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Sample records for amyloid bacterial inclusion

  1. Amyloid-linked cellular toxicity triggered by bacterial inclusion bodies

    International Nuclear Information System (INIS)

    Gonzalez-Montalban, Nuria; Villaverde, Antonio; Aris, Anna

    2007-01-01

    The aggregation of proteins in the form of amyloid fibrils and plaques is the characteristic feature of some pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. The mechanisms by which the aggregation processes result in cell damage are under intense investigation but recent data indicate that prefibrillar aggregates are the most proximate mediators of toxicity rather than mature fibrils. Since it has been shown that prefibrillar forms of the nondisease-related misfolded proteins are highly toxic to cultured mammalian cells we have studied the cytoxicity associated to bacterial inclusion bodies that have been recently described as protein deposits presenting amyloid-like structures. We have proved that bacterial inclusion bodies composed by a misfolding-prone β-galactosidase fusion protein are clearly toxic for mammalian cells but the β-galactosidase wild type enzyme forming more structured thermal aggregates does not impair cell viability, despite it also binds and enter into the cells. These results are in the line that the most cytotoxic aggregates are early prefibrilar assemblies but discard the hypothesis that the membrane destabilization is Key event to subsequent disruption of cellular processes, such as ion balance, oxidative state and the eventually cell death

  2. Towards revealing the structure of bacterial inclusion bodies.

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    Wang, Lei

    2009-01-01

    Protein aggregation is a widely observed phenomenon in human diseases, biopharmaceutical production, and biological research. Protein aggregates are generally classified as highly ordered, such as amyloid fibrils, or amorphous, such as bacterial inclusion bodies. Amyloid fibrils are elongated filaments with diameters of 6-12 nm, they are comprised of residue-specific cross-beta structure, and display characteristic properties, such as binding with amyloid-specific dyes. Amyloid fibrils are associated with dozens of human pathological conditions, including Alzheimer disease and prion diseases. Distinguished from amyloid fibrils, bacterial inclusion bodies display apparent amorphous morphology. Inclusion bodies are formed during high-level recombinant protein production, and formation of inclusion bodies is a major concern in biotechnology. Despite of the distinctive morphological difference, bacterial inclusion bodies have been found to have some amyloid-like properties, suggesting that they might contain structures similar to amyloid-like fibrils. Recent structural data further support this hypothesis, and this review summarizes the latest progress towards revealing the structural details of bacterial inclusion bodies.

  3. Bacterial Inclusion Bodies: Discovering Their Better Half.

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    Rinas, Ursula; Garcia-Fruitós, Elena; Corchero, José Luis; Vázquez, Esther; Seras-Franzoso, Joaquin; Villaverde, Antonio

    2017-09-01

    Bacterial inclusion bodies (IBs) are functional, non-toxic amyloids occurring in recombinant bacteria showing analogies with secretory granules of the mammalian endocrine system. The scientific interest in these mesoscale protein aggregates has been historically masked by their status as a hurdle in recombinant protein production. However, progressive understanding of how the cell handles the quality of recombinant polypeptides and the main features of their intriguing molecular organization has stimulated the interest in inclusion bodies and spurred their use in diverse technological fields. The engineering and tailoring of IBs as functional protein particles for materials science and biomedicine is a good example of how formerly undesired bacterial byproducts can be rediscovered as promising functional materials for a broad spectrum of applications. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Amyloid-like protein inclusions in tobacco transgenic plants.

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    Anna Villar-Piqué

    Full Text Available The formation of insoluble protein deposits in human tissues is linked to the onset of more than 40 different disorders, ranging from dementia to diabetes. In these diseases, the proteins usually self-assemble into ordered β-sheet enriched aggregates known as amyloid fibrils. Here we study the structure of the inclusions formed by maize transglutaminase (TGZ in the chloroplasts of tobacco transplastomic plants and demonstrate that they have an amyloid-like nature. Together with the evidence of amyloid structures in bacteria and fungi our data argue that amyloid formation is likely a ubiquitous process occurring across the different kingdoms of life. The discovery of amyloid conformations inside inclusions of genetically modified plants might have implications regarding their use for human applications.

  5. Yeast prions form infectious amyloid inclusion bodies in bacteria

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    Espargaró Alba

    2012-06-01

    Full Text Available Abstract Background Prions were first identified as infectious proteins associated with fatal brain diseases in mammals. However, fungal prions behave as epigenetic regulators that can alter a range of cellular processes. These proteins propagate as self-perpetuating amyloid aggregates being an example of structural inheritance. The best-characterized examples are the Sup35 and Ure2 yeast proteins, corresponding to [PSI+] and [URE3] phenotypes, respectively. Results Here we show that both the prion domain of Sup35 (Sup35-NM and the Ure2 protein (Ure2p form inclusion bodies (IBs displaying amyloid-like properties when expressed in bacteria. These intracellular aggregates template the conformational change and promote the aggregation of homologous, but not heterologous, soluble prionogenic molecules. Moreover, in the case of Sup35-NM, purified IBs are able to induce different [PSI+] phenotypes in yeast, indicating that at least a fraction of the protein embedded in these deposits adopts an infectious prion fold. Conclusions An important feature of prion inheritance is the existence of strains, which are phenotypic variants encoded by different conformations of the same polypeptide. We show here that the proportion of infected yeast cells displaying strong and weak [PSI+] phenotypes depends on the conditions under which the prionogenic aggregates are formed in E. coli, suggesting that bacterial systems might become useful tools to generate prion strain diversity.

  6. TDP-43 inclusion bodies formed in bacteria are structurally amorphous, non-amyloid and inherently toxic to neuroblastoma cells.

