of social interaction, impairment of normal housetraining, and changes in sleep-wake cycle and general activity. We have clinically examined 215 dogs, 28 of which underwent autopsy. With canine brains, we performed extensive analysis of pathological abnormalities characteristic of human Alzheimer's disease and frontotemporal lobar degeneration, including β-amyloid senile plaques, tau neurofibrillary tangles, and fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP43) inclusions. Most demented dogs displayed senile plaques, mainly in the frontal and temporal cortex. Tau neurofibrillary inclusions were found in only one dog. They were identified with antibodies used to detect tau neurofibrillary lesions in the human brain. The inclusions were also positive for Gallyas silver staining. As in humans, they were distributed mainly in the entorhinal cortex, hippocampus, and temporal cortex. On the other hand, FUS and TDP43 aggregates were not present in any of the examined brain samples. We also found that CDS was characterized by the presence of reactive and senescent microglial cells in the frontal cortex. Our transcriptomic study revealed a significant dysregulation of genes involved in neuroinflammation. Finally, we analyzed tau phosphoproteome in the synaptosomes. Proteomic studies revealed a significant increase of hyperphosphorylated tau in synaptosomes of demented dogs compared with nondemented dogs. This study suggests that cognitive decline in dogs is related to the tau synaptic impairment and neuroinflammation. J. Comp. Neurol. 524:874-895, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  7. Human tau expression reduces adult neurogenesis in a mouse model of tauopathy.

    Science.gov (United States)

    Komuro, Yutaro; Xu, Guixiang; Bhaskar, Kiran; Lamb, Bruce T

    2015-06-01

    Accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) is a central feature of a class of neurodegenerative diseases termed tauopathies. Notably, there is increasing evidence that tauopathies, including Alzheimer's disease, are also characterized by a reduction in neurogenesis, the birth of adult neurons. However, the exact relationship between hyperphosphorylation and aggregation of MAPT and neurogenic deficits remains unclear, including whether this is an early- or late-stage disease marker. In the present study, we used the genomic-based hTau mouse model of tauopathy to examine the temporal and spatial regulation of adult neurogenesis during the course of the disease. Surprisingly, hTau mice exhibited reductions in adult neurogenesis in 2 different brain regions by as early as 2 months of age, before the development of robust MAPT pathology in this model. This reduction was found to be due to reduced proliferation and not because of enhanced apoptosis in the hippocampus. At these same time points, hTau mice also exhibited altered MAPT phosphorylation with neurogenic precursors. To examine whether the effects of MAPT on neurogenesis were cell autonomous, neurospheres prepared from hTau animals were examined in vitro, revealing a growth deficit when compared with non-transgenic neurosphere cultures. Taken together, these studies provide evidence that altered adult neurogenesis is a robust and early marker of altered, cell-autonomous function of MAPT in the hTau mouse mode of tauopathy and that altered adult neurogenesis should be examined as a potential marker and therapeutic target for human tauopathies. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice.

    Science.gov (United States)

    Elahi, Montasir; Hasan, Zafrul; Motoi, Yumiko; Matsumoto, Shin-Ei; Ishiguro, Koichi; Hattori, Nobutaka

    2016-01-01

    Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD. However, the brain region specificity of AD-related neurodegeneration, which mainly occurs in the hippocampus while the cerebellum is relatively unaffected, has not yet been clarified. Therefore, we used experimental DM mice (caused by an intraperitoneal injection of streptozotocin [STZ]) to determine whether these neurodegeneration-associated mechanisms were associated with region-specific selective vulnerability or tau phosphorylation. The hippocampus, midbrain, and cerebellum of aged (14 to 18 months old) non-transgenic (NTg) and transgenic mice overexpressing wild-type human tau (Tg601 mice) were evaluated after a treatment with STZ. The STZ injection increased reactive oxygen species, lipid peroxidation markers such as 4-hydroxynonenal and malondialdehyde in the hippocampus, but not in the midbrain or cerebellum. The STZ treatment also increased the number of Iba-1-positive and CD68-positive microglial cells, astrocytes, and IL-1β, IL-6, IL-10, and IL-18 levels in the hippocampus, but not in the midbrain or cerebellum. Tau hyperphosphorylation was also enhanced in the hippocampus, but not in the midbrain or cerebellum. When the effects of STZ were compared between Tg601 and NTg mice, microglial proliferation and elevations in IL-6 and phosphorylated tau were higher in Tg601 mice. These results suggest that neuroinflammation and oxidative stress in STZ-treated mice are associated with tau hyperphosphorylation, which may contribute to selective neurodegeneration in human AD.

  9. A measurement of the $\\tau^{-} \\to \\mu^{-} \

    CERN Document Server

    Abbiendi, G; Åkesson, P F; Alexander, G; Allison, J; Amaral, P; Anagnostou, G; Anderson, K J; Arcelli, S; Asai, S; Axen, D A; Azuelos, Georges; Bailey, I; Barberio, E; Barlow, R J; Batley, J Richard; Bechtle, P; Behnke, T; Bell, K W; Bell, P J; Bella, G; Bellerive, A; Benelli, G; Bethke, Siegfried; Biebel, O; Bloodworth, Ian J; Boeriu, O; Bock, P; Bonacorsi, D; Boutemeur, M; Braibant, S; Brigliadori, L; Brown, R M; Büsser, K; Burckhart, H J; Campana, S; Carnegie, R K; Caron, B; Carter, A A; Carter, J R; Chang, C Y; Charlton, D G; Csilling, Akos; Cuffiani, M; Dado, S; Dallison, S; de Roeck, A; De Wolf, E A; Desch, Klaus; Dienes, B; Donkers, M; Dubbert, J; Duchovni, E; Duckeck, G; Duerdoth, I P; Elfgren, E; Etzion, E; Fabbri, Franco Luigi; Feld, L; Ferrari, P; Fiedler, F; Fleck, I; Ford, M; Frey, A; Fürtjes, A; Gagnon, P; Gary, J W; Gaycken, G; Geich-Gimbel, C; Giacomelli, G; Giacomelli, P; Giunta, M; Goldberg, J; Gross, E; Grunhaus, Jacob; Gruwé, M; Günther, P O; Sen-Gupta, A; Hajdu, C; Hamann, M; Hanson, G G; Harder, K; Harel, A; Harin-Dirac, M; Hauschild, M; Hauschildt, J; Hawkes, C M; Hawkings, R; Hemingway, Richard J; Hensel, C; Herten, G; Heuer, R D; Hill, J C; Hoffman, K; Homer, R J; Horváth, D; Howard, R; Igo-Kemenes, P; Ishii, K; Jeremie, H; Jovanovic, P; Junk, T R; Kanaya, N; Kanzaki, J; Karapetian, G V; Karlen, Dean A; Kartvelishvili, V G; Kawagoe, K; Kawamoto, T; Keeler, Richard K; Kellogg, R G; Kennedy, B W; Kim, D H; Klein, K; Klier, A; Kluth, S; Kobayashi, T; Kobel, M; Komamiya, S; Kormos, L L; Krämer, T; Kress, T; Krieger, P; Von Krogh, J; Krop, D; Krüger, K; Kühl, T; Kupper, M; Lafferty, G D; Landsman, Hagar Yaël; Lanske, D; Layter, J G; Leins, A; Lellouch, D; Letts, J; Levinson, L; Lillich, J; Lloyd, S L; Loebinger, F K; Lü, J; Ludwig, J; MacPherson, A; Mader, W; Marcellini, S; Marchant, T E; Martin, A J; Martin, J P; Masetti, G; Mashimo, T; Mättig, P; McDonald, W J; McKenna, J A; McMahon, T J; McPherson, R A; Meijers, F; Méndez-Lorenzo, P; Menges, W; Merritt, F S; Mes, H; Michelini, Aldo; Mihara, S; Mikenberg, G; Miller, D J; Moed, S; Mohr, W; Mori, T; Mutter, A; Nagai, K; Nakamura, I; Neal, H A; Nisius, R; O'Neale, S W; Oh, A; Okpara, A N; Oreglia, M J; Orito, S; Pahl, C; Pásztor, G; Pater, J R; Patrick, G N; Pilcher, J E; Pinfold, J L; Plane, D E; Poli, B; Polok, J; Pooth, O; Przybycien, M B; Quadt, A; Rabbertz, K; Rembser, C; Renkel, P; Rick, Hartmut; Roney, J M; Rosati, S; Rozen, Y; Runge, K; Sachs, K; Saeki, T; Sahr, O; Sarkisyan-Grinbaum, E; Schaile, A D; Schaile, O; Scharff-Hansen, P; Schieck, J; Schörner-Sadenius, T; Schröder, M; Schumacher, M; Schwick, C; Scott, W G; Seuster, R; Shears, T G; Shen, B C; Sherwood, P; Siroli, G P; Skuja, A; Smith, A M; Sobie, R J; Söldner-Rembold, S; Spanó, F; Stahl, A; Stephens, K; Strom, D; Ströhmer, R; Tarem, S; Tasevsky, M; Taylor, R J; Teuscher, R; Thomson, M A; Torrence, E; Toya, D; Tran, P; Trefzger, T M; Tricoli, A; Trigger, I; Trócsányi, Z L; Tsur, E; Turner-Watson, M F; Ueda, I; Ujvári, B; Vachon, B; Vollmer, C F; Vannerem, P; Verzocchi, M; Voss, H; Vossebeld, Joost Herman; 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, L

    2003-01-01

    The tau /sup -/ to mu /sup -/ nu /sub mu / nu /sub tau / branching ratio has been measured using data collected from 1990 to 1995 by the OPAL detector at the LEP collider. The resulting value of B( tau /sup -/ to mu /sup -/ nu /sub mu / nu /sub tau /) = 0.1734 +or- 0.0009 (stat) +or- 0.0006(syst) has been used in conjunction with other OPAL measurements to test lepton universality, yielding the coupling constant ratios g/sub mu //g/sub e/ = 1.0005 +or- 0.0044 and g/sub tau //g/sub e/ = 1.0031 +or- 0.0048, in good agreement with the Standard Model prediction of unity. A value for the Michel parameter eta = 0.004 +or- 0.037 has also been determined and used to find a limit for the mass of the charged Higgs boson, m/sub H/+or- > 1.28 tan beta , in the minimal supersymmetric standard model. (23 refs).CER 4095216 BASE L 13

  10. 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 + } \

  11. Chronic consumption of Annona muricata juice triggers and aggravates cerebral tau phosphorylation in wild-type and MAPT transgenic mice.

    Science.gov (United States)

    Rottscholl, Robert; Haegele, Marlen; Jainsch, Britta; Xu, Hong; Respondek, Gesine; Höllerhage, Matthias; Rösler, Thomas W; Bony, Emilie; Le Ven, Jessica; Guérineau, Vincent; Schmitz-Afonso, Isabelle; Champy, Pierre; Oertel, Wolfgang H; Yamada, Elizabeth S; Höglinger, Günter U

    2016-11-01

    In the pathogenesis of tauopathies, genetic and environmental factors have been identified. While familial clustering led to the identification of mutations in MAPT encoding the microtubule-associated protein tau, the high incidence of a sporadic tauopathy endemic in Guadeloupe was linked to the plant-derived mitochondrial complex I inhibitor annonacin. The interaction of both factors was studied in the present work in a realistic paradigm over a period of 12 months. Mice over-expressing either human wild-type tau or R406W mutant tau as well as non-transgenic mice received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. HPLC-MS analysis of this juice identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline). After 12 month of juice consumption, several brain regions showed an increased number of neurons with phosphorylated tau in the somatodendritic compartment of R406W mice and, to a much lesser extent, of non-transgenic mice and mice over-expressing human wild-type tau. Moreover, juice drinking was associated with a reduction in synaptophysin immunoreactivity, as well as an increase in 3-nitrotyrosine (3NT) reactivity in all three genotypes. The increase in 3NT suggests that Annona muricata juice promotes the generation of reactive nitrogen species. This study provides first experimental evidence that long-lasting oral ingestion of a widely consumed environmental factor can induce somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild-type tau, and can accelerate tau pathology in R406W-MAPT transgenic mice. © 2016 International Society for Neurochemistry.

  12. Tau identification using multivariate techniques in ATLAS

    CERN Document Server

    O'Neil, D; The ATLAS collaboration

    2011-01-01

    Tau leptons will play an important role in the physics program at the LHC. They will be used in electroweak measurements and in detector related studies like the determination of the missing transverse energy scale, but also in searches for new phenomena like the Higgs boson or Supersymmetry. Due to the huge background from QCD processes, efficient tau identification techniques with large fake rejection are essential. Tau object appear as collimated jets with low track multiplicity and single variable criteria are not enough to efficiently separate them from jets and electrons. This can be achieved using modern multivariate techniques which make optimal use of all the information available. They are particularly useful when the discriminating variables are not independent and no single variable provides good signal and background separation. In ATLAS several advanced algorithms are applied to identify taus, in particular a projective likelihood estimator and boosted decision trees. All multivariate methods ap...

