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  • 1
    In: Smith, Rachel A. S. and Abell, Benjamin and Smith, David P. and Nabok, Aleksey and Blakeman, Ben J. F. and Xue, Wei-Feng (2015) Analysis of Toxic Amyloid Fibril Interactions at Natively Derived Membranes by Ellipsometry. PLOS ONE, 10 (7). e0132309.
    Description: There is an ongoing debate regarding the culprits of cytotoxicity associated with amyloid disorders. Although small pre-fibrillar amyloid oligomers have been implicated as the primary toxic species, the fibrillar amyloid material itself can also induce cytotoxicity. To investigate membrane disruption and cytotoxic effects associated with intact and fragmented fibrils, the novel in situ spectroscopic technique of Total Internal Reflection Ellipsometry (TIRE) was used. Fibril lipid interactions were monitored using natively derived whole cell membranes as a model of the in vivo environment. We show that fragmented fibrils have an increased ability to disrupt these natively derived membranes by causing a loss of material from the deposited surface when compared with unfragmented fibrils. This effect was corroborated by observations of membrane disruption in live cells, and by dye release assay using synthetic liposomes. Through these studies we demonstrate the use of TIRE for the analysis of protein-lipid interactions on natively derived lipid surfaces, and provide an explanation on how amyloid fibrils can cause a toxic gain of function, while entangled amyloid plaques exert minimal biological activity.
    Keywords: Q Science
    ISSN: 1932-6203
    Source: University of Kent
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(7), p.e0132309
    Description: There is an ongoing debate regarding the culprits of cytotoxicity associated with amyloid disorders. Although small pre-fibrillar amyloid oligomers have been implicated as the primary toxic species, the fibrillar amyloid material itself can also induce cytotoxicity. To investigate membrane disruption and cytotoxic effects associated with intact and fragmented fibrils, the novel in situ spectroscopic technique of Total Internal Reflection Ellipsometry (TIRE) was used. Fibril lipid interactions were monitored using natively derived whole cell membranes as a model of the in vivo environment. We show that fragmented fibrils have an increased ability to disrupt these natively derived membranes by causing a loss of material from the deposited surface when compared with unfragmented fibrils. This effect was corroborated by observations of membrane disruption in live cells, and by dye release assay using synthetic liposomes. Through these studies we demonstrate the use of TIRE for the analysis of protein-lipid interactions on natively derived lipid surfaces, and provide an explanation on how amyloid fibrils can cause a toxic gain of function, while entangled amyloid plaques exert minimal biological activity.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Description: The polymorphic nature of amyloid fibrils is important in the understanding of structural based relationships, such as a morphology influence on cytotoxicity and disease progression. The work reported here uses Atomic force microscopy (AFM) to enhance the understanding of fibril morphology in addition to the relationship between structure and stability towards breakage. A novel quantitative cluster analysis was developed here to identify the vast range of fibril morphologies present within a population. Using fibrils formed from three peptide sequences identified by the WALTZ algorithm, we have characterised the polymorphism displayed by each fibril population and provided structural models to predict the likely filament arrangements accessible to each. The range of fibril polymorphism also conveys mechanical differences, defined here by persistence length values for each respective population. These mechanical differences subsequently affect fibrils stability towards breakage, quantified here using AFM and subsequent image analysis. Additionally, using AFM, a structural comparison was performed between Sup35NM amyloid fibrils formed in vitro and those formed in situ using a synthetic biology approach with the Curli-dependent amyloid generator (C-DAG) in E. Coli. Structural similarities between fibrils formed using this system and those formed in vitro is of great value given the importance of a sequence-structure relationship. The work in this thesis expands on possible fibril morphologies and the related mechanical properties, which has implications in the understanding of disease enhancing structural motifs and the utilisation of amyloid fibrils in a biotechnology role.
    Keywords: 500
    Source: Networked Digital Library of Theses and Dissertations
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  • 4
    Language: English
    Description: The polymorphic nature of amyloid fibrils is important in the understanding of structural based relationships, such as a morphology influence on cytotoxicity and disease progression. The work reported here uses Atomic force microscopy (AFM) to enhance the understanding of fibril morphology in addition...
    Keywords: 500
    Source: The British Library
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  • 5
    In: Al-Hilaly, Youssra K and Biasetti, Luca and Blakeman, Ben J F and Pollack, Saskia J and Zibaee, Shahin and Abdul-Sada, Alaa and Thorpe, Julian R and Xue, Wei-Feng and Serpell, Louise C (2016) The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson's disease. Scientific Reports, 6 . p. 39171.
    Description: Parkinson's disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable α-synuclein (α-syn) amyloid fibrils. α-synuclein is an intrinsically disordered protein that has the capacity to assemble to form β-sheet rich fibrils. Oxidiative stress and metal rich environments have been implicated in triggering assembly. Here, we have explored the composition of Lewy bodies in post-mortem tissue using electron microscopy and immunogold labeling and revealed dityrosine crosslinks in Lewy bodies in brain tissue from PD patients. In vitro, we show that dityrosine cross-links in α-syn are formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress by fluorescence and confirmed using mass-spectrometry. A covalently cross-linked dimer isolated by SDS-PAGE and mass analysis showed that dityrosine dimer was formed via the coupling of Y39-Y39 to give a homo dimer peptide that may play a key role in formation of oligomeric and seeds for fibril formation. Atomic force microscopy analysis reveals that the covalent dityrosine contributes to the stabilization of α-syn assemblies. Thus, the presence of oxidative stress induced dityrosine could play an important role in assembly and toxicity of α-syn in PD.