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    Claudia Capitini

    Full Text Available Accumulation of ubiquitin-positive, tau- and α-synuclein-negative intracellular inclusions of TDP-43 in the central nervous system represents the major hallmark correlated to amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Such inclusions have variably been described as amorphous aggregates or more structured deposits having an amyloid structure. Following the observations that bacterial inclusion bodies generally consist of amyloid aggregates, we have overexpressed full-length TDP-43 and C-terminal TDP-43 in E. coli, purified the resulting full-length and C-terminal TDP-43 containing inclusion bodies (FL and Ct TDP-43 IBs and subjected them to biophysical analyses to assess their structure/morphology. We show that both FL and Ct TDP-43 aggregates contained in the bacterial IBs do not bind amyloid dyes such as thioflavin T and Congo red, possess a disordered secondary structure, as inferred using circular dichroism and infrared spectroscopies, and are susceptible to proteinase K digestion, thus possessing none of the hallmarks for amyloid. Moreover, atomic force microscopy revealed an irregular structure for both types of TDP-43 IBs and confirmed the absence of amyloid-like species after proteinase K treatment. Cell biology experiments showed that FL TDP-43 IBs were able to impair the viability of cultured neuroblastoma cells when added to their extracellular medium and, more markedly, when transfected into their cytosol, where they are at least in part ubiquitinated and phosphorylated. These data reveal an inherently high propensity of TDP-43 to form amorphous aggregates, which possess, however, an inherently high ability to cause cell dysfunction. This indicates that a gain of toxic function caused by TDP-43 deposits is effective in TDP-43 pathologies, in addition to possible loss of function mechanisms originating from the cellular mistrafficking of the protein.

  7. Functional bacterial amyloid increases Pseudomonas biofilm hydrophobicity and stiffness

    DEFF Research Database (Denmark)

    Zeng, Guanghong; Vad, Brian S; Dueholm, Morten S

    2015-01-01

    The success of Pseudomonas species as opportunistic pathogens derives in great part from their ability to form stable biofilms that offer protection against chemical and mechanical attack. The extracellular matrix of biofilms contains numerous biomolecules, and it has recently been discovered...... that in Pseudomonas one of the components includes β-sheet rich amyloid fibrils (functional amyloid) produced by the fap operon. However, the role of the functional amyloid within the biofilm has not yet been investigated in detail. Here we investigate how the fap-based amyloid produced by Pseudomonas affects biofilm...... hydrophobicity and mechanical properties. Using atomic force microscopy imaging and force spectroscopy, we show that the amyloid renders individual cells more resistant to drying and alters their interactions with hydrophobic probes. Importantly, amyloid makes Pseudomonas more hydrophobic and increases biofilm...

  8. Detection of Pathogenic Biofilms with Bacterial Amyloid Targeting Fluorescent Probe, CDy11

    DEFF Research Database (Denmark)

    Kim, Jun Young; Sahu, Srikanta; Yau, Yin Hoe

    2016-01-01

    Bacterial biofilms are responsible for a wide range of persistent infections. In the clinic, diagnosis of biofilm-associated infections relies heavily on culturing methods, which fail to detect nonculturable bacteria. Identification of novel fluorescent probes for biofilm imaging will greatly...... facilitate diagnosis of pathogenic bacterial infection. Herein, we report a novel fluorescent probe, CDy11 (compound of designation yellow 11), which targets amyloid in the Pseudomonas aeruginosa biofilm matrix through a diversity oriented fluorescent library approach (DOFLA). CDy11 was further demonstrated...

  9. Isolation of cell-free bacterial inclusion bodies.

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    Rodríguez-Carmona, Escarlata; Cano-Garrido, Olivia; Seras-Franzoso, Joaquin; Villaverde, Antonio; García-Fruitós, Elena

    2010-09-17

    Bacterial inclusion bodies are submicron protein clusters usually found in recombinant bacteria that have been traditionally considered as undesirable products from protein production processes. However, being fully biocompatible, they have been recently characterized as nanoparticulate inert materials useful as scaffolds for tissue engineering, with potentially wider applicability in biomedicine and material sciences. Current protocols for inclusion body isolation from Escherichia coli usually offer between 95 to 99% of protein recovery, what in practical terms, might imply extensive bacterial cell contamination, not compatible with the use of inclusion bodies in biological interfaces. Using an appropriate combination of chemical and mechanical cell disruption methods we have established a convenient procedure for the recovery of bacterial inclusion bodies with undetectable levels of viable cell contamination, below 10⁻¹ cfu/ml, keeping the particulate organization of these aggregates regarding size and protein folding features. The application of the developed protocol allows obtaining bacterial free inclusion bodies suitable for use in mammalian cell cultures and other biological interfaces.

  10. Packaging protein drugs as bacterial inclusion bodies for therapeutic applications

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    Villaverde Antonio

    2012-06-01

    Full Text Available Abstract A growing number of insights on the biology of bacterial inclusion bodies (IBs have revealed intriguing utilities of these protein particles. Since they combine mechanical stability and protein functionality, IBs have been already exploited in biocatalysis and explored for bottom-up topographical modification in tissue engineering. Being fully biocompatible and with tuneable bio-physical properties, IBs are currently emerging as agents for protein delivery into mammalian cells in protein-replacement cell therapies. So far, IBs formed by chaperones (heat shock protein 70, Hsp70, enzymes (catalase and dihydrofolate reductase, grow factors (leukemia inhibitory factor, LIF and structural proteins (the cytoskeleton keratin 14 have been shown to rescue exposed cells from a spectrum of stresses and restore cell functions in absence of cytotoxicity. The natural penetrability of IBs into mammalian cells (reaching both cytoplasm and nucleus empowers them as an unexpected platform for the controlled delivery of essentially any therapeutic polypeptide. Production of protein drugs by biopharma has been traditionally challenged by IB formation. However, a time might have arrived in which recombinant bacteria are to be engineered for the controlled packaging of therapeutic proteins as nanoparticulate materials (nanopills, for their extra- or intra-cellular release in medicine and cosmetics.

  11. The nuclear inclusion a (NIa protease of turnip mosaic virus (TuMV cleaves amyloid-β.

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    Hye-Eun Han

    Full Text Available BACKGROUND: The nuclear inclusion a (NIa protease of turnip mosaic virus (TuMV is responsible for the processing of the viral polyprotein into functional proteins. NIa was previously shown to possess a relatively strict substrate specificity with a preference for Val-Xaa-His-Gln↓, with the scissile bond located after Gln. The presence of the same consensus sequence, Val(12-His-His-Gln(15, near the presumptive α-secretase cleavage site of the amyloid-β (Aβ peptide led us to hypothesize that NIa could possess activity against Aβ. METHODOLOGY/PRINCIPAL FINDINGS: Western blotting results showed that oligomeric as well as monomeric forms of Aβ can be degraded by NIa in vitro. The specific cleavage of Aβ was further confirmed by mass spectrometry analysis. NIa was shown to exist predominantly in the cytoplasm as observed by immunofluorescence microscopy. The overexpression of NIa in B103 neuroblastoma cells resulted in a significant reduction in cell death caused by both intracellularly generated and exogenously added Aβ. Moreover, lentiviral-mediated expression of NIa in APP(sw/PS1 transgenic mice significantly reduced the levels of Aβ and plaques in the brain. CONCLUSIONS/SIGNIFICANCE: These results indicate that the degradation of Aβ in the cytoplasm could be a novel strategy to control the levels of Aβ, plaque formation, and the associated cell death.