  13. ERP-based detection of brain pathology in rat models for preclinical Alzheimer's disease

    Science.gov (United States)

    Nouriziabari, Seyed Berdia

    Early pathological features of Alzheimer's disease (AD) include the accumulation of hyperphosphorylated tau protein (HP-tau) in the entorhinal cortex and progressive loss of basal forebrain (BF) cholinergic neurons. These pathologies are known to remain asymptomatic for many years before AD is clinically diagnosed; however, they may induce aberrant brain processing which can be captured as an abnormality in event-related potentials (ERPs). Here, we examined cortical ERPs while a differential associative learning paradigm was applied to adult male rats with entorhinal HP-tau, pharmacological blockade of muscarinic acetylcholine receptors, or both conditions. Despite no impairment in differential associative and reversal learning, each pathological feature induced distinct abnormality in cortical ERPs to an extent that was sufficient for machine classifiers to accurately detect a specific type of pathology based on these ERP features. These results highlight a potential use of ERPs during differential associative learning as a biomarker for asymptomatic AD pathology.

  14. Monoclonal antibodies selective for α‐synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α‐synuclein transgenic mice with the disease‐causing A30P mutation

    National Research Council Canada - National Science Library

    Fagerqvist, Therese; Lindström, Veronica; Nordström, Eva; Lord, Anna; Tucker, Stina M. E; Su, Xingjian; Sahlin, Charlotte; Kasrayan, Alex; Andersson, Jessica; Welander, Hedvig; Näsström, Thomas; Holmquist, Mats; Schell, Heinrich; Kahle, Philipp J; Kalimo, Hannu; Möller, Christer; Gellerfors, Pär; Lannfelt, Lars; Bergström, Joakim; Ingelsson, Martin

    2013-01-01

    ...‐synuclein oligomers were generated. These antibodies, which do not bind amyloid‐beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in α...

  15. 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.)

  16. A study of tau decays involving eta and omega mesons

    CERN Document Server

    Buskulic, Damir; Décamp, D; Ghez, P; Goy, C; Lees, J P; Lucotte, A; Minard, M N; Nief, J Y; Odier, P; Pietrzyk, B; Casado, M P; Chmeissani, M; Crespo, J M; Delfino, M C; Efthymiopoulos, I; Fernández, E; Fernández-Bosman, M; Carrido, L; Juste, A; Martínez, 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; Girone, M; 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; Alemany, R; Bazarko, A O; Bonvicini, G; Bright-Thomas, P G; Cattaneo, M; Comas, P; Coyle, P; Drevermann, H; Forty, Roger W; Frank, M; Hagelberg, R; Harvey, J; Janot, P; Jost, B; Kneringer, E; Knobloch, J; Lehraus, Ivan; Lutters, G; Martin, E B; Mato, P; Minten, Adolf G; Miquel, R; Mir, L M; Moneta, L; Oest, T; Pacheco, A; Pusztaszeri, J F; Ranjard, F; Rensing, P E; Rizzo, G; Rolandi, Luigi; Schlatter, W D; Schmelling, M; Schmitt, M; Schneider, O; Tejessy, W; Tomalin, I R; Venturi, A; Wachsmuth, H W; Wagner, A; Ajaltouni, Ziad J; 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; Rosnet, P; Rossignol, J M; Fearnley, Tom; Hansen, J B; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Rensch, B; Wäänänen, A; Kyriakis, A; Markou, C; Simopoulou, Errietta; Siotis, I; Vayaki, Anna; Zachariadou, K; 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; 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; Reeves, P; Scarr, J M; Smith, K; Teixeira-Dias, P; Thompson, A S; Thomson, F; Thorn, S; Turnbull, R M; Becker, U; 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; Abbaneo, D; Beuselinck, R; Binnie, David M; Cameron, W; Dornan, Peter J; Moutoussi, A; Nash, J; Sedgbeer, J K; Stacey, A M; Williams, M D; Dissertori, G; Girtler, P; Kuhn, D; Rudolph, G; Betteridge, A P; Bowdery, C K; Colrain, P; Crawford, G; Finch, A J; Foster, F; Hughes, G; 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; Bencheikh, A M; Benchouk, C; Bonissent, A; Bujosa, G; Calvet, D; Carr, J; Diaconu, C A; Etienne, F; Konstantinidis, N P; Payre, P; Rousseau, D; Talby, M; Sadouki, A; Thulasidas, M; Trabelsi, K; Aleppo, M; Ragusa, F; Bauer, C; Berlich, R; Blum, Walter; Büscher, V; Dietl, H; Dydak, Friedrich; 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; 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; Park, H J; Schune, M H; Simion, S; 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; Spagnolo, P; Steinberger, Jack; Tenchini, Roberto; Tonelli, G; Vannini, C; Verdini, P G; Walsh, J; Blair, G A; Bryant, L M; Cerutti, F; 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; Marx, B; 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; Köksal, A; Lehto, M H; Newton, W M; Reeve, J; Thompson, L F; Böhrer, A; Brandt, S; Cowan, G D; Grupen, Claus; Minguet-Rodríguez, J A; Rivera, F; 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; Elmer, P; Feng, Z; Ferguson, D P S; Gao, Y S; González, S; Grahl, J; Greening, T C; Hayes, O J; Hu, H; McNamara, P A; Nachtman, J M; Orejudos, W; Pan, Y B; Saadi, Y; Scott, I J; Walsh, A M; Wu, X; Yamartino, J M; Zheng, M; Zobernig, G

    1997-01-01

    The 132 pb$^{-1}$ of data collected by ALEPH from 1991 to 1994 have been used to analyze $\\eta$ and $\\omega$ production in $\\tau$ decays. The following branching fractions have been measured: \\begin{eqnarray*} B(\\tau^-\\to\

  17. Tau phosphorylation induced by severe closed head traumatic brain injury is linked to the cellular prion protein.

    Science.gov (United States)

    Rubenstein, Richard; Chang, Binggong; Grinkina, Natalia; Drummond, Eleanor; Davies, Peter; Ruditzky, Meir; Sharma, Deep; Wang, Kevin; Wisniewski, Thomas

    2017-04-18

    Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer's disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrP(C)) and amyloid-β oligomers (Aβo). This PrP(C)-Aβo complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrP(C) accumulate Aβ, but show normal survival and no loss of spatial learning and memory suggesting that PrP(C) functions downstream of Aβo production but upstream of intracellular toxicity within neurons. Since AD and traumatic brain injury (TBI)-linked chronic traumatic encephalopathy are tauopathies, we examined whether similar mechanistic pathways are responsible for both AD and TBI pathophysiologies. Using transgenic mice expressing different levels of PrP(C), our studies investigated the influence and necessity of PrP(C) on biomarker (total-tau [T-Tau], P-Tau, GFAP) levels in brain and blood as measured biochemically following severe TBI in the form of severe closed head injury (sCHI). We found that following sCHI, increasing levels of T-Tau and P-Tau in the brain were associated with the PrP(C) expression levels. A similar relationship between PrP(C) expression and P-Tau levels following sCHI were found in blood in the absence of significant T-Tau changes. This effect was not seen with GFAP which increased within 24 h following sCHI and progressively decreased by the 7 day time point regardless of the PrP(C) expression levels. Changes in the levels of all biomarkers were independent of gender. We further enhanced and expanded the quantitation of brain biomarkers with correlative studies using immunohisochemistry. We also demonstrate that a TBI-induced calpain hyperactivation is not required for the generation of P-Tau. A relationship was demonstrated between the presence/absence of PrP(C), the levels of P-Tau and cognitive dysfunction. Our

  18. MIDBRAIN CATECHOLAMINERGIC NEURONS CO-EXPRESS α-SYNUCLEIN AND TAU IN PROGRESSIVE SUPRANUCLEAR PALSY

    Directory of Open Access Journals (Sweden)

    María Elena eErro Aguirre

    2015-03-01

    Full Text Available Objective: To analyze the frequency and distribution of α-synuclein deposits in progressive supranuclear palsy (PSP.Methods: The brains of 25 cases of pathologically confirmed PSP were evaluated with immunohistochemistry for α-synuclein and tau. Multiple immunofluorescent stains were applied to analyze the expression of tau and α-synuclein aggregates in catecholaminergic neurons. Patients’ clinical symptoms were retrospectively recorded. Results: Deposits α-synuclein in the form of typical Lewy bodies (LBs were only found in two PSP cases (8% that fulfilled the clinical subtype of PSP known as Richardson’s syndrome (RS. LBs were present in the locus ceruleus, substantia nigra pars compacta, basal forebrain, amygdala and cingulated cortex in a distribution mimicking that of Parkinson’s disease. Triple-immunolabeling revealed co-expression of α-synuclein and tau proteins in some tyrosine hydroxilase-positive neurons of the locus ceruleus and substantia nigra pars compacta.Conclusions: There is no apparent clinical correlation between the presence of LBs in PSP. Tau protein co-aggregate with α-synuclein in catecholaminergic neurons of PSP brains suggesting a synergistic interaction between the two proteins. This is in keeping with the current view of neurodegenerative disorders as ‘misfolded protein diseases’.

  19. Considerations and code for partial volume correcting [18F]-AV-1451 tau PET data.

    Science.gov (United States)

    Baker, Suzanne L; Maass, Anne; Jagust, William J

    2017-12-01

    [18F]-AV-1451 is a leading tracer used with positron emission tomography (PET) to quantify tau pathology. However, [18F]-AV-1451 shows "off target" or non-specific binding, which we define as binding of the tracer in unexpected areas unlikely to harbor aggregated tau based on autopsy literature [1]. Along with caudate, putamen, pallidum and thalamus non-specific binding [2], [3], we have found binding in the superior portion of the cerebellar gray matter, leading us to use inferior cerebellar gray as the reference region. We also addressed binding in the posterior portion of the choroid plexus. PET signal unlikely to be associated with tau also occurs in skull, meninges and soft tissue (see e.g. [4]). We refer to [18F]-AV-1451 binding in the skull and meninges as extra-cortical hotspots (ECH) and find them near lateral and medial orbitofrontal, lateral occipital, inferior and middle temporal, superior and inferior parietal, and inferior cerebellar gray matter. Lastly, the choroid plexus also shows non-specific binding that bleeds into hippocampus. We are providing the code (http://www.runmycode.org/companion/view/2798) used to create different regions of interest (ROIs) that we then used to perform Partial Volume Correction (PVC) using the Rousset geometric transfer matrix method (GTM, [5]). This method was used in the companion article, "Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's Disease" ([6], DOI 10.1016/j.neuroimage.2017.05.058).

  20. The limbic and neocortical contribution of α-synuclein, tau, and β-amyloid to disease duration in dementia with Lewy bodies.

    Science.gov (United States)

    Ferman, Tanis J; Aoki, Naoya; Crook, Julia E; Murray, Melissa E; Graff-Radford, Neill R; van Gerpen, Jay A; Uitti, Ryan J; Wszolek, Zbigniew K; Graff-Radford, Jonathan; Pedraza, Otto; Kantarci, Kejal; Boeve, Bradley F; Dickson, Dennis W

    2017-10-31

    We sought to assess the individual and combined contribution of limbic and neocortical α-synuclein, tau, and β-amyloid to duration of illness in dementia with Lewy bodies (DLB). Quantitative digital pathology of neocortical and limbic α-synuclein, tau, and β-amyloid was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration. Patients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α-synuclein alone or in combination with tau and β-amyloid. When the diffuse Lewy body disease group was examined separately, α-synuclein deposition significantly exceeded that of tau and β-amyloid. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α-synuclein. In DLB, α-synuclein is an important predictor of disease duration, both independently and synergistically with tau and β-amyloid. Copyright © 2017. Published by Elsevier Inc.

  1. Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases.