    Keywords: Q Science ; QP517 Biochemistry
    ISSN: 2045-2322
    Source: University of Kent
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  • 6
    In: Scientific Reports, 2016, Vol.6
    Description: Parkinson's disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable α-synuclein (α-syn) amyloid fibrils. α-synuclein is an intrinsically disordered protein that has the capacity to assemble to form β-sheet rich fibrils. Oxidiative stress and metal rich environments have been implicated in triggering assembly. Here, we have explored the composition of Lewy bodies in post-mortem tissue using electron microscopy and immunogold labeling and revealed dityrosine crosslinks in Lewy bodies in brain tissue from PD patients. In vitro, we show that dityrosine cross-links in α-syn are formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress by fluorescence and confirmed using mass-spectrometry. A covalently cross-linked dimer isolated by SDS-PAGE and mass analysis showed that dityrosine dimer was formed via the coupling of Y39-Y39 to give a homo dimer peptide that may play a key role in formation of oligomeric and seeds for fibril formation. Atomic force microscopy analysis reveals that the covalent dityrosine contributes to the stabilization of α-syn assemblies. Thus, the presence of oxidative stress induced dityrosine could play an important role in assembly and toxicity of α-syn in PD.
    Keywords: Lewy Bodies -- Metabolism ; Parkinson Disease -- Pathology ; Tyrosine -- Analogs & Derivatives ; Alpha-Synuclein -- Metabolism;
    E-ISSN: 2045-2322
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  • 7
    Language: English
    In: International Journal for Parasitology, March 2018, Vol.48(3-4), pp.197-201
    Description: parasites are a major cause of diarrhoea that pose a particular threat to children in developing areas and immunocompromised individuals. Curative therapies and vaccines are lacking, mainly due to lack of a long-term culturing system of this parasite. Here, we show that COLO-680N cells infected with two different strains produce sufficient infectious oocysts to infect subsequent cultures, showing a substantial fold increase in production, depending on the experiment, over the most optimistic HCT-8 models. Oocyst identity was confirmed using a variety of microscopic- and molecular-based methods. This culturing system will accelerate research on and the development of anti- drugs.
    Keywords: Cryptosporidium ; Cell Culture ; Colo-680n ; Lipidomics ; Proteomics ; Atomic Force Microscopy ; Immunofluorescence Microscopy ; Electron Microscopy ; Biology ; Zoology
    ISSN: 0020-7519
    E-ISSN: 1879-0135
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  • 8
    Language: English
    In: http://hdl.handle.net/1842/3744
    Description: Over the past few decades numerous archaeological approaches to predictive modeling have been presented but more recently the application of Dempster-Shafer theory has provided advancement in the way these models can handle uncertainty, ignorance and bias. As these factors are highly prevalent in archaeology, and in particular archaeological survey, the D-S technique of predictive modeling is one which should be looked at closely not only by archaeologists but also cultural heritage management. It is hoped that a Predictive Model based upon empirical data and which utilises Dempster-Shafer theory can help provide academics and planners with a tool capable of assessing the archaeological ‘potential’ of an area. This study will focus on data from the Western Cyprus Survey (WCS), whose aim is to investigate the nature and extent of regional interaction prior to the Bronze Age. Environmental variables will be investigated to see if relationships occur between them and the WCS site locations. Suitable variables will then be placed into the Belief Module of IDRISI, which employs Dempster-Shafer theory, where the predictive model will be constructed. Finally an element of uncertainty will be introduced into the model to quantify the impact of archaeological bias.
    Keywords: Archaeological Predictive Modeling ; Cyprus ; Dempster-Shafer ; Archaeology ; Msc Geographical Information Science ; Gis
    Source: Edinburgh Research Archive
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  • 9
    Article
    Article
    Language: English
    In: Calliope, March, 2009, Vol.19(6), p.9(3)
    Keywords: Excavations (Archaeology) -- Ireland ; Excavations (Archaeology) -- Analysis ; Housing -- History ; Irish History
    ISSN: 1050-7086
    Source: Cengage Learning, Inc.
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  • 10
    Language: English
    In: Trials, May 8, 2014, Vol.15(1)
    Description: Background Chronic kidney disease (CKD) is common and increasing in prevalence. Cardiovascular disease (CVD) is a major cause of morbidity and death in CKD, though of a different phenotype to the general CVD population. Few therapies have proved effective in modifying the increased CVD risk or rate of renal decline in CKD. There are accumulating data that aldosterone receptor antagonists (ARA) may offer cardio-protection and delay renal impairment in patients with the CV phenotype in CKD. The use of ARA in CKD has therefore been increasingly advocated. However, no large study of ARA with renal or CVD outcomes is underway. Methods The study is a prospective randomised open blinded endpoint (PROBE) trial set in primary care where patients will mainly be identified by their GPs or from existing CKD lists. They will be invited if they have been formally diagnosed with CKD stage 3b or there is evidence of stage 3b CKD from blood results (eGFR 30-44 mL/min/1.73 m.sup.2) and fulfil the other inclusion/exclusion criteria. Patients will be randomised to either spironolactone 25 mg once daily in addition to routine care or routine care alone and followed-up for 36 months. Discussion BARACK D is a PROBE trial to determine the effect of ARA on mortality and cardiovascular outcomes (onset or progression of CVD) in patients with stage 3b CKD. Trial registration EudraCT: 2012-002672-13 ISRTN: ISRCTN44522369 Keywords: Cardiovascular disease, Chronic kidney disease, CKD mortality, CKD aldosterone receptor antagonist
    Keywords: Chronic Kidney Failure -- Patient Outcomes ; Mortality
    ISSN: 1745-6215
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