  12. Chemical Assistance in Refolding of Bacterial Inclusion Bodies

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    Mona Alibolandi

    2011-01-01

    Full Text Available Escherichia coli is one of the most widely used hosts for the production of recombinant proteins but insoluble expression of heterologous proteins is a major bottleneck in production of recombinant proteins in E. coli. In vitro refolding of inclusion body into proteins with native conformations is a solution for this problem but there is a need for optimization of condition for each protein specifically. Several approaches have been described for in vitro refolding; most of them involve the use of additives for assisting correct folding. Cosolutes play a major role in refolding process and can be classified according to their function as aggregation suppressors and folding enhancers. This paper presents a review of additives that are used in refolding process of insoluble recombinant proteins in small scale and industrial processes.

  13. Widespread abundance of functional bacterial amyloid in Mycolata and other Gram-positive bacteria

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    Jordal, Peter Bruun; Dueholm, Morten Simonsen; Larsen, Poul

    2009-01-01

    extracellular fibrils were also produced. In three cases, FuBA was only revealed after extensive removal of extracellular material by saponification, indicating an integrated attachment within the cellular envelope. Spores from species within the genera Streptomyces, Bacillus and Nocardia were all coated...... analysis. We conclude that amyloid is widespread among Gram-positive bacteria and may in many species constitute a hitherto overlooked integral part of the spores and the cellular envelope....

  14. Molecular mechanism of pore creation in bacterial membranes by amyloid proteins

    International Nuclear Information System (INIS)

    Tsigelny, I F; Sharikov, Y; Miller, M A; Masliah, E

    2009-01-01

    This study explores the mechanism of pore creation in cellular membranes by MccE92 bacterial proteins. The results of this study are then compared with the mechanism of alpha-synuclein (aS)-based pore formation in mammalian cells, and its role in Parkinson's disease.

  15. Tunable geometry of bacterial inclusion bodies as substrate materials for tissue engineering

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    GarcIa-Fruitos, Elena; Seras-Franzoso, JoaquIn; Vazquez, Esther; Villaverde, Antonio [CIBER en BioingenierIa, Biomateriales y Nanomedicina, Bellaterra, 08193 Barcelona (Spain); Institut de Biotecnologia i de Biomedicina and Departament de Genetica i de Microbiologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Cerdanyola del Valles), Barcelona (Spain)

    2010-05-21

    A spectrum of materials for biomedical applications is produced in bacteria, and some of them, such as metals or polyhydroxyalkanoates, are straightforwardly obtained as particulate entities. We have explored the biofabrication process of bacterial inclusion bodies, particulate proteinaceous materials (ranging from 50 to 500 nm in diameter) recently recognized as suitable for surface topographical modification and tissue engineering. Inclusion bodies have been widely described as spherical or pseudo-spherical particles with only minor morphological variability, mostly restricted to their size. Here we have identified a cellular gene in Escherichia coli (clpP) that controls the in vivo fabrication process of inclusion bodies. In the absence of the encoded protease, the dynamics of protein deposition is perturbed, resulting in unusual tear-shaped particles with enhanced surface-volume ratios. This fact modifies the ability of inclusion bodies to promote mammalian cell attachment and differentiation upon surface decoration. The implications of the genetic control of inclusion body geometry are discussed in the context of their biological fabrication and regarding the biomedical potential of these protein clusters in regenerative medicine.

  16. Tunable geometry of bacterial inclusion bodies as substrate materials for tissue engineering

    International Nuclear Information System (INIS)

    GarcIa-Fruitos, Elena; Seras-Franzoso, JoaquIn; Vazquez, Esther; Villaverde, Antonio

    2010-01-01

    A spectrum of materials for biomedical applications is produced in bacteria, and some of them, such as metals or polyhydroxyalkanoates, are straightforwardly obtained as particulate entities. We have explored the biofabrication process of bacterial inclusion bodies, particulate proteinaceous materials (ranging from 50 to 500 nm in diameter) recently recognized as suitable for surface topographical modification and tissue engineering. Inclusion bodies have been widely described as spherical or pseudo-spherical particles with only minor morphological variability, mostly restricted to their size. Here we have identified a cellular gene in Escherichia coli (clpP) that controls the in vivo fabrication process of inclusion bodies. In the absence of the encoded protease, the dynamics of protein deposition is perturbed, resulting in unusual tear-shaped particles with enhanced surface-volume ratios. This fact modifies the ability of inclusion bodies to promote mammalian cell attachment and differentiation upon surface decoration. The implications of the genetic control of inclusion body geometry are discussed in the context of their biological fabrication and regarding the biomedical potential of these protein clusters in regenerative medicine.

  17. Limit for the Survivability from Potassium Decay of Bacterial Spores in Halite Fluid Inclusions

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    Kminek, G.; Bada, J. L.