    Science.gov (United States)

    Kovacs, Gabor G; Robinson, John L; Xie, Sharon X; Lee, Edward B; Grossman, Murray; Wolk, David A; Irwin, David J; Weintraub, Dan; Kim, Christopher F; Schuck, Theresa; Yousef, Ahmed; Wagner, Stephanie T; Suh, Eunran; Van Deerlin, Vivianna M; Lee, Virginia M-Y; Trojanowski, John Q

    2017-04-01

    The term "aging-related tau astrogliopathy" (ARTAG) describes pathological accumulation of abnormally phosphorylated tau protein in astrocytes. We evaluated the correlates of ARTAG types (i.e., subpial, subependymal, white and gray matter, and perivascular) in different neuroanatomical regions. Clinical, neuropathological, and genetic (eg, APOE ε4 allele, MAPT H1/H2 haplotype) data from 628 postmortem brains from subjects were investigated; most of the patients had been longitudinally followed at the University of Pennsylvania. We found that (i) the amygdala is a hotspot for all ARTAG types; (ii) age at death, male sex, and presence of primary frontotemporal lobar degeneration (FTLD) tauopathy are significantly associated with ARTAG; (iii) age at death, greater degree of brain atrophy, ventricular enlargement, and Alzheimer disease (AD)-related variables are associated with subpial, white matter, and perivascular ARTAG types; (iv) AD-related variables are associated particularly with lobar white matter ARTAG; and (v) gray matter ARTAG in primary FTLD-tauopathies appears in areas without neuronal tau pathology. We provide a reference map of ARTAG types and propose at least 5 constellations of ARTAG. Furthermore, we propose a conceptual link between primary FTLD-tauopathy and ARTAG-related astrocytic tau pathologies. Our observations serve as a basis for etiological stratification and definition of progression patterns of ARTAG. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  2. Measurement of the Tau Lepton Polarisation at LEP2

    CERN Document Server

    Abdallah, J.; Adam, W.; Adzic, P.; Albrecht, T.; Alemany-Fernandez, R.; Allmendinger, T.; Allport, P.P.; Amaldi, U.; Amapane, N.; Amato, Sandra F.; Anashkin, E.; Andreazza, A.; Andringa, S.; Anjos, N.; Antilogus, Pierre; Apel, W-D.; Arnoud, Y.; Ask, S.; Asman, B.; Augustin, Jean-Eudes; Augustinus, A.; Baillon, P.; Ballestrero, A.; Bambade, P.; Barbier, R.; Bardin, D.; Barker, G.J.; Baroncelli, Antonio; Battaglia, M.; Baubillier, M.; Becks, K-H.; Begalli, M.; Behrmann, A.; Ben-Haim, Eli; Benekos, N.; Benvenuti, A.; Berat, C.; Berggren, Mikael; Bertrand, D.; Besancon, M.; Besson, N.; Bloch, D.; Blom, M.; Bluj, Michal; Bonesini, Maurizio; Boonekamp, M.; Booth, P.S.L.; Borisov, G.; Botner, Olga; Bouquet, B.; Bowcock, T.J.V.; Boyko, I.; Bracko, Marko; Brenner, R.; Brodet, E.; Bruckman, P.; Brunet, J.M.; Buschbeck, B.; Buschmann, P.; Calvi, M.; Camporesi, Tiziano; Canale, V.; Carena, F.; Castro, Nuno Filipe; Cavallo, F.; Chapkin, M.; Charpentier, Ph.; Checchia, Paolo; Chierici, R.; Chliapnikov, P.; Chudoba, J.; Chung, Suh-Urk; Cieslik, K.; Collins, P.; Contri, Roberto; Cosme, G.; Cossutti, Fabio; Costa, M.J.; Crennell, D.; Cuevas, J.; D'Hondt, J.; da Silva, T.; Da Silva, W.; Dedovich, D.; Della Ricca, Giuseppe; De Angelis, Alessandro; De Boer, W.; De Clercq, C.; De Lotto, Barbara; De Maria, N.; De Min, A.; de Paula, L.; Di Ciaccio, L.; Di Simone, A.; Doroba, K.; Eigen, G.; Ekelof, Tord; Ellert, Mattias; Elsing, M.; Espirito Santo, Maria Catarina; Fanourakis, George K.; Feindt, Michael; Fernandez, J.; Ferrer, A.; Ferro, F.; Flagmeyer, U.; Foeth, H.; Fokitis, E.; Fulda-Quenzer, F.; Fuster, J.; Gandelman, Miriam; Garcia, C.; Gavillet, Philippe; Gazis, Evangelos; Gomez-Ceballos, G.; Goncalves, P.; Graziani, E.; Grosdidier, G.; Grzelak, K.; Guy, J.; Haag, C.; Hallgren, A.; Hamacher, Klaus; Hamilton, K.; Haug, S.; Hauler, F.; Hedberg, Vincent; Hennecke, M.; Herr, H.; Hoffman, J.; Holmgren, S-O.; Holt, P.J.; Houlden, M.A.; Jackson, John Neil; Jarlskog, Goran; Jarry, P.; Jeans, D.; Johansson, E.K.; Jonsson, P.; Joram, C.; Jungermann, L.; Kapusta, Frederic; Katsanevas, S.; Katsoufis, E.; Kernel, Gabrijel; Kerzel, U.; King, B.T.; Kjaer, N.J.; Kluit, Peter; Kokkinias, P.; Kourkoumelis, C.; Kouznetsov, O.; Krumstein, Z.; Kucharczyk, M.; Lamsa, J.; Leder, G.; Ledroit, F.; Leinonen, L.; Leitner, R.; Lemonne, Jacques; Lepeltier, V.; Lesiak, T.; Liebig, W.; Liko, D.; Lipniacka, A.; Lopes, J.H.; Lopez, J.M.; Loukas, D.; Lutz, Pierre; Lyons, Louis; MacNaughton, J.; Malek, A.; Maltezos, S.; Mandl, F.; Marco, J.; Marco, R.; Marechal, B.; Margoni, M.; Marin, J-C.; Mariotti, C.; Markou, Athanasios; Martinez-Rivero, C.; Masik, J.; Mastroyiannopoulos, N.; Matorras, Francisco; Matteuzzi, C.; Mazzucato, F.; Mazzucato, M.; Nulty, R.Mc; Meroni, C.; Migliore, E.; Mitaroff, Winfried A.; Mjoernmark, U.; Moa, T.; Moch, M.; Monge, R.; Montenegro, J.; Moraes, D.; Moreno, S.; Morettini, P.; Mueller, U.; Muenich, K.; Mulders, M.; Mundim Filho, Luiz Martins; Murray, W.; Muryn, B.; Myatt, G.; Myklebust, T.; Nassiakou, M.; Navarria, F.; Nawrocki, K.; Nicolaidou, R.; Oblakowska-Mucha, A.; Obraztsov, V.; Olshevski, A.; Onofre, A.; Orava, R.; Osterberg, K.; Ouraou, A.; Oyanguren, A.; Paganoni, M.; Paiano, S.; Palacios, J.P.; Palka, Henryk; Papadopoulou, Th.D.; Pape, L.; Parkes, C.; Parodi, F.; Parzefall, U.; Passeri, A.; Passon, O.; Peralta, L.; Perepelitsa, V.; Perrotta, Andrea; Petrolini, Alessandro; Piedra, Jonatan; Pieri, L.; Pierre, Francois; Pimenta, M.; Piotto, E.; Poireau, V.; Pol, M.E.; Polok, G.; Pozdniakov, V.; Pukhaeva, N.; Pullia, A.; Rames, J.; Read, A.; Rebecchi, P.; Rehn, J.; Reid, D.; Reinhardt, R.; Renton, Peter; Richard, F.; Ridky, Jan; Rivero, M.; Rodriguez, D.; Romero, A.; Ronchese, P.; Roudeau, P.; Rovelli, T.; Ruhlmann, Vanina; Ryabtchikov, D.; Sadovsky, A.; Salmi, L.; Salt, J.; Sander, C.; Savoy-Navarro, A.; Schwickerath, U.; Segar, A.; Sekulin, R.; Siebel, Martin; Sisakian, A.; Smadja, G.; Smirnova, O.; Sokolov, A.; Sopczak, A.; Sosnowski, R.; Spassov, T.; Stanitzki, M.; Stocchi, A.; Strauss, J.; Stugu, B.; Szczekowski, M.; Szeptycka, M.; Szumlak, T.; Tabarelli de Fatis, T.; Taffard, A.C.; Tegenfeldt, F.; Timmermans, Jan; Tkatchev, L.; Tobin, M.; Todorovova, S.; Tome, B.; Tonazzo, A.; Tortosa, P.; Travnicek, Petr; Treille, D.; Tristram, G.; Trochimczuk, M.; Troncon, Clara; Turluer, M-L.; Tyapkin, I.A.; Tyapkin, P.; Tzamarias, S.; Uvarov, V.; Valenti, Giovanni; Van Dam, P.; Van Eldik, J.; van Remortel, N.; Van Vulpen, I.; Vegni, G.; Veloso, F.; Venus, W.; Verdier, Patrice; Verzi, V.; Vilanova, D.; Vitale, Lorenzo; Vrba, V.; Wahlen, H.; Washbrook, A.J.; Weiser, C.; Wicke, D.; Wickens, J.; Wilkinson, G.; Winter, M.; Witek, M.; Yushchenko, O.; Zalewska, A.; Zalewski, P.; Zavrtanik, Danilo; Zhuravlov, V.; Zimine, N.I.; Zintchenko, Alexandre

    2008-01-01

    A first measurement of the average polarisation P_tau of tau leptons produced in e+e- annihilation at energies significantly above the Z resonance is presented. The polarisation is determined from the kinematic spectra of tau hadronic decays. The measured value P_tau = -0.164 +/- 0.125 is consistent with the Standard Model prediction for the mean LEP energy of 197 GeV.

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

    Directory of Open Access Journals (Sweden)

    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

  4. Pathological Role of Peptidyl-Prolyl Isomerase Pin1 in the Disruption of Synaptic Plasticity in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Lingyan Xu

    2017-01-01

    Full Text Available Synaptic loss is the structural basis for memory impairment in Alzheimer’s disease (AD. While the underlying pathological mechanism remains elusive, it is known that misfolded proteins accumulate as β-amyloid (Aβ plaques and hyperphosphorylated Tau tangles decades before the onset of clinical disease. The loss of Pin1 facilitates the formation of these misfolded proteins in AD. Pin1 protein controls cell-cycle progression and determines the fate of proteins by the ubiquitin proteasome system. The activity of the ubiquitin proteasome system directly affects the functional and structural plasticity of the synapse. We localized Pin1 to dendritic rafts and postsynaptic density (PSD and found the pathological loss of Pin1 within the synapses of AD brain cortical tissues. The loss of Pin1 activity may alter the ubiquitin-regulated modification of PSD proteins and decrease levels of Shank protein, resulting in aberrant synaptic structure. The loss of Pin1 activity, induced by oxidative stress, may also render neurons more susceptible to the toxicity of oligomers of Aβ and to excitation, thereby inhibiting NMDA receptor-mediated synaptic plasticity and exacerbating NMDA receptor-mediated synaptic degeneration. These results suggest that loss of Pin1 activity could lead to the loss of synaptic plasticity in the development of AD.

  5. Pathology of the Superior Colliculus in Chronic Traumatic Encephalopathy.

    Science.gov (United States)

    Armstrong, Richard A; McKee, Ann C; Cairns, Nigel J

    2017-01-01

    To investigate neuropathological changes in the superior colliculus in chronic traumatic encephalopathy. The densities of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, astrocytic tangles, and neuritic plaques, together with abnormally enlarged neurons, typical neurons, vacuolation, and frequency of contacts with blood vessels, were studied across the superior colliculus from pia mater to the periaqueductal gray in eight chronic traumatic encephalopathy and six control cases. Tau-immunoreactive pathology was absent in the superior colliculus of controls but present in varying degrees in all chronic traumatic encephalopathy cases, significant densities of tau-immunoreactive neurofibrillary tangles, NT, or dot-like grains being present in three cases. No significant differences in overall density of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, enlarged neurons, vacuoles, or contacts with blood vessels were observed in control and chronic traumatic encephalopathy cases, but chronic traumatic encephalopathy cases had significantly lower mean densities of neurons. The distribution of surviving neurons across the superior colliculus suggested greater neuronal loss in intermediate and lower laminae in chronic traumatic encephalopathy. Changes in density of the tau-immunoreactive pathology across the laminae were variable, but in six chronic traumatic encephalopathy cases, densities of tau-immunoreactive neurofibrillary tangles, neuropil threads, or dot-like grains were significantly greater in intermediate and lower laminae. Pathological changes were not correlated with the distribution of blood vessels. The data suggest significant pathology affecting the superior colliculus in a proportion of chronic traumatic encephalopathy cases with a laminar distribution which could compromise motor function rather than sensory analysis.