    2001-12-01

    Vreeland et al.1 recently claimed to have isolated and cultured a viable spore forming halotolerant bacterium from a 250 million year old brine inclusion present in a salt crystal from the Salado formation. An earlier report suggested that viable bacterial spores could be revived from samples obtained from insects entombed in 25-40 million year old Dominican amber2. On the bases of these reports, Parkes3 raised the question of whether bacterial spores under some conditions might be effectively immortal. Sporulation, induced by an adverse change in the environmental conditions, is able to stabilize the DNA primarily against hydrolytic depurination for extended periods of time4. However, the organism is still exposed to ionizing radiation from the environment. Dormant spores have a reduced sensitivity to ionizing radiation per se, but unlike active organisms are unable to repair DNA damage encountered during long-term exposure to ionizing radiation. The accumulated damage may overwhelm any repair mechanism that starts in the early stage of spore germination5. The main radionuclide in a halite fluid inclusion is 40K, which accounts for 0.0117% of natural potassium. 40K decays via beta decay to 40Ca and via electron capture to 40Ar, releasing a primary gamma-ray. About 83.3 % of the beta's emitted are in the energy range of 0.3-1.3 MeV. We assume 7 g/l for an average concentration of natural potassium in a halite fluid inclusion, which means that the amount of 40K in a 10 μ l fluid inclusion is 8.19 ng. We have chosen a 10 μ l because this volume is typical of that used to obtain chemical data and in the attempts to extract bacteria. Less than a percent of the gamma decay energy is absorbed in a fluid inclusion of 10 μ l. Thus, we will not take the gamma decay energy into account for the further discussion. Almost all the beta energy is absorbed in the fluid inclusion. The total decay energy absorbed in a time period of 250 million years is about 87 kGy. The most

  18. Sodium phenylbutyrate reverses lysosomal dysfunction and decreases amyloid-β42 in an in vitro-model of inclusion-body myositis.

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    Nogalska, Anna; D'Agostino, Carla; Engel, W King; Askanas, Valerie

    2014-05-01

    Sporadic inclusion-body myositis (s-IBM) is a severe, progressive muscle disease for which there is no enduring treatment. Pathologically characteristic are vacuolated muscle fibers having: accumulations of multi-protein aggregates, including amyloid-β(Aβ) 42 and its toxic oligomers; increased γ-secretase activity; and impaired autophagy. Cultured human muscle fibers with experimentally-impaired autophagy recapitulate some of the s-IBM muscle abnormalities, including vacuolization and decreased activity of lysosomal enzymes, accompanied by increased Aβ42, Aβ42 oligomers, and increased γ-secretase activity. Sodium phenylbutyrate (NaPB) is an orally bioavailable small molecule approved by the FDA for treatment of urea-cycle disorders. Here we describe that NaPB treatment reverses lysosomal dysfunction in an in vitro model of inclusion-body myositis, involving cultured human muscle fibers. NaPB treatment improved lysosomal activity, decreased Aβ42 and its oligomers, decreased γ-secretase activity, and virtually prevented muscle-fiber vacuolization. Accordingly, NaPB might be considered a potential treatment of s-IBM patients. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Identification of key amino acid residues modulating intracellular and in vitro microcin E492 amyloid formation

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    Paulina eAguilera

    2016-01-01

    Full Text Available Microcin E492 (MccE492 is a pore-forming bacteriocin produced and exported by Klebsiella pneumoniae RYC492. Besides its antibacterial activity, excreted MccE492 can form amyloid fibrils in vivo as well as in vitro. It has been proposed that bacterial amyloids can be functional playing a biological role, and in the particular case of MccE492 it would control the antibacterial activity. MccE492 amyloid fibril’s morphology and formation kinetics in vitro have been well characterized, however it is not known which amino acid residues determine its amyloidogenic propensity, nor if it forms intracellular amyloid inclusions as has been reported for other bacterial amyloids. In this work we found the conditions in which MccE492 forms intracellular amyloids in E. coli cells, that were visualized as round-shaped inclusion bodies recognized by two amyloidophillic probes, 2-4´-methylaminophenyl benzothiazole and thioflavin-S. We used this property to perform a flow cytometry-based assay to evaluate the aggregation propensity of MccE492 mutants, that were designed using an in silico prediction of putative aggregation hotspots. We established that the predicted amino acid residues 54-63, effectively act as a pro-amyloidogenic stretch. As in the case of other amyloidogenic proteins, this region presented two gatekeeper residues (P57 and P59, which disfavor both intracellular and in vitro MccE492 amyloid formation, preventing an uncontrolled aggregation. Mutants in each of these gatekeeper residues showed faster in vitro aggregation and bactericidal inactivation kinetics, and the two mutants were accumulated as dense amyloid inclusions in more than 80% of E. coli cells expressing these variants. In contrast, the MccE492 mutant lacking residues 54-63 showed a significantly lower intracellular aggregation propensity and slower in vitro polymerization kinetics. Electron microscopy analysis of the amyloids formed in vitro by these mutants revealed that, although

  20. Organization and Biology of the Porcine Serum Amyloid A (SAA) Gene Cluster: Isoform Specific Responses to Bacterial Infection

    DEFF Research Database (Denmark)

    Olsen, Helle G; Skovgaard, Kerstin; Nielsen, Ole L

    2013-01-01

    Serum amyloid A (SAA) is a prominent acute phase protein. Although its biological functions are debated, the wide species distribution of highly homologous SAA proteins and their uniform behavior in response to injury or inflammation in itself suggests a significant role for this protein. The pig...... is increasingly being used as a model for the study of inflammatory reactions, yet only little is known about how specific SAA genes are regulated in the pig during acute phase responses and other responses induced by pro-inflammatory host mediators. We designed SAA gene specific primers and quantified the gene...... expression of porcine SAA1, SAA2, SAA3, and SAA4 by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in liver, spleen, and lung tissue from pigs experimentally infected with the Gram-negative swine specific bacterium Actinobacillus pleuropneumoniae, as well as from pigs experimentally...

  1. L-arginine mediated renaturation enhances yield of human, α6 Type IV collagen non-collagenous domain from bacterial inclusion bodies.

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    Gunda, Venugopal; Boosani, Chandra Shekhar; Verma, Raj Kumar; Guda, Chittibabu; Sudhakar, Yakkanti Akul

    2012-10-01

    The anti-angiogenic, carboxy terminal non-collagenous domain (NC1) derived from human Collagen type IV alpha 6 chain, [α6(IV)NC1] or hexastatin, was earlier obtained using different recombinant methods of expression in bacterial systems. However, the effect of L-arginine mediated renaturation in enhancing the relative yields of this protein from bacterial inclusion bodies has not been evaluated. In the present study, direct stirring and on-column renaturation methods using L-arginine and different size exclusion chromatography matrices were applied for enhancing the solubility in purifying the recombinant α6(IV)NC1 from bacterial inclusion bodies. This methodology enabled purification of higher quantities of soluble protein from inclusion bodies, which inhibited endothelial cell proliferation, migration and tube formation. Thus, the scope for L-arginine mediated renaturation in obtaining higher yields of soluble, biologically active NC1 domain from bacterial inclusion bodies was evaluated.