  6. Search for anomalous weak dipole moments of the $\\tau$ lepton

    CERN Document Server

    Heister, A; Barate, R; De Bonis, I; Décamp, D; Goy, C; Lees, J P; Merle, E; Minard, M N; Pietrzyk, B; Bravo, S; Casado, M P; Chmeissani, M; Crespo, J M; Fernández, E; Fernández-Bosman, M; Garrido, L; Martínez, M; Pacheco, A; Ruiz, H; Colaleo, A; Creanza, D; De Palma, M; 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; Azzurri, P; Buchmüller, O L; Cattaneo, M; Cerutti, F; Clerbaux, B; Drevermann, H; Forty, R W; Frank, M; Gianotti, F; Hansen, J B; Harvey, J; Hutchcroft, D E; Janot, P; Jost, B; Kado, M; Mato, P; Moutoussi, A; Ranjard, F; Rolandi, Luigi; Schlatter, W D; Schneider, O; Sguazzoni, G; Tejessy, W; Teubert, F; Valassi, Andrea; Videau, I; Ward, J; Badaud, F; Falvard, A; Gay, P; Henrard, P; Jousset, J; Michel, B; Monteil, S; Montret, J C; Pallin, D; Perret, P; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Kyriakis, A; Markou, C; Simopoulou, Errietta; Vayaki, Anna; Zachariadou, K; Blondel, A; Bonneaud, G R; Brient, J C; Rougé, A; Rumpf, M; Swynghedauw, M; Verderi, M; Videau, H L; Ciulli, V; Focardi, E; Parrini, G; Antonelli, A; Antonelli, M; Bencivenni, G; Bossi, F; Capon, G; Chiarella, V; Laurelli, P; Mannocchi, G; Murtas, G P; Passalacqua, L; Pepé-Altarelli, M; Lynch, J G; Negus, P; O'Shea, V; Raine, C; Thompson, A S; Wasserbaech, S R; Cavanaugh, R J; Geweniger, C; Hanke, P; Hepp, V; Kluge, E E; Putzer, A; Stenzel, H; Tittel, K; Wunsch, M; Beuselinck, R; Binnie, David M; Cameron, W; Dornan, P J; Girone, M; Marinelli, N; Sedgbeer, J K; Thompson, J C; Ghete, V M; Girtler, P; Kneringer, E; Kuhn, D; Rudolph, G; Bouhova-Thacker, E; Bowdery, C K; Finch, A J; Foster, F; Hughes, G; Jones, R W L; Pearson, M R; Robertson, N A; Jakobs, K; Kleinknecht, K; Renk, B; Sander, H G; Wachsmuth, H W; Zeitnitz, C; Bonissent, A; Coyle, P; Leroy, O; Payre, P; Rousseau, D; Talby, M; Ragusa, F; David, A; Dietl, H; Ganis, G; Hüttmann, K; Lütjens, G; Männer, W; Moser, H G; Settles, Ronald; Wolf, G; Boucrot, J; Callot, O; Davier, M; Duflot, L; Grivaz, J F; Heusse, P; Jacholkowska, A; Lefrançois, J; Veillet, J J; Yuan, C; Bagliesi, G; Boccali, T; Foà, L; Giammanco, A; Giassi, A; Ligabue, F; Messineo, A; Palla, Fabrizio; Sanguinetti, G; Sciabà, A; Tenchini, Roberto; Venturi, A; Verdini, P G; Blair, G A; Cowan, G; Green, M G; Medcalf, T; Misiejuk, A; Strong, J A; Teixeira-Dias, P; Clifft, R W; Edgecock, T R; Norton, P R; Tomalin, I R; Bloch-Devaux, B; Colas, P; Lançon, E; Lemaire, M C; Locci, E; Pérez, P; Rander, J; Schuller, J P; Vallage, B; Konstantinidis, N P; Litke, A M; Taylor, G; Booth, C N; Cartwright, S L; Combley, F; Lehto, M H; Thompson, L F; Böhrer, A; Brandt, S; Grupen, Claus; Ngac, A; Prange, G; Giannini, G; Rothberg, J E; Armstrong, S R; Berkelman, K; Cranmer, K; Ferguson, D P S; Gao, Y; Gonzáles, S; Hayes, O J; Hu, H; Jin, S; Kile, J; McNamara, P A; Nielsen, J; Pan, Y B; Von Wimmersperg-Töller, J H; Wiedenmann, W; Wu, J; Wu Sau Lan; Wu, X; Zobernig, G; Dissertori, G

    2003-01-01

    The anomalous weak dipole moments of the $\\tau$ lepton are measured in a data sample collected by ALEPH from 1990 to 1995 corresponding to an integrated luminosity of 155~pb$^{-1}$. Tau leptons produced in the reaction $e^+ e^- \\rightarrow \\tau^+ \\tau^-$ at energies close to the ${\\rm Z}$ mass are studied using their semileptonic decays to $\\pi$, $\\rho$, $a_1 \\rightarrow \\pi 2\\pi^0$ or $a_1 \\rightarrow 3 \\pi$. The real and imaginary components of both the anomalous weak magnetic dipole moment and the CP-violating anomalous weak electric dipole moment, $ {\\rm Re}\\,\\mu_{\\tau}$, ${\\rm Im}\\,\\mu_{\\tau}$, ${\\rm Re}\\,d_{\\tau}$ and ${\\rm Im}\\,d_{\\tau}$, are measured simultaneously by means of a likelihood fit built from the full differential cross section. No evidence of new physics is found. The following bounds are obtained (95\\% CL): $|{\\rm Re}\\, \\mu_{\\tau} | < 1.14 \\times 10^{-3}$, $|{\\rm Im}\\, \\mu_{\\tau} | < 2.65 \\times 10^{-3}$, $|{\\rm Re}\\, d_{\\tau} | < 0.91 \\times 10^{-3}$, and $|{\\rm Im}\\, d_{\\tau} ...

  7. Performance of the ATLAS Tau Trigger in Run-II

    CERN Document Server

    Ikai, Takashi; The ATLAS collaboration

    2016-01-01

    As proton-proton collisions at the LHC reach instantaneous luminosities of over 10^{34}cm^{-2}s{-1}, tau trigger operation is more challenging. Hadronic tau trigger plays a important role and is used to measure Yukawa coupling constant and to search physics of Beyond Standard Model. This presents tau trigger system, operation, performance in Run2 and strategy in the future.

  8. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank.

    Science.gov (United States)

    Bieniek, Kevin F; Ross, Owen A; Cormier, Kerry A; Walton, Ronald L; Soto-Ortolaza, Alexandra; Johnston, Amelia E; DeSaro, Pamela; Boylan, Kevin B; Graff-Radford, Neill R; Wszolek, Zbigniew K; Rademakers, Rosa; Boeve, Bradley F; McKee, Ann C; Dickson, Dennis W

    2015-12-01

    Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future

  9. Radiative $B_{u} \\to \\tau \

    CERN Document Server

    Sirvanli, B B

    1999-01-01

    The radiative B/sub u/ to tau nu gamma decay is investigated in the standard model. The branching ratio of this decay is calculated. The contributions of the Bremstrahlung and structure dependent parts are compared. It is obtained that this decay can be detected at LHC. (6 refs).

  10. CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

    Science.gov (United States)

    Ritchie, Craig; Smailagic, Nadja; Noel-Storr, Anna H; Ukoumunne, Obioha; Ladds, Emma C; Martin, Steven

    2017-03-22

    Research suggests that measurable change in cerebrospinal fluid (CSF) biomarkers occurs years in advance of the onset of clinical symptoms (Beckett 2010). In this review, we aimed to assess the ability of CSF tau biomarkers (t-tau and p-tau) and the CSF tau (t-tau or p-tau)/ABeta ratio to enable the detection of Alzheimer's disease pathology in patients with mild cognitive impairment (MCI). These biomarkers have been proposed as important in new criteria for Alzheimer's disease dementia that incorporate biomarker abnormalities. To determine the diagnostic accuracy of 1) CSF t-tau, 2) CSF p-tau, 3) the CSF t-tau/ABeta ratio and 4) the CSF p-tau/ABeta ratio index tests for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease dementia or other forms of dementia at follow-up. The most recent search for this review was performed in January 2013. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection, including Conference Proceedings Citation Index (Thomson Reuters Web of Science), PsycINFO (OvidSP), and LILACS (BIREME). We searched specialized sources of diagnostic test accuracy studies and reviews. We checked reference lists of relevant studies and reviews for additional studies. We contacted researchers for possible relevant but unpublished data. We did not apply any language or data restriction to the electronic searches. We did not use any methodological filters as a method to restrict the search overall. We selected those studies that had prospectively well-defined cohorts with any accepted definition of MCI and with CSF t-tau or p-tau and CSF tau (t-tau or p-tau)/ABeta ratio values, documented at or around the time the MCI diagnosis was made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing those biomarker results by disease status. Moreover

  11. Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer's diseases.

    Directory of Open Access Journals (Sweden)

    Valeriy Duka

    Full Text Available OBJECTIVE: Most neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson's disease, dementia with Lewy bodies and Alzheimer's disease, and also select Tau kinases. METHODS: Postmortem frontal cortex from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease and striata from Parkinson's disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls. RESULTS: In Alzheimer's disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer's disease, while in Parkinson's frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer's disease. In Parkinson's disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer's disease. Between frontal cortex of Parkinson's disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson's disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3β, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation. INTERPRETATION: Our studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in

  12. Search for the Lepton Flavor Violation Processes $J/\\psi \\to$ $\\mu\\tau$ and $e\\tau$

    CERN Document Server

    Ablikim, M; Ban, Y; Bian, J G; Cai, X; Chang, J F; Chen, H F; Chen, H S; Chen, H X; Chen, J C; Chen, M L; Chen, Y B; Chi, S P; Chu, Y P; Cui, X Z; Dai, H L; Dai, Y S; Deng, Z Y; Dong, L Y; Du, S X; Du, Z Z; Fang, J; Fang, S S; Fu, C D; Fu, H Y; Gao, C S; Gao, Y N; Gong, M Y; Gong, W X; Gu, S D; Guo, Y N; Guo, Y Q; Guo, Z J; Harris, F A; He, K L; He, M; He, X; Heng, Y K; Hu, H M; Hu, T; Huang, G S; Huang, L; Huang, X P; Ji, X B; Jia, Q Y; Jiang, C H; Jiang, X S; Jin, D P; Jin, S; Jin, Y; Lai, Y F; Li, F; Li, G; Li, H H; Li, J; Li, J C; Li, Q J; Li, R B; Li, R Y; Li, S M; Li, W G; Li, X L; Li, X Q; Li, X S; Liang, Y F; Liao, H B; Liu, C X; Liu, F; Liu, H M; Liu, J B; Liu, J P; Liu, R G; Liu, Z A; Liu, Z X; Lu, F; Lu, G R; Lu, J G; Luo, C L; Luo, X L; Ma, F C; Ma, J M; Ma, L L; Ma, Q M; Ma, X Y; Mao, Z P; Mo, X H; Nie, J; Nie, Z D; Olsen, S L; Peng, H P; Qi, N D; Qian, C D; Qin, H; Qiu, J F; Ren, Z Y; Rong, G; Shan, L Y; Shang, L; Shen, D L; Shen, X Y; Sheng, H Y; Shi, F; Shi, X; Sun, H S; Sun, S S; Sun, Y Z; Sun, Z J; Tang, X; Tao, N; Tian, Y R; Tong, G L; Varner, G S; Wang, D Y; Wang, J Z; Wang, K; Wang, L; Wang, L S; Wang, M; Wang, P; Wang, P L; Wang, S Z; Wang, W F; Wang, Y F; Wang, Z; Wang, Z Y; Wei, C L; Wei, D H; Wu, N; Wu, Y M; Xia, X M; Xie, X X; Xin, B; Xu, G F; Xu, H; Xu, Y; Xue, S T; Yan, M L; Yang, F; Yang, H X; Yang, J; Yang, S D; Yang, Y X; Ye, M; Ye, M H; Ye, Y X; Yi, L H; Yi, Z Y; Yu, C S; Yu, G W; Yuan, C Z; Yuan, J M; Yuan, Y; Yue, Q; Zang, S L; Zeng, Yu; Zeng, Y; Zhang, B X; Zhang, B Y; Zhang, C C; Zhang, D H; Zhang, H Y; Zhang, J; Zhang, J Y; Zhang, J W; Zhang, L S; Zhang, Q J; Zhang, S Q; Zhang Xiao Min; Zhang, X Y; Zhang, Y J; Zhang, Y Y; Zhang, Z P; Zhang, Z Q; Zhao, D X; Zhao, J B; Zhao, J W; Zhao, M G; Zhao, P P; Zhao, W R; Zhao, X J; Zhao, Y B; Zhao, Z G; Zheng, H Q; Zheng, J P; Zheng, L S; Zheng, Z P; Zhong, X C; Zhou, B Q; Zhou, G M; Zhou, L; Zhou, N F; Zhu, K J; Zhu, Q M; Zhu, Y C; Zhu, Y S; Zhu, Z A; Zhuang, B A; Zou, B S

    2004-01-01

    The lepton flavor violation processes $J/\\psi \\to \\mu\\tau$ and $e\\tau$ are searched for using a sample of 5.8$\\times 10^7$ $J/\\psi$ events collected with the BESII detector. Zero and one candidate events, consistent with the estimated background, are observed in $J/\\psi \\to \\mu\\tau, \\tau\\to e\\bar\

  13. Pathology Reports

    Science.gov (United States)

    ... Flow cytometry can be used in the diagnosis, classification, and management of cancers such as acute leukemia, chronic lymphoproliferative disorders, and non-Hodgkin lymphoma ( 2 ). Finally, the pathology report may include ...

  14. Resolved Multifrequency Radio Observations of GG Tau

    Science.gov (United States)

    Andrews, Sean M.; Chandler, Claire J.; Isella, Andrea; Birnstiel, T.; Rosenfeld, K. A.; Wilner, D. J.; Pérez, L. M.; Ricci, L.; Carpenter, J. M.; Calvet, N.; Corder, S. A.; Deller, A. T.; Dullemond, C. P.; Greaves, J. S.; Harris, R. J.; Henning, Th.; Kwon, W.; Lazio, J.; Linz, H.; Mundy, L. G.; Sargent, A. I.; Storm, S.; Testi, L.

    2014-06-01

    We present subarcsecond resolution observations of continuum emission associated with the GG Tau quadruple star system at wavelengths of 1.3, 2.8, 7.3, and 50 mm. These data confirm that the GG Tau A binary is encircled by a circumbinary ring at a radius of 235 AU with a FWHM width of ~60 AU. We find no clear evidence for a radial gradient in the spectral shape of the ring, suggesting that the particle size distribution is spatially homogeneous on angular scales gsim0.''1. A central point source, likely associated with the primary component (GG Tau Aa), exhibits a composite spectrum from dust and free-free emission. Faint emission at 7.3 mm is observed toward the low-mass star GG Tau Ba, although its origin remains uncertain. Using these measurements of the resolved, multifrequency emission structure of the GG Tau A system, models of the far-infrared to radio spectrum are developed to place constraints on the grain size distribution and dust mass in the circumbinary ring. The non-negligible curvature present in the ring spectrum implies a maximum particle size of 1-10 mm, although we are unable to place strong constraints on the distribution shape. The corresponding dust mass is 30-300 M ⊕, at a temperature of 20-30 K. We discuss how this significant concentration of relatively large particles in a narrow ring at a large radius might be produced in a local region of higher gas pressures (i.e., a particle "trap") located near the inner edge of the circumbinary disk.

  15. Brain intraventricular injection of amyloid-β in zebrafish embryo impairs cognition and increases tau phosphorylation, effects reversed by lithium.

    Directory of Open Access Journals (Sweden)

    Laura Roesler Nery

    Full Text Available Alzheimer's disease (AD is a devastating neurodegenerative disorder with no effective treatment and commonly diagnosed only on late stages. Amyloid-β (Aβ accumulation and exacerbated tau phosphorylation are molecular hallmarks of AD implicated in cognitive deficits and synaptic and neuronal loss. The Aβ and tau connection is beginning to be elucidated and attributed to interaction with different components of common signaling pathways. Recent evidences suggest that non-fibrillary Aβ forms bind to membrane receptors and modulate GSK-3β activity, which in turn phosphorylates the microtubule-associated tau protein leading to axonal disruption and toxic accumulation. Available AD animal models, ranging from rodent to invertebrates, significantly contributed to our current knowledge, but complementary platforms for mechanistic and candidate drug screenings remain critical for the identification of early stage biomarkers and potential disease-modifying therapies. Here we show that Aβ1-42 injection in the hindbrain ventricle of 24 hpf zebrafish embryos results in specific cognitive deficits and increased tau phosphorylation in GSK-3β target residues at 5dpf larvae. These effects are reversed by lithium incubation and not accompanied by apoptotic markers. We believe this may represent a straightforward platform useful to identification of cellular and molecular mechanisms of early stage AD-like symptoms and the effects of neuroactive molecules in pharmacological screenings.

  16. Infective Exacerbation of Pasteurella multocida

    Directory of Open Access Journals (Sweden)

    Mayumi Hamada

    2016-01-01

    Full Text Available An 89-year-old lady presented with a one-day history of shortness of breath as well as a cough productive of brown sputum. Her medical history was significant for chronic obstructive pulmonary disease (COPD. She was in severe type one respiratory failure and blood tests revealed markedly raised inflammatory markers; however her chest X-ray was clear. On examination there was bronchial breathing with widespread crepitations and wheeze. She was treated as per an infective exacerbation of COPD. Subsequent blood cultures grew Pasteurella multocida, a common commensal in the oropharynx of domesticated animals. The patient was then asked about any contact with animals, after which she revealed she had a dog and was bitten on her left hand the day before admission. We should not forget to enquire about recent history of injuries or animal bites when patients present acutely unwell. She made a complete recovery after treatment with penicillin.

  17. Asthma exacerbation prediction: recent insights.

    Science.gov (United States)

    Fleming, Louise

    2018-04-01

    Asthma attacks are frequent in children with asthma and can lead to significant adverse outcomes including time off school, hospital admission and death. Identifying children at risk of an asthma attack affords the opportunity to prevent attacks and improve outcomes. Clinical features, patient behaviours and characteristics, physiological factors, environmental data and biomarkers are all associated with asthma attacks and can be used in asthma exacerbation prediction models. Recent studies have better characterized children at risk of an attack: history of a severe exacerbation in the previous 12 months, poor adherence and current poor control are important features which should alert healthcare professionals to the need for remedial action. There is increasing interest in the use of biomarkers. A number of novel biomarkers, including patterns of volatile organic compounds in exhaled breath, show promise. Biomarkers are likely to be of greatest utility if measured frequently and combined with other measures. To date, most prediction models are based on epidemiological data and population-based risk. The use of digital technology affords the opportunity to collect large amounts of real-time data, including clinical and physiological measurements and combine these with environmental data to develop personal risk scores. These developments need to be matched by changes in clinical guidelines away from a focus on current asthma control and stepwise escalation in drug therapy towards inclusion of personal risk scores and tailored management strategies including nonpharmacological approaches. There have been significant steps towards personalized prediction models of asthma attacks. The utility of such models needs to be tested in the ability not only to predict attacks but also to reduce them.

  18. Deficient hippocampal insulin signaling and augmented Tau phosphorylation is related to obesity- and age-induced peripheral insulin resistance: a study in Zucker rats.

    Science.gov (United States)

    Špolcová, Andrea; Mikulášková, Barbora; Kršková, Katarína; Gajdošechová, Lucia; Zórad, Štefan; Olszanecki, Rafał; Suski, Maciej; Bujak-Giżycka, Beata; Železná, Blanka; Maletínská, Lenka

    2014-09-25

    Insulin signaling and Tau protein phosphorylation in the hippocampi of young and old obese Zucker fa/fa rats and their lean controls were assessed to determine whether obesity-induced peripheral insulin resistance and aging are risk factors for central insulin resistance and whether central insulin resistance is related to the pathologic phosphorylation of the Tau protein. Aging and obesity significantly attenuated the phosphorylation of the insulin cascade kinases Akt (protein kinase B, PKB) and GSK-3β (glycogen synthase kinase 3β) in the hippocampi of the fa/fa rats. Furthermore, the hyperphosphorylation of Tau Ser396 alone and both Tau Ser396 and Thr231 was significantly augmented by aging and obesity, respectively, in the hippocampi of these rats. Both age-induced and obesity-induced peripheral insulin resistance are associated with central insulin resistance that is linked to hyperTau phosphorylation. Peripheral hyperinsulinemia, rather than hyperglycemia, appears to promote central insulin resistance and the Tau pathology in fa/fa rats.

  19. The Role of MicroRNAs in Aβ Deposition and Tau Phosphorylation in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Juanjuan Zhao

    2017-07-01

    Full Text Available Alzheimer’s disease (AD, with main clinical features of progressive impairment in cognitive and behavioral functions, is the most common degenerative disease of the central nervous system. Recent evidence showed that microRNAs (miRNAs played important roles in the pathological progression of AD. In this article, we reviewed the promising role of miRNAs in both Aβ deposition and Tau phosphorylation, two key pathological characters in the pathological progression of AD, which might be helpful for the understanding of pathogenesis and the development of new strategies of clinical diagnosis and treatment of AD.

  20. 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.)

  1. The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease

    Directory of Open Access Journals (Sweden)

    Halina Car

    2012-05-01

    Full Text Available  Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase-3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and β-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes.

  2. Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease.

    Science.gov (United States)

    Basurto-Islas, Gustavo; Grundke-Iqbal, Inge; Tung, Yunn Chyn; Liu, Fei; Iqbal, Khalid

    2013-06-14

    Neurofibrillary pathology of abnormally hyperphosphorylated Tau is a key lesion of Alzheimer disease and other tauopathies, and its density in the brain directly correlates with dementia. The phosphorylation of Tau is regulated by protein phosphatase 2A, which in turn is regulated by inhibitor 2, I2(PP2A). In acidic conditions such as generated by brain ischemia and hypoxia, especially in association with hyperglycemia as in diabetes, I2(PP2A) is cleaved by asparaginyl endopeptidase at Asn-175 into the N-terminal fragment (I2NTF) and the C-terminal fragment (I2CTF). Both I2NTF and I2CTF are known to bind to the catalytic subunit of protein phosphatase 2A and inhibit its activity. Here we show that the level of activated asparaginyl endopeptidase is significantly increased, and this enzyme and I2(PP2A) translocate, respectively, from neuronal lysosomes and nucleus to the cytoplasm where they interact and are associated with hyperphosphorylated Tau in Alzheimer disease brain. Asparaginyl endopeptidase from Alzheimer disease brain could cleave GST-I2(PP2A), except when I2(PP2A) was mutated at the cleavage site Asn-175 to Gln. Finally, an induction of acidosis by treatment with kainic acid or pH 6.0 medium activated asparaginyl endopeptidase and consequently produced the cleavage of I2(PP2A), inhibition of protein phosphatase 2A, and hyperphosphorylation of Tau, and the knockdown of asparaginyl endopeptidase with siRNA abolished this pathway in SH-SY5Y cells. These findings suggest the involvement of brain acidosis in the etiopathogenesis of Alzheimer disease, and asparaginyl endopeptidase-I2(PP2A)-protein phosphatase 2A-Tau hyperphosphorylation pathway as a therapeutic target.

  3. Characterization of the radiolabeled metabolite of tau PET tracer {sup 18}F-THK5351

    Energy Technology Data Exchange (ETDEWEB)

    Harada, Ryuichi [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Furumoto, Shozo; Tago, Tetsuro; Iwata, Ren; Tashiro, Manabu [Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Katsutoshi, Furukawa; Ishiki, Aiko; Tomita, Naoki; Arai, Hiroyuki [Tohoku University, Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Sendai (Japan); Yanai, Kazuhiko [Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Okamura, Nobuyuki [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Tohoku Medical and Pharmaceutical University, Division of Pharmacology, Faculty of Medicine, Sendai (Japan)

    2016-11-15

    {sup 18}F-THK5351 is a novel radiotracer developed for in vivo imaging of tau pathology in the brain. For the quantitative assessment of tau deposits in the brain, it is important that the radioactive metabolite does not enter the brain and that it does not bind to tau fibrils. The purpose of the study was to identify a radiolabeled metabolite of {sup 18}F-THK5351 in blood samples from human subjects and to characterize its pharmacological properties. Venous blood samples were collected from three human subjects after injection of {sup 18}F-THK5351 and the plasma metabolite was measured by high performance thin layer chromatography. In addition, mass spectrometry analysis and enzymatic assays were used to identify this metabolite. Mice were used to investigate the blood-brain barrier permeability of the radioactive metabolite. Furthermore, the binding ability of the metabolite to tau aggregates was evaluated using autoradiography and binding assays using human brain samples. About 13 % of the unmetabolized radiotracer was detectable in human plasma at 60 min following the injection of {sup 18}F-THK5351. The isolated radiometabolite of {sup 18}F-THK5351 was the sulphoconjugate of THK5351. This metabolite could be produced in vitro by incubating THK5351 with liver but not brain homogenates. The metabolite did not penetrate the blood-brain barrier in mice, and exhibited little binding to tau protein aggregates in post-mortem human brain samples. These results suggest that the sole metabolite detectable in plasma seems to be generated outside the brain and does not cross into the brain, which does not affect quantitative analysis of PET images. (orig.)