  2. Bacterial inclusion bodies as potential synthetic devices for pathogen recognition and a therapeutic substance release.

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    Talafová, Klaudia; Hrabárová, Eva; Chorvát, Dušan; Nahálka, Jozef

    2013-02-07

    Adhesins of pathogens recognise the glycans on the host cell and mediate adherence. They are also crucial for determining the tissue preferences of pathogens. Currently, glyco-nanomaterials provide potential tool for antimicrobial therapy. We demonstrate that properly glyco-tailored inclusion bodies can specifically bind pathogen adhesins and release therapeutic substances. In this paper, we describe the preparation of tailored inclusion bodies via the conjugation of indicator protein aggregated to form inclusion bodies with soluble proteins. Whereas the indicator protein represents a remedy, the soluble proteins play a role in pathogen recognition. For conjugation, glutaraldehyde was used as linker. The treatment of conjugates with polar lysine, which was used to inactivate the residual glutaraldehyde, inhibited unwanted hydrophobic interactions between inclusion bodies. The tailored inclusion bodies specifically interacted with the SabA adhesin from Helicobacter pylori aggregated to form inclusion bodies that were bound to the sialic acids decorating the surface of human erythrocytes. We also tested the release of indicator proteins from the inclusion bodies using sortase A and Ssp DNAB intein self-cleaving modules, respectively. Sortase A released proteins in a relatively short period of time, whereas the intein cleavage took several weeks. The tailored inclusion bodies are promising "nanopills" for biomedical applications. They are able to specifically target the pathogen, while a self-cleaving module releases a soluble remedy. Various self-cleaving modules can be enabled to achieve the diverse pace of remedy release.

  3. Investigation of the phase morphology of bacterial PHA inclusion bodies by contrast variation SANS

    International Nuclear Information System (INIS)

    Russell, R.A.; Holden, P.J.; Garvey, C.J.; Wilde, K.L.; Hammerton, K.M.; Foster, L.J.

    2006-01-01

    Under growth-limiting conditions, many bacteria are able to metabolise excess organic acids into polyhydroxyalkanoates (PHA) and store these polymers as intracellular inclusions until the return of favourable conditions. Various models have been proposed for the macromolecular organisation of the boundary layer surrounding the polymer, and contrast-variation small-angle neutron scattering (SANS) was used to study its organisation. Inclusions formed by Pseudomonas oleovorans under hydrogenating conditions showed lowest scattering intensity at ca. 20% D 2 O. The inclusions consist of protein and membrane lipids in the boundary layer and polyhydroxyoctanoate (lipid) in the inclusion body. At 20% D 2 O the contributions of lipids were contrast matched with the solvent, indicating that lipids contributed the bulk of the scattering intensity observed at other D 2 O/H 2 O ratios. These results are inconsistent with a model of the boundary layer which proposed outer and inner layers of crystalline protein lattice sandwiching a membrane lipid membrane layer [E.S. Stuart, R.W. Lenz, R.C. Fuller, Can J Microbiol 41(Suppl 1) (1995) 84-93], and is more consistent with a model consisting of a lipid monolayer containing embedded proteins [U. Pieper-furst, M.H. Madkour, F. Mayer, A. Steinbuchel, J. Bacteriol. 176 (1994) 4328-4337.] By altering the H/D content of the precursors, we were able to collect SANS data from preparations of both deuterated and H/D copolymer inclusions, where initial PHA produced was hydrogenated followed by deuteration. Deuterated inclusions showed minimum intensity above 90% D 2 O/H 2 O whereas the sequentially produced copolymer (assumed to be in a core/shell arrangement) displayed minimum scattering some 20% lower, which is consistent with the increased hydrogenation of the boundary layer expected from its synthesis during supply of hydrogenated followed by deuterated precursors

  4. Rab11-family of interacting protein 2 associates with chlamydial inclusions through its Rab-binding domain and promotes bacterial multiplication.

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    Leiva, Natalia; Capmany, Anahí; Damiani, María Teresa

    2013-01-01

    Chlamydia trachomatis, an obligate intracellular pathogen, survives within host cells in a special compartment named 'inclusion' and takes advantage of host vesicular transport pathways for its growth and replication. Rab GTPases are key regulatory proteins of intracellular trafficking. Several Rabs, among them Rab11 and Rab14, are implicated in chlamydial development. FIP2, a member of the Rab11-Family of Interacting Proteins, presents at the C-terminus a Rab-binding domain that interacts with both Rab11 and Rab14. In this study, we determined and characterized the recruitment of endogenous and GFP-tagged FIP2 to the chlamydial inclusions. The recruitment of FIP2 is specific since other members of the Rab11-Family of Interacting Proteins do not associate with the chlamydial inclusions. The Rab-binding domain of FIP2 is essential for its association. Our results indicate that FIP2 binds to Rab11 at the chlamydial inclusion membrane through its Rab-binding domain. The presence of FIP2 at the chlamydial inclusion favours the recruitment of Rab14. Furthermore, our results show that FIP2 promotes inclusion development and bacterial replication. In agreement, the silencing of FIP2 decreases the bacterial progeny. C. trachomatis likely recruits FIP2 to hijack host intracellular trafficking to redirect vesicles full of nutrients towards the inclusion. © 2012 Blackwell Publishing Ltd.

  5. [Amyloid goiter].

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    Hrívó, A; Péter, I; Bánkúti, B; Péley, G; Baska, F; Besznyák, I

    1999-03-21

    Amyloid goitre is at an extremely rare occurrence. Authors review the origin of disease and its symptoms, diagnostic and therapeutic tools. The disease may be due to either primary or secondary systemic or local amyloidosis. Diagnosis may be made even before surgery on anamnestic data, on very rapid growth of thyroid glands, on diffuse appearance, on other symptoms of systemic amyloidosis, on findings of iconographic procedures and on detection of amyloid in aspirates. Final diagnosis is based on histology. Surgical therapy is aiming at avoidance of the existing and the threatening consequences of expanding mass. The outcome is independent from thyroid surgery, it is related to other manifestations of amyloidosis. Concerning with the present case the chronic superior vena cava syndrome and chylous pleural effusion as first described symptoms and asymptomatic hyperthyroxinaemia is emphasised. Neither other organ involvement, nor primary amyloidogenous molecula was found during the 18 months follow up, so patient has secondary and localised amyloidosis.