  4. 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...

  5. Spin effects in tau-lepton pair production

    CERN Document Server

    Pierzchala, T.; Was, Z.; Worek, M.

    2001-01-01

    Question of the proper incorporation of spin effects in tau lepton decays is often of importance. In present work, case of the Z/gamma to tau+ tau- production mechanism is studied in detail. As an example, the effects due to the spin correlations on the potential for the Minimal Supersymmetric Standard Model (MSSM) Higgs searches in the tau tau decay channel at the Large Hadron Collider (LHC) are discussed. For these processes, the Standard Model Z/gamma to tau tau -pair production is a dominant background. The spin effects in high energy physics reactions, can be implemented up to certain approximation, independently of the algorithm and matrix elements used by the production program. Information stored on every generated event can be sufficient. The algorithm based on such approximation is documented. Question of the theoretical uncertaintity is discussed only partly.

  6. APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

    Directory of Open Access Journals (Sweden)

    Steven Moore

    2015-05-01

    Full Text Available Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD. To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons.

  7. Mechanisms in dominant parkinsonism: The toxic triangle of LRRK2, alpha-synuclein, and tau.

    Science.gov (United States)

    Taymans, Jean-Marc; Cookson, Mark R

    2010-03-01

    Parkinson's disease (PD) is generally sporadic but a number of genetic diseases have parkinsonism as a clinical feature. Two dominant genes, alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2), are important for understanding inherited and sporadic PD. SNCA is a major component of pathologic inclusions termed Lewy bodies found in PD. LRRK2 is found in a significant proportion of PD cases. These two proteins may be linked as most LRRK2 PD cases have SNCA-positive Lewy bodies. Mutations in both proteins are associated with toxic effects in model systems although mechanisms are unclear. LRRK2 is an intracellular signaling protein possessing both GTPase and kinase activities that may contribute to pathogenicity. A third protein, tau, is implicated as a risk factor for PD. We discuss the potential relationship between these genes and suggest a model for PD pathogenesis where LRRK2 is upstream of pathogenic effects through SNCA, tau, or both proteins.

  8. X-ray diffraction from intact tau aggregates in human brain tissue

    Energy Technology Data Exchange (ETDEWEB)

    Landahl, Eric C.; Antipova, Olga; Bongaarts, Angela; Barrea, Raul; Berry, Robert; Binder, Lester I.; Irving, Thomas; Orgel, Joseph; Vana, Laurel; Rice, Sarah E. (DePaul); (IIT); (NWU)

    2011-09-15

    We describe an instrument to record X-ray diffraction patterns from diseased regions of human brain tissue by combining an in-line visible light fluorescence microscope with an X-ray diffraction microprobe. We use thiazine red fluorescence to specifically label and detect the filamentous tau protein pathology associated with Pick's disease, as several laboratories have done previously. We demonstrate that thiazine red-enhanced regions within the tissue show periodic structure in X-ray diffraction, which is not observed in healthy tissue. One observed periodicity (4.2 {angstrom}) is characteristic of cross-beta sheet structure, consistent with previous results from powder diffraction studies performed on purified, dried tau protein.

  9. X-ray diffraction from intact tau aggregates in human brain tissue

    Energy Technology Data Exchange (ETDEWEB)

    Landahl, Eric C. [DePaul University, Department of Physics, 2219 N. Kenmore Ave., IL 60614, Chicago (United States); Antipova, Olga [Illinois Institute of Technology, Department of Biological Chemical and Physical Sciences, 3101 South Dearborn St., IL 60616, Chicago (United States); Bongaarts, Angela [Northwestern University, Department of Cell and Molecular Biology, 303 E. Chicago Ave., IL 60611, Chicago (United States); Barrea, Raul [Illinois Institute of Technology, Department of Biological Chemical and Physical Sciences, 3101 South Dearborn St., IL 60616, Chicago (United States); Berry, Robert; Binder, Lester I. [Northwestern University, Department of Cell and Molecular Biology, 303 E. Chicago Ave., IL 60611, Chicago (United States); Irving, Thomas; Orgel, Joseph [Illinois Institute of Technology, Department of Biological Chemical and Physical Sciences, 3101 South Dearborn St., IL 60616, Chicago (United States); Vana, Laurel [Northwestern University, Department of Cell and Molecular Biology, 303 E. Chicago Ave., IL 60611, Chicago (United States); Rice, Sarah E., E-mail: s-rice@northwestern.edu [Northwestern University, Department of Cell and Molecular Biology, 303 E. Chicago Ave., IL 60611, Chicago (United States)

    2011-09-01

    We describe an instrument to record X-ray diffraction patterns from diseased regions of human brain tissue by combining an in-line visible light fluorescence microscope with an X-ray diffraction microprobe. We use thiazine red fluorescence to specifically label and detect the filamentous tau protein pathology associated with Pick's disease, as several laboratories have done previously. We demonstrate that thiazine red-enhanced regions within the tissue show periodic structure in X-ray diffraction, which is not observed in healthy tissue. One observed periodicity (4.2 A) is characteristic of cross-beta sheet structure, consistent with previous results from powder diffraction studies performed on purified, dried tau protein.

  10. Fibrillization of human tau is accelerated by exposure to lead via interaction with His-330 and His-362.

    Directory of Open Access Journals (Sweden)

    Hai-Li Zhu

    Full Text Available BACKGROUND: Neurofibrillary tangles, mainly consisted of bundles of filaments formed by the microtubule-associated protein Tau, are a hallmark of Alzheimer disease. Lead is a potent neurotoxin for human being especially for the developing children, and Pb(2+ at high concentrations is found in the brains of patients with Alzheimer disease. However, it has not been reported so far whether Pb(2+ plays a role in the pathology of Alzheimer disease through interaction with human Tau protein and thereby mediates Tau filament formation. In this study, we have investigated the effect of Pb(2+ on fibril formation of recombinant human Tau fragment Tau(244-372 and its mutants at physiological pH. METHODOLOGY/PRINCIPAL FINDINGS: As revealed by thioflavin T and 8-anilino-1-naphthalene sulfonic acid fluorescence, the addition of 5-40 µM Pb(2+ significantly accelerates the exposure of hydrophobic region and filament formation of wild-type Tau(244-372 on the investigated time scale. As evidenced by circular dichroism and Fourier transform infrared spectroscopy, fibrils formed by wild-type Tau(244-372 in the presence of 5-40 µM Pb(2+ contain more β-sheet structure than the same amount of fibrils formed by the protein in the absence of Pb(2+. However, unlike wild-type Tau(244-372, the presence of 5-40 µM Pb(2+ has no obvious effects on fibrillization kinetics of single mutants H330A and H362A and double mutant H330A/H362A, and fibrils formed by such mutants in the absence and in the presence of Pb(2+ contain similar amounts of β-sheet structure. The results from isothermal titration calorimetry show that one Pb(2+ binds to one Tau monomer via interaction with His-330 and His-362, with sub-micromolar affinity. CONCLUSIONS/SIGNIFICANCE: We demonstrate for the first time that the fibrillization of human Tau protein is accelerated by exposure to lead via interaction with His-330 and His-362. Our results suggest the possible involvement of Pb(2+ in the

  11. Tau deposition drives neuropathological, inflammatory and behavioral abnormalities independently of neuronal loss in a novel mouse model

    Science.gov (United States)

    Cook, Casey; Kang, Silvia S.; Carlomagno, Yari; Lin, Wen-Lang; Yue, Mei; Kurti, Aishe; Shinohara, Mitsuru; Jansen-West, Karen; Perkerson, Emilie; Castanedes-Casey, Monica; Rousseau, Linda; Phillips, Virginia; Bu, Guojun; Dickson, Dennis W.; Petrucelli, Leonard; Fryer, John D.

    2015-01-01

    Aberrant tau protein accumulation drives neurofibrillary tangle (NFT) formation in several neurodegenerative diseases. Currently, efforts to elucidate pathogenic mechanisms and assess the efficacy of therapeutic targets are limited by constraints of existing models of tauopathy. In order to generate a more versatile mouse model of tauopathy, somatic brain transgenesis was utilized to deliver adeno-associated virus serotype 1 (AAV1) encoding human mutant P301L-tau compared with GFP control. At 6 months of age, we observed widespread human tau expression with concomitant accumulation of hyperphosphorylated and abnormally folded proteinase K resistant tau. However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95. Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments. In addition to classic markers of tauopathy, significant neuroinflammation and extensive gliosis were detected in AAV1-TauP301L mice. This model also recapitulates the behavioral phenotype characteristic of mouse models of tauopathy, including abnormalities in exploration, anxiety, and learning and memory. These findings indicate that biochemical and neuropathological hallmarks of tauopathies are accurately conserved and are independent of cell death in this novel AAV-based model of tauopathy, which offers exceptional versatility and speed in comparison with existing transgenic models. Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets. PMID:26276810

  12. Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Francesco Panza

    2016-01-01

    Full Text Available The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI is methylthioninium (MT, a drug existing in equilibrium between a reduced (leuco-methylthioninium and oxidized form (MT+. MT chloride (methylene blue was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

  13. 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.

  14. Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.

    Science.gov (United States)

    Watamura, Naoto; Toba, Junya; Yoshii, Aya; Nikkuni, Miyu; Ohshima, Toshio

    2016-01-01

    Alzheimer's disease (AD) is the most common type of dementia among the elderly. Neurofibrillary tangles (NFTs), a major pathological hallmark of AD, are composed of tau protein that is hyperphosphorylated by cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK3β). NFTs also contain Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) and collapsin response-mediator protein 2 (CRMP2). Although Cdk5 is known to phosphorylate tau, WAVE1, and CRMP2, the significance of this with respect to NFT formation remains to be elucidated. This study examines the involvement of phosphorylated (p-) CRMP2 and WAVE1 in p-tau aggregates using a triple-transgenic (3×Tg; APPswe/PS1M146V/tauP301L) AD mouse model. First, we verified the colocalization of p-WAVE1 and p-CRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates. To test the significance of phosphorylation of these proteins further, we administered all-trans-retinoic acid (ATRA) to the 3×Tg mice, which downregulates Cdk5 and GSK3β activity. In ATRA-treated mice, fewer and smaller tau aggregates were observed compared with non-ATRA-treated mice. These results suggest the possibility of novel therapeutic target molecules for preventing tau pathology. © 2015 Wiley Periodicals, Inc.

  15. Blood Coagulation and Asthma Exacerbation in Children.

    Science.gov (United States)

    Manuyakorn, Wiparat; Mairiang, Dara; Sirachainan, Nongnuch; Kadegasem, Praguywan; Kamchaisatian, Wasu; Benjaponpitak, Suwat; Chuansumrit, Ampaiwan

    2016-01-01

    Recent studies have demonstrated the activation of coagulation pathways in asthmatic airways. This study aimed to determine systemic blood coagulation during asthma exacerbation compared with the stable state in children. Pediatric patients (aged between 5 and 15 years) suffering from asthma exacerbation were enrolled. von Willebrand factor (vWF), plasminogen activator inhibitor type-1 (PAI-1), protein C, D-dimer, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), and C-reactive protein (CRP) levels were measured during asthma exacerbation and stable state. A total of 22 patients were enrolled. The median vWF, PAI-1, and CRP during asthma exacerbation were significantly higher than those of the stable state: 147.5% (interquartile range, IQR: 111.05-196.57) versus 94% (IQR: 69.72-109.62, p coagulation in asthma exacerbation. © 2016 S. Karger AG, Basel.

  16. [Treatment and prevention of COPD exacerbation].

    Science.gov (United States)

    Yamaya, Mutsuo; Yasuda, Hiroyasu; Yoshida, Motoki; Nishimura, Hidekazu; Nakayama, Katsutoshi

    2007-04-01

    Airway inflammation, mucosal edema, epithelial hyperpermeability, mucus secretion and airway smooth muscle contraction induced by airway bacterial, virus infection and exposure to air pollution may be associated with COPD exacerbation. Severity of COPD exacerbation is estimated by blood gas analysis, serum CRP values and the chest radiograph. Patients with COPD exacerbations are recommended to be treated with additional inhalations of beta-2 agonists and anti -cholinergic agents, systemic administered glucocorticosteroids, oxygen inhalation, and, in cases with purulent sputum, antibiotics. Glucocorticosteroids, beta-2 agonists and anti-cholinergic agents reduce the frequency of COPD exacerbation. We reported the inhibitory effects of glucocorticosteroids on rhinovirus infection, the major cause of common colds, and the inhibitory effects of L-carbocisteine and erythromycin on COPD exacerbations and rhinovirus infection.