  6. Amyloid myopathy: a diagnostic challenge

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    Heli Tuomaala

    2009-08-01

    Full Text Available Amyloid myopathy (AM is a rare manifestation of primary systemic amyloidosis (AL. Like inflammatory myopathies, it presents with proximal muscle weakness and an increased creatine kinase level. We describe a case of AL with severe, rapidly progressive myopathy as the initial symptom. The clinical manifestation and muscle biopsy were suggestive of inclusion body myositis. AM was not suspected until amyloidosis was seen in the gastric mucosal biopsy. The muscle biopsy was then re-examined more specifically, and Congo red staining eventually showed vascular and interstitial amyloid accumulation, which led to a diagnosis of AM. The present case illustrates the fact that the clinical picture of AM can mimic that of inclusion body myositis.

  7. Sporadic inclusion-body myositis: conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau.

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    Askanas, Valerie; Engel, W King

    2011-04-01

    The pathogenesis of sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is complex and multifactorial. Both the muscle fiber degeneration and the mononuclear-cell inflammation are components of the s-IBM pathology, but how each relates to the pathogenesis remains unsettled. We consider that the intramuscle fiber degenerative component plays the primary and the major pathogenic role leading to muscle fiber destruction and clinical weakness. In this article we review the newest research advances that provide a better understanding of the s-IBM pathogenesis. Cellular abnormalities occurring in s-IBM muscle fibers are discussed, including: several proteins that are accumulated in the form of aggregates within muscle fibers, including amyloid-β42 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; cellular mechanisms leading to protein misfolding and aggregation, including evidence of their inadequate disposal; pathogenic importance of endoplasmic reticulum stress and the unfolded protein response demonstrated in s-IBM muscle fibers; and decreased deacetylase activity of SIRT1. All these factors are combined with, and perhaps provoked by, an ageing intracellular milieu. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with ageing. Muscle biopsy diagnostic criteria are also described and illustrated. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  8. Functional Amyloids in Reproduction.

    Science.gov (United States)

    Hewetson, Aveline; Do, Hoa Quynh; Myers, Caitlyn; Muthusubramanian, Archana; Sutton, Roger Bryan; Wylie, Benjamin J; Cornwall, Gail A

    2017-06-29

    Amyloids are traditionally considered pathological protein aggregates that play causative roles in neurodegenerative disease, diabetes and prionopathies. However, increasing evidence indicates that in many biological systems nonpathological amyloids are formed for functional purposes. In this review, we will specifically describe amyloids that carry out biological roles in sexual reproduction including the processes of gametogenesis, germline specification, sperm maturation and fertilization. Several of these functional amyloids are evolutionarily conserved across several taxa, including human, emphasizing the critical role amyloids perform in reproduction. Evidence will also be presented suggesting that, if altered, some functional amyloids may become pathological.

  9. Amyloid and immune homeostasis.

    Science.gov (United States)

    Wang, Ying-Hui; Zhang, Yu-Gen

    2018-03-01

    Extracellular amyloid deposition defines a range of amyloidosis and amyloid-related disease. Addition to primary and secondary amyloidosis, amyloid-related disease can be observed in different tissue/organ that sharing the common pathogenesis based on the formation of amyloid deposition. Currently, both Alzheimer's disease and type 2 diabetes can be diagnosed with certainly only based on the autopsy results, by which amyloidosis of the associative tissue/organ is observed. Intriguingly, since it demonstrated that amyloid deposits trigger inflammatory reaction through the activation of cascaded immune response, wherein several lines of evidence implies a protective role of amyloid in preventing autoimmunity. Furthermore, attempts for preventing amyloid formation and/or removing amyloid deposits from the brain have caused meningoencephalitis and consequent deaths among the subjects. Hence, it is important to note that amyloid positively participates in maintaining immune homeostasis and contributes to irreversible inflammatory response. In this review, we will focus on the interactive relationship between amyloid and the immune system, discussing the potential functional roles of amyloid in immune tolerance and homeostasis. Copyright © 2017 Elsevier GmbH. All rights reserved.

  10. Functional amyloid formation by Streptococcus mutans

    Science.gov (United States)

    Oli, M. W.; Otoo, H. N.; Crowley, P. J.; Heim, K. P.; Nascimento, M. M.; Ramsook, C. B.; Lipke, P. N.

    2012-01-01

    Dental caries is a common infectious disease associated with acidogenic and aciduric bacteria, including Streptococcus mutans. Organisms that cause cavities form recalcitrant biofilms, generate acids from dietary sugars and tolerate acid end products. It has recently been recognized that micro-organisms can produce functional amyloids that are integral to biofilm development. We now show that the S. mutans cell-surface-localized adhesin P1 (antigen I/II, PAc) is an amyloid-forming protein. This conclusion is based on the defining properties of amyloids, including binding by the amyloidophilic dyes Congo red (CR) and Thioflavin T (ThT), visualization of amyloid fibres by transmission electron microscopy and the green birefringent properties of CR-stained protein aggregates when viewed under cross-polarized light. We provide evidence that amyloid is present in human dental plaque and is produced by both laboratory strains and clinical isolates of S. mutans. We provide further evidence that amyloid formation is not limited to P1, since bacterial colonies without this adhesin demonstrate residual green birefringence. However, S. mutans lacking sortase, the transpeptidase enzyme that mediates the covalent linkage of its substrates to the cell-wall peptidoglycan, including P1 and five other proteins, is not birefringent when stained with CR and does not form biofilms. Biofilm formation is inhibited when S. mutans is cultured in the presence of known inhibitors of amyloid fibrillization, including CR, Thioflavin S and epigallocatechin-3-gallate, which also inhibited ThT uptake by S. mutans extracellular proteins. Taken together, these results indicate that S. mutans is an amyloid-forming organism and suggest that amyloidogenesis contributes to biofilm formation by this oral microbe. PMID:23082034

  11. Functional amyloids in bacteria.

    Science.gov (United States)