  17. HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology

    NARCIS (Netherlands)

    Sepulveda-Diaz, J.E.; Naini, S.M. Alavi; Huynh, M.B.; Ouidja, M.O.; Yanicostas, C.; Chantepie, S.; Villares, J.; Lamari, F.; Jospin, E.; Kuppevelt, T.H. van; Mensah-Nyagan, A.G.; Raisman-Vozari, R.; Soussi-Yanicostas, N.; Papy-Garcia, D.

    2015-01-01

    Heparan sulphate (glucosamine) 3-O-sulphotransferase 2 (HS3ST2, also known as 3OST2) is an enzyme predominantly expressed in neurons wherein it generates rare 3-O-sulphated domains of unknown functions in heparan sulphates. In Alzheimer's disease, heparan sulphates accumulate at the intracellular

  18. Digital pathology

    CERN Document Server

    Sucaet, Yves

    2014-01-01

    Digital pathology has experienced exponential growth, in terms of its technology and applications, since its inception just over a decade ago. Though it has yet to be approved for primary diagnostics, its values as a teaching tool, facilitator of second opinions and quality assurance reviews and research are becoming, if not already, undeniable. It also offers the hope of providing pathology consultant and educational services to under-served areas, including regions of the world that could not possibly sustain this level of services otherwise. And this is just the beginning, as its adoption b

  19. Muon Neutrino Disappearance and Tau Neutrino Appearance

    CERN Document Server

    Sanchez, M C

    2011-01-01

    Since evidence for neutrino oscillations was first observed in 1998, the study of muon neutrino oscillations has been aggressively pursued. In doing so, atmospheric and accelerator-based neutrino experiments have measured with the highest precision two fundamental neutrino parameters: the mass-square difference and the large mixing angle in the atmospheric neutrino sector. Furthermore, the dominant mode of these oscillations has recently been established to be from muon to tau neutrinos with both direct and indirect observations. Also, for the first time the anti-neutrino counterparts to these oscillation parameters are being studied. While a consistent picture of the mu-tau sector is thus emerging, a new generation of accelerator-based experiments using off-axis neutrino beams to access this sector could lead to new discoveries.

  20. Testing QCD with Hypothetical Tau Leptons

    Energy Technology Data Exchange (ETDEWEB)

    Brodsky, Stanley J.

    1998-10-21

    We construct new tests of perturbative QCD by considering a hypothetical {tau} lepton of arbitrary mass, which decays hadronically through the electromagnetic current. We can explicitly compute its hadronic width ratio directly as an integral over the e{sup +}e{sup -} annihilation cross section ratio, R{sub e{sup +}e{sup -}}. Furthermore, we can design a set of commensurate scale relations and perturbative QCD tests by varying the weight function away from the form associated with the V-A decay of the physical {tau}. This method allows the wide range of the R{sub e{sup +}e{sup -}} data to be used as a probe of perturbative QCD.

  1. Optimizing antibiotic selection in treating COPD exacerbations

    Directory of Open Access Journals (Sweden)

    Attiya Siddiqi

    2008-03-01

    Full Text Available Attiya Siddiqi, Sanjay SethiDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Veterans Affairs Western New York Health Care System and University of Buffalo, State University of New York, Buffalo, New York, USAAbstract: Our understanding of the etiology, pathogenesis and consequences of acute exacerbations of chronic obstructive pulmonary disease (COPD has increased substantially in the last decade. Several new lines of evidence demonstrate that bacterial isolation from sputum during acute exacerbation in many instances reflects a cause-effect relationship. Placebo-controlled antibiotic trials in exacerbations of COPD demonstrate significant clinical benefits of antibiotic treatment in moderate and severe episodes. However, in the multitude of antibiotic comparison trials, the choice of antibiotics does not appear to affect the clinical outcome, which can be explained by several methodological limitations of these trials. Recently, comparison trials with nontraditional end-points have shown differences among antibiotics in the treatment of exacerbations of COPD. Observational studies that have examined clinical outcome of exacerbations have repeatedly demonstrated certain clinical characteristics to be associated with treatment failure or early relapse. Optimal antibiotic selection for exacerbations has therefore incorporated quantifying the risk for a poor outcome of the exacerbation and choosing antibiotics differently for low risk and high risk patients, reserving the broader spectrum drugs for the high risk patients. Though improved outcomes in exacerbations with antibiotic choice based on such risk stratification has not yet been demonstrated in prospective controlled trials, this approach takes into account concerns of disease heterogeneity, antibiotic resistance and judicious antibiotic use in exacerbations.Keywords: COPD, exacerbation, bronchitis, antibiotics

  2. 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

  3. The strong coupling from ALEPH tau decays

    Science.gov (United States)

    Rodríguez Sánchez, Antonio

    2017-06-01

    We analyze some of the different determinations of αs (mτ2) that can be found in the literature and the numerical impact of their possible weaknesses with the publicly available non-strange spectral function from ALEPH tau decays. We also introduce some novel approaches. We find very stable results and uncertainties dominated by the perturbative part. Our final value is αs (mτ2>) = 0.328 ± 0.013.

  4. Multilevel hybrid Chernoff tau-leap

    KAUST Repository

    Moraes, Alvaro

    2015-04-08

    In this work, we extend the hybrid Chernoff tau-leap method to the multilevel Monte Carlo (MLMC) setting. Inspired by the work of Anderson and Higham on the tau-leap MLMC method with uniform time steps, we develop a novel algorithm that is able to couple two hybrid Chernoff tau-leap paths at different levels. Using dual-weighted residual expansion techniques, we also develop a new way to estimate the variance of the difference of two consecutive levels and the bias. This is crucial because the computational work required to stabilize the coefficient of variation of the sample estimators of both quantities is often unaffordable for the deepest levels of the MLMC hierarchy. Our method bounds the global computational error to be below a prescribed tolerance, TOL, within a given confidence level. This is achieved with nearly optimal computational work. Indeed, the computational complexity of our method is of order O(TOL−2), the same as with an exact method, but with a smaller constant. Our numerical examples show substantial gains with respect to the previous single-level approach and the Stochastic Simulation Algorithm.

  5. ALEPH Tau Spectral Functions and QCD

    CERN Document Server

    Davier, M; Zhang, Z; Davier, Michel; Hoecker, Andreas; Zhang, Zhiqing

    2007-01-01

    Hadronic $\\tau$ decays provide a clean laboratory for the precise study of quantum chromodynamics (QCD). Observables based on the spectral functions of hadronic $\\tau$ decays can be related to QCD quark-level calculations to determine fundamental quantities like the strong coupling constant, quark and gluon condensates. Using the ALEPH spectral functions and branching ratios, complemented by some other available measurements, and a revisited analysis of the theoretical framework, the value $\\asm = 0.345 \\pm 0.004_{\\rm exp} \\pm 0.009_{\\rm th}$ is obtained. Taken together with the determination of \\asZ from the global electroweak fit, this result leads to the most accurate test of asymptotic freedom: the value of the logarithmic slope of $\\alpha_s^{-1}(s)$ is found to agree with QCD at a precision of 4%. The value of \\asZ obtained from $\\tau$ decays is $\\asZ = 0.1215 \\pm 0.0004_{\\rm exp} \\pm 0.0010_{\\rm th} \\pm 0.0005_{\\rm evol} = 0.1215 \\pm 0.0012$.

  6. SURGICAL PATHOLOGY

    African Journals Online (AJOL)

    Methods: The histology records of patients diagnosed as cases of malignant melanoma in the pathology laboratory of Jos University Teaching Hospital over a ... patients (82.4%) presented with foot lesions, six (8.8%) with groin lesions and 2 (2.9%) each with upper limb and conjuctival lesions. The vulva and oral mucosa ...

  7. Can we predict fall asthma exacerbations? Validation of the seasonal asthma exacerbation index.

    Science.gov (United States)

    Hoch, Heather E; Calatroni, Agustin; West, Joseph B; Liu, Andrew H; Gergen, Peter J; Gruchalla, Rebecca S; Khurana Hershey, Gurjit K; Kercsmar, Carolyn M; Kim, Haejin; Lamm, Carin I; Makhija, Melanie M; Mitchell, Herman E; Teach, Stephen J; Wildfire, Jeremy J; Busse, William W; Szefler, Stanley J

    2017-10-01

    A Seasonal Asthma Exacerbation Predictive Index (saEPI) was previously reported based on 2 prior National Institute of Allergy and Infectious Diseases Inner City Asthma Consortium trials. This study sought to validate the saEPI in a separate trial designed to prevent fall exacerbations with omalizumab therapy. The saEPI and its components were analyzed to characterize those who had an asthma exacerbation during the Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations (PROSE) study. We characterized those inner-city children with and without asthma exacerbations in the fall period treated with guidelines-based therapy (GBT) in the absence and presence of omalizumab. A higher saEPI was associated with an exacerbation in both the GBT alone (P asthma exacerbation in both groups. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.

  8. Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy.

    Science.gov (United States)

    Spires-Jones, Tara L; Friedman, Taylor; Pitstick, Rose; Polydoro, Manuela; Roe, Allyson; Carlson, George A; Hyman, Bradley T

    2014-03-06

    Alzheimer's disease is characterized pathologically by aggregation of amyloid beta into senile plaques and aggregation of pathologically modified tau into neurofibrillary tangles. While changes in amyloid processing are strongly implicated in disease initiation, the recent failure of amyloid-based therapies has highlighted the importance of tau as a therapeutic target. "Tangle busting" compounds including methylene blue and analogous molecules are currently being evaluated as therapeutics in Alzheimer's disease. Previous studies indicated that methylene blue can reverse tau aggregation in vitro after 10 min, and subsequent studies suggested that high levels of drug reduce tau protein levels (assessed biochemically) in vivo. Here, we tested whether methylene blue could remove established neurofibrillary tangles in the rTg4510 model of tauopathy, which develops robust tangle pathology. We find that 6 weeks of methylene blue dosing in the water from 16 months to 17.5 months of age decreases soluble tau but does not remove sarkosyl insoluble tau, or histologically defined PHF1 or Gallyas positive tangle pathology. These data indicate that methylene blue treatment will likely not rapidly reverse existing tangle pathology. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. First Measurement of the Branching Fraction of the Decay $\\psi(2S) \\to \\tau\\tau$

    CERN Document Server

    Bai, J Z; Bian, J G; Blum, I K; Chen, G P; Chen, H F; Chen, J; Chen Jia Chao; Chen, Y; Chen, Y B; Chen, Y Q; Cheng Bao Sen; Cui, X Z; Ding, H L; Dong, L Y; Du, Z Z; Dunwoodie, W M; Gao, C S; Gao, M L; Gao, S Q; Gratton, P; Gu, J H; Gu, S D; Gu, W X; Gu, Y F; Guo, Z J; Guo, Y N; Han, S W; Han, Y; Harris, F A; He, J; He, J T; He, K L; He, M; Heng, Y K; Hitlin, D G; Hu, G Y; Hu, H M; Hu, J L; Hu, Q H; Hu, T; Hu Xiao Qing; Huang, G S; Huang, Y Z; Izen, J M; Jiang, C H; Jin, Y; Jones, B D; Ju, X; Ke, Z J; Kelsey, M H; Kim, B K; Kong, D; Lai, Y F; Lang, P F; Lankford, A J; Li, C G; Li, D; Li, H B; Li, J; Li, J C; Li, P Q; Li, R B; Li, W; Li, W G; Li, X H; Li Xiao Nan; Liu, H M; Liu, J; Liu, R G; Liu, Y; Lou, X C; Lowery, B; Lu, F; Lu, J G; Luo, X L; Ma, E C; Ma, J M; Malchow, R; Mao, H S; Mao, Z P; Meng, X C; Nie, J; Olsen, S L; Oyang, J Y T; Paluselli, D; Pan, L J; Panetta, J; Porter, F; Qi, N D; Qi, X R; Qian, C D; Qiu, J F; Qu, Y H; Que, Y K; Rong, G; Schernau, M; Shao, Y Y; Shen, B W; Shen, D L; Shen, H; Shen, X Y; Sheng, H Y; Shi, H Z; Song, X F; Standifird, J; Sun, F; Sun, H S; Sun, Y; Sun, Y Z; Tang, S Q; Toki, W; Tong, G L; Varner, G S; Wang, F; Wang, L S; Wang, L Z; Wang, M; Wang, P; Wang, P L; Wang, S M; Wang, T J; Wang, Y Y; Weaver, M; Wei, C L; Wu, J M; Wu, N; Wu, Y G; Xi, D M; Xia, X M; Xie, P P; Xie, Y; Xie, Y H; Xu, G F; Xue, S T; Yan, J; Yan, W G; Yang, C M; Yang, C Y; Yang, H X; Yang, J; Yang, W; Yang, X F; Ye, M H; Ye Shu Wei; Ye, Y X; Yu, C S; Yu, C X; Yu, G W; Yu Yu Hei; Yu, Z Q; Yuan, C Z; Yuan, Y; Zhang Bing Yun; Zhang, C; Zhang, C C; Zhang, D H; Zhang, H L; Zhang, J; Zhang, J W; Zhang, L; Zhang, L S; Zhang, P; Zhang, Q J; Zhang, S Q; Zhang, X Y; Zhang, Y Y; Zhao, D X; Zhao, H W; Zhao Jia Wei; Zhao, M; Zhao Wei Ren; Zhao, Z G; Zheng Jian Ping; Zheng Lin Sheng; Zheng Zhi Peng; Zhou, B Q; Zhou, G P; Zhou, H S; Zhou, L; Zhu, K J; Zhu, Q M; Zhu, Y C; Zhu, Y S; Zhuang, B A

    2002-01-01

    The branching fraction of the psi(2S) decay into tau pair has been measured for the first time using the BES detector at the Beijing Electron-Positron Collider. The result is $B_{\\tau\\tau}=(2.71\\pm 0.43 \\pm 0.55) \\times 10^{-3}$, where the first error is statistical and the second is systematic. This value, along with those for the branching fractions into e+e- and mu+mu of this resonance, satisfy well the relation predicted by the sequential lepton hypothesis. Combining all these values with the leptonic width of the resonance the total width of the psi(2S) is determined to be $(252 \\pm 37)$ keV.