    Romero, Diego; Kolter, Roberto

    2014-06-01

    The term amyloidosis is used to refer to a family of pathologies altering the homeostasis of human organs. Despite having a name that alludes to starch content, the amyloid accumulations are made up of proteins that polymerize as long and rigid fibers. Amyloid proteins vary widely with respect to their amino acid sequences but they share similarities in their quaternary structure; the amyloid fibers are enriched in β-sheets arranged perpendicular to the axis of the fiber. This structural feature provides great robustness, remarkable stability, and insolubility. In addition, amyloid proteins specifically stain with certain dyes such as Congo red and thioflavin-T. The aggregation into amyloid fibers, however, it is not restricted to pathogenic processes, rather it seems to be widely distributed among proteins and polypeptides. Amyloid fibers are present in insects, fungi and bacteria, and they are important in maintaining the homeostasis of the organism. Such findings have motivated the use of the term "functional amyloid" to differentiate these amyloid proteins from their toxic siblings. This review focuses on systems that have evolved in bacteria that control the expression and assembly of amyloid proteins on cell surfaces, such that the robustness of amyloid proteins are used towards a beneficial end. Copyright© by the Spanish Society for Microbiology and Institute for Catalan Studies.

  12. Biofilm inhibitors that target amyloid proteins.

    Science.gov (United States)

    Romero, Diego; Sanabria-Valentín, Edgardo; Vlamakis, Hera; Kolter, Roberto

    2013-01-24

    Bacteria establish stable communities, known as biofilms, that are resistant to antimicrobials. Biofilm robustness is due to the presence of an extracellular matrix, which for several species-among them Bacillus subtilis-includes amyloid-like protein fibers. In this work, we show that B. subtilis biofilms can be a simple and reliable tool for screening of molecules with antiamyloid activity. We identified two molecules, AA-861 and parthenolide, which efficiently inhibited biofilms by preventing the formation of amyloid-like fibers. Parthenolide also disrupted pre-established biofilms. These molecules also impeded the formation of biofilms of other bacterial species that secrete amyloid proteins, such as Bacillus cereus and Escherichia coli. Furthermore, the identified molecules decreased the conversion of the yeast protein New1 to the prion state in a heterologous host, indicating the broad range of activity of the molecules. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Kosicka, Iga

    2014-01-01

    Diabetes mellitus type II is a metabolic disease affecting millions of people worldwide. The disease is associated with occurence of insoluble, fibrillar, protein aggregates in islets of Langerhans in the pancreas - islet amyloid. The main constituent of these protein fibers is the human islet...... of diabetes type II, while revealing the structure(s) of islet amyloid fibrils is necessary for potential design of therapeutic agents....

  14. {beta} - amyloid imaging probes

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Jae Min [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    Imaging distribution of {beta} - amyloid plaques in Alzheimer's disease is very important for early and accurate diagnosis. Early trial of the {beta} -amyloid plaques includes using radiolabeled peptides which can be only applied for peripheral {beta} - amyloid plaques due to limited penetration through the blood brain barrier (BBB). Congo red or Chrysamine G derivatives were labeled with Tc-99m for imaging {beta} - amyloid plaques of Alzheimer patient's brain without success due to problem with BBB penetration. Thioflavin T derivatives gave breakthrough for {beta} - amyloid imaging in vivo, and a benzothiazole derivative [C-11]6-OH-BTA-1 brought a great success. Many other benzothiazole, benzoxazole, benzofuran, imidazopyridine, and styrylbenzene derivatives have been labeled with F-18 and I-123 to improve the imaging quality. However, [C-11]6-OH-BTA-1 still remains as the best. However, short half-life of C-11 is a limitation of wide distribution of this agent. So, it is still required to develop an Tc-99m, F-18 or I-123 labeled agent for {beta} - amyloid imaging agent.

  15. β - amyloid imaging probes

    International Nuclear Information System (INIS)

    Jeong, Jae Min

    2007-01-01

    Imaging distribution of β - amyloid plaques in Alzheimer's disease is very important for early and accurate diagnosis. Early trial of the β -amyloid plaques includes using radiolabeled peptides which can be only applied for peripheral β - amyloid plaques due to limited penetration through the blood brain barrier (BBB). Congo red or Chrysamine G derivatives were labeled with Tc-99m for imaging β - amyloid plaques of Alzheimer patient's brain without success due to problem with BBB penetration. Thioflavin T derivatives gave breakthrough for β - amyloid imaging in vivo, and a benzothiazole derivative [C-11]6-OH-BTA-1 brought a great success. Many other benzothiazole, benzoxazole, benzofuran, imidazopyridine, and styrylbenzene derivatives have been labeled with F-18 and I-123 to improve the imaging quality. However, [C-11]6-OH-BTA-1 still remains as the best. However, short half-life of C-11 is a limitation of wide distribution of this agent. So, it is still required to develop an Tc-99m, F-18 or I-123 labeled agent for β - amyloid imaging agent

  16. A potential amyloid-imaging probe for Alzheimer's disease

    International Nuclear Information System (INIS)

    Cai Jiong; Wang Shizhen; Yuan Jiangang; Qiang Boqin

    2004-01-01

    Purpose: To screen out the human single-chain fragment variable (scFv) against amyloid β peptide 40 from a human synthetic antibody library, sub-clone its gene into E. coli expression system, and express and purify it for amyloid peptide imaging research. The overload of amyloid β peptide and the appearance of senile plaques in the human brain tissue is one of the hallmark of the Alzheimer's disease, and in vivo imaging of amyloidβ peptide is valuable for the earlier diagnosis of Alzheimer's disease. Methods: Amyloid β peptide 40 was bound on the solid surface of Nunc plates as antigen and a human antibody library constructed with human antibody heavy and light chain variable gene and nucleotides sequence coded (Gly4Ser)3 linker and displayed on the protein surface of filamentous phage was used to screen the binding clones. After five rounds of bio-panning, the host E. coli TG1 was infected with eluted filamentous phage from the last turn of selection. 55 well-separated colonies were picked randomly from the plates and several specific positive clones were identified by ELISA testing, and their binding sites were determined by competitive ELISA with amyloid 13 peptide 40, 1-16, 25-35. The single-chain Fv antibody gene was sequenced and their amino acids sequence was deduced. The scFv antibody gene was sub-cloned into a protokayotic expression vector pET-22b(+) and transformed into bacteria strain BL21 to express the His6-tagged single-chain antibody and the whole cell culture was subjected to SDS-PAGE analysis. The antibody was expressed in inclusion bodies and purified with serial buffers and verified with western blotting and their activity was tested by ELISA against amyloid β peptide 40. Results: ELISA testing showed that 33 clones could bind amyloid β peptide 40 and 10 of these clones could be inhibited by amyloid β peptide 40 itself to below 50% of its original binding activities. Five clones could also be inhibited by amyloid β peptide 1-16. DNA