  10. Asthma Exacerbation in Children: A Practical Review

    Directory of Open Access Journals (Sweden)

    Lin-Shien Fu

    2014-04-01

    Full Text Available Asthma is the most common chronic lower respiratory tract disease in childhood throughout the world. Despite advances in asthma management, acute exacerbations continue to be a major problem in patients and they result in a considerable burden on direct/indirect health care providers. A severe exacerbation occurring within 1 year is an independent risk factor. Respiratory tract viruses have emerged as the most frequent triggers of exacerbations in children. It is becoming increasingly clear that interactions may exist between viruses and other triggers, increasing the likelihood of an exacerbation. In this study, we provide an overview of current knowledge about asthma exacerbations, including its definition, impact on health care providers, and associated factors. Prevention management in intermittent asthma as well as intermittent wheeze in pre-school children and those with persistent asthma are discussed. Our review findings support the importance of controlling persistent asthma, as indicated in current guidelines. In addition, we found that early episodic intervention appeared to be crucial in preventing severe attacks and future exacerbations. Besides the use of medication, timely education after an exacerbation along with a comprehensive plan in follow up is also vitally important.

  11. Prevention of exacerbations of COPD with pharmacotherapy.

    Science.gov (United States)

    Miravitlles, M

    2010-06-01

    Exacerbations are a frequent event in the evolution of chronic obstructive pulmonary disease (COPD) patients. Individuals with COPD have a mean of 1-3 episodes per year, some of which lead to hospital admission and may even be a cause of death. The importance of COPD exacerbations has become increasingly apparent due to the impact these episodes have on the natural history of disease. It is now known that frequent exacerbations can adversely affect health-related quality of life and short- and long-term pulmonary function. Optimising treatment for stable COPD will help to reduce exacerbations. Long-acting bronchodilators, alone or combined with inhaled corticosteroids, have demonstrated efficacy in reducing the rate of exacerbations in patients with COPD. Other innovative approaches are being investigated, such as the long-term use of macrolides or the use of antibiotics in an effort to suppress bronchial colonisation and consequent exacerbations. Other drugs, such as mucolytics and immunomodulators, have recently provided positive results. Non-pharmacological interventions such as rehabilitation, self-management plans and the maintenance of high levels of physical activity in daily life are also useful strategies to prevent exacerbations in patients with COPD and should be implemented in regular clinical practice.

  12. Prevention of exacerbations of COPD with pharmacotherapy

    Directory of Open Access Journals (Sweden)

    M. Miravitlles

    2010-06-01

    Full Text Available Exacerbations are a frequent event in the evolution of chronic obstructive pulmonary disease (COPD patients. Individuals with COPD have a mean of 1–3 episodes per year, some of which lead to hospital admission and may even be a cause of death. The importance of COPD exacerbations has become increasingly apparent due to the impact these episodes have on the natural history of disease. It is now known that frequent exacerbations can adversely affect health-related quality of life and short- and long-term pulmonary function. Optimising treatment for stable COPD will help to reduce exacerbations. Long-acting bronchodilators, alone or combined with inhaled corticosteroids, have demonstrated efficacy in reducing the rate of exacerbations in patients with COPD. Other innovative approaches are being investigated, such as the long-term use of macrolides or the use of antibiotics in an effort to suppress bronchial colonisation and consequent exacerbations. Other drugs, such as mucolytics and immunomodulators, have recently provided positive results. Non-pharmacological interventions such as rehabilitation, self-management plans and the maintenance of high levels of physical activity in daily life are also useful strategies to prevent exacerbations in patients with COPD and should be implemented in regular clinical practice.

  13. Interactions between Aβ and mutated Tau lead to polymorphism and induce aggregation of Aβ-mutated tau oligomeric complexes.

    Directory of Open Access Journals (Sweden)

    Yoav Raz

    Full Text Available One of the main hallmarks of the fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17 is the accumulation of neurofibrillary tangles in the brain as an outcome of the aggregation of mutated tau protein. This process occurs due to a number of genetic mutations in the MAPT gene. One of these mutations is the ∆K280 mutation in the tau R2 repeat domain, which promotes the aggregation vis-à-vis that for the wild-type tau. Experimental studies have shown that in Alzheimer's disease Aβ peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between Aβ and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between Aβ and mutated tau, we constructed fourteen ∆K280 mutated tau-Aβ17-42 oligomeric complexes. In seven of the mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited salt-bridge interactions in their core domain. We considered two types of interactions between mutated tau oligomers and Aβ oligomers: interactions of one monomer of the Aβ oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire Aβ oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of Aβ trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of Aβ and mutated tau oligomers, polymorphic mutated tau-Aβ17-42 oligomeric complexes were observed, with a slight preference for the double-layer conformation. Aβ trimers alternating with mutated tau trimers constituted a structurally stable confined β-structure, albeit one

  14. Ablation of TNF-RI/RII expression in Alzheimer's disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-α suppressive therapeutic strategies in the brain.

    Science.gov (United States)

    Montgomery, Sara L; Mastrangelo, Michael A; Habib, Diala; Narrow, Wade C; Knowlden, Sara A; Wright, Terry W; Bowers, William J

    2011-10-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss and cognitive impairment. Neuroinflammation, including the extensive production of pro-inflammatory molecules and the activation of microglia, has been implicated in the disease process. Tumor necrosis factor (TNF)-α, a prototypic pro-inflammatory cytokine, is elevated in AD, is neurotoxic, and colocalizes with amyloid plaques in AD animal models and human brains. We previously demonstrated that the expression of TNF-α is increased in AD mice at ages preceding the development of hallmark amyloid and tau pathological features and that long-term expression of this cytokine in these mice leads to marked neuronal death. Such observations suggest that TNF-α signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-α receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-α receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-α. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced amyloid-β phagocytic marker expression and phagocytosis activity, indicating that intact TNF-α receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-β peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-α inhibitors for the treatment of AD. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  15. Prevention of exacerbations of COPD with pharmacotherapy

    OpenAIRE

    M. Miravitlles

    2010-01-01

    Exacerbations are a frequent event in the evolution of chronic obstructive pulmonary disease (COPD) patients. Individuals with COPD have a mean of 1–3 episodes per year, some of which lead to hospital admission and may even be a cause of death. The importance of COPD exacerbations has become increasingly apparent due to the impact these episodes have on the natural history of disease. It is now known that frequent exacerbations can adversely affect health-related quality of life and short- an...

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

    Science.gov (United States)

    2016-10-01

    During the last year we have worked on the first point of the hypothesis. We have found that administration of tau purified from shockwave-exposed mice...accomplished under these goals? We have found that administration of tau purified from shockwave-exposed mice onto wild-type mice markedly reduces 1...DeKosky, S.T., M.D. Ikonomovic, and S. Gandy, Traumatic brain injury-- football , warfare, and long-term effects. N Engl J Med, 2010. 363(14): p. 1293-6. 2

  17. Optimisation of the reconstruction of high energetic tau leptons with ATLAS

    CERN Document Server

    Morgenstern, Marcus; Mader, Wolfgang

    2010-01-01

    Searches for Higgs bosons as well as for new physics are the main goals of the LHC physics programme. Such physics processes are predicted to involve tau leptons in the final state. Therefore, tau leptons provide an important signature for new physics at ATLAS. Efficient tau reconstruction and tau identification are required over a wide kinematic range. In particular, hadronic tau decays in the high transverse momentum regime are of interest. In this thesis a method using dynamic cone sizes for tau reconstruction is studied in order to optimise the overall performance for the measurement of tau leptons. Both, tau reconstruction and tau identification are considered in this performance study.

  18. Urban Pathology

    OpenAIRE

    Pitcher, Brian L.

    1997-01-01

    Urban theorists have long debated to what extend and how the social problems of the city have been brought about or exaggerated in some consistent way by the urban environments in which they occur. This presentation reviews theories of urbanism, and the features of cities which contribute to the augmentation and control of various types of social pathology. Special emphasis is given to some types and patterns of urban unrest, and the structural characteristics associated with deleterious urba...

  19. Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3β and CDK5 dependent manner: Relevance to neurological disorders.

    Science.gov (United States)

    Gąssowska, Magdalena; Baranowska-Bosiacka, Irena; Moczydłowska, Joanna; Tarnowski, Maciej; Pilutin, Anna; Gutowska, Izabela; Strużyńska, Lidia; Chlubek, Dariusz; Adamczyk, Agata

    2016-03-10

    Hyperphosphorylation of Tau is involved in the pathomechanism of neurological disorders such as Alzheimer's, Parkinson's diseases as well as Autism. Epidemiological data suggest the significance of early life exposure to lead (Pb) in etiology of disorders affecting brain function. However, the precise mechanisms by which Pb exerts neurotoxic effects are not fully elucidated. The purpose of this study was to evaluate the effect of perinatal exposure to low dose of Pb on the Tau pathology in the developing rat brain. Furthermore, the involvement of two major Tau-kinases: glycogen synthase kinase-3 beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5) in Pb-induced Tau modification was evaluated. Pregnant female rats were divided into control and Pb-treated group. The control animals were maintained on drinking water while females from the Pb-treated group received 0.1% lead acetate (PbAc) in drinking water, starting from the first day of gestation until weaning of the offspring. During the feeding of pups, mothers from the Pb-treated group were still receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and Tau mRNA and protein level as well as Tau phosphorylation were analyzed in forebrain cortex (FC), cerebellum (C) and hippocampus (H). Concomitantly, we examined the effect of Pb exposure on GSK-3β and CDK5 activation. Our data revealed that pre- and neonatal exposure to Pb (concentration of Pb in whole blood below 10μg/dL, considered safe for humans) caused significant increase in the phosphorylation of Tau at Ser396 and Ser199/202 with parallel rise in the level of total Tau protein in FC and C. Tau hyperphosphorylation in Pb-treated animals was accompanied by elevated activity of GSK-3β and CDK5. Western blot analysis revealed activation of GSK-3β in FC and C as well as CDK5 in C, via increased phosphorylation of Tyr-216 and calpain-dependent p25

  20. Waring's problem with the Ramanujan \\tau-function

    Science.gov (United States)

    Garaev, M. Z.; Garcia, V. C.; Konyagin, S. V.

    2008-02-01

    We prove that for every integer N the Diophantine equation \\sum_{i=1}^{74000}\\tau(n_i)=N, where \\tau(n) is the Ramanujan \\tau-function, has a solution in positive integers n_1, n_2,\\dots, n_{74000} satisfying the condition \\max_{1\\le i\\le 74000}n_i\\,{\\ll}\\vert N\\vert^{2/11}+1. We also consider similar questions in residue fields modulo a large prime p.

  1. Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy

    Science.gov (United States)

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0399 TITLE: Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy PRINCIPAL INVESTIGATOR: John F...Include area code) October 2015 Annual Report 30 Sep 2014 - 29 Sep 2015 Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy John...available, work will commence. Tau, genetics, susceptibility, MAPT, chronic traumatic encephalopathy , Alzheimer disease U U U U 1 USAMRMC Table of