  17. Cerebral Amyloid Angiopathy

    Directory of Open Access Journals (Sweden)

    Mahmut Edip Gürol

    2009-03-01

    Full Text Available Cerebral amyloid angiopathy (CAA is characterized by the accumulation of amyloid beta-peptides (Ab in the walls of leptomeningeal arteries, arterioles, and veins. Despite the fact that these pathological changes were first described in 1909, major advancement in our understanding of the clinicoradiological manifestations, neurobiology, and course of CAA has occurred only during the last 30 years. No significant associations have been shown between CAA and other systemic/visceral amyloidoses or vascular risk factors, including hypertension. CAA is well known as the most common cause of spontaneous and anticoagulant-related lobar parenchymal ICH in the elderly. It also causes lobar cerebral microbleeds (CMBs, small dot-like dark susceptibility artifacts visible with gradient recalled echo (GRE-magnetic resonance imaging (MRI. CMBs are important markers of disease severity and predictors of CAA progression. Amyloid angiopathy is also a common cause of ischemic microvascular white matter disease (WMD and deep cerebral infarctions. Such WMD is defined as subcortical and periventricular white matter changes without obvious infarction, as well as a dark appearance on computerized tomography (CT and a bright appearance on fluid attenuated inversion recovery (FLAIR-MRI. CAA-related vascular dysfunction, with its hemorrhagic and ischemic complications, is a recognized contributor to vascular cognitive impairment in the elderly, an independent effect that is synergistically increased by Alzheimer pathologies, such as plaques and tangles. A set of clinicoradiological criteria was established for the accurate diagnosis of CAA. According to the Boston Criteria, patients aged 55 years and older with multiple hemorrhages (on CT or GRE-MRI restricted to the lobar, cortical, or corticosubcortical regions (cerebellar hemorrhage allowed are diagnosed as probable CAA when no other etiology is found; a single hemorrhage in the same region is classified as possible

  18. The broad-spectrum antiviral compound ST-669 restricts chlamydial inclusion development and bacterial growth and localizes to host cell lipid droplets within treated cells.

    Science.gov (United States)

    Sandoz, Kelsi M; Valiant, William G; Eriksen, Steven G; Hruby, Dennis E; Allen, Robert D; Rockey, Daniel D

    2014-07-01

    Novel broad-spectrum antimicrobials are a critical component of a strategy for combating antibiotic-resistant pathogens. In this study, we explored the activity of the broad-spectrum antiviral compound ST-669 for activity against different intracellular bacteria and began a characterization of its mechanism of antimicrobial action. ST-669 inhibits the growth of three different species of chlamydia and the intracellular bacterium Coxiella burnetii in Vero and HeLa cells but not in McCoy (murine) cells. The antichlamydial and anti-C. burnetii activity spectrum was consistent with those observed for tested viruses, suggesting a common mechanism of action. Cycloheximide treatment in the presence of ST-669 abrogated the inhibitory effect, demonstrating that eukaryotic protein synthesis is required for tested activity. Immunofluorescence microscopy demonstrated that different chlamydiae grow atypically in the presence of ST-669, in a manner that suggests the compound affects inclusion formation and organization. Microscopic analysis of cells treated with a fluorescent derivative of ST-669 demonstrated that the compound localized to host cell lipid droplets but not to other organelles or the host cytosol. These results demonstrate that ST-669 affects intracellular growth in a host-cell-dependent manner and interrupts proper development of chlamydial inclusions, possibly through a lipid droplet-dependent process. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  19. Serum amyloid A and C-reactive protein combined determination for diagnosis of bacterial infection in neonates%血清淀粉样蛋白A与C反应蛋白联合检测在新生儿细菌感染诊断中的应用

    Institute of Scientific and Technical Information of China (English)

    沈伟虹; 岳朝艳; 孙振东; 应春妹

    2016-01-01

    目的:研究血清淀粉样蛋白 A(SAA)和 C 反应蛋白(CRP)以及白细胞总数在新生儿细菌感染诊断中的应用价值。方法分别检测80例细菌感染新生儿及58名体检正常的新生儿(非感染组)SAA、CRP 和白细胞总数并做比较。结果新生儿细菌感染组 SAA 与 CRP 水平分别为(67.3±38.4)、(19.2±11.2)mg/L,明显高于非感染组[(8.7±2.1)、(5.6±2.5)mg/L](P15.00×109/L,明显高于非感染组[24例(41%)]。结论 SAA 和 CRP 可作为新生儿细菌感染诊断的重要指标,SAA 较 CRP 更为敏感,SAA 与 CRP 的联合检测能够提高新生儿细菌感染的检出率,为疾病的早期诊断和监测提供实验依据。%Objective To study the significance of serum amyloid A(SAA),C-reactive protein(CRP)and white blood cell count determinations for diagnosis of bacterial infection in neonates. Methods SAA,CRP and white blood cell count were determined in 80 neonates with bacterial infection and 58 healthy neonates(non-bacterial infection group),and the results were analyzed. Results The concentrations of SAA and CRP in infection group [(67.3±38.4)and(19.2±11.2) mg/L] were significantly higher than those in non-bacterial infection group [(8.7±2.1)and(5.6±2.5)mg/L](P15.00×109/L in 64 neonates of 80 cases of infection group(80%),which was higher than that in non-bacterial infection group [24 cases(41%)]. Conclusions SAA and CRP could be used as important markers for monitoring bacterial infection in neonates,and SAA is more sensitive than CRP. The combined determination of SAA and CRP could improve the determination rate of bacterial infection,which provides an experimental reference for early diagnosis and monitoring of bacterial infection.

  20. Protein Polymers and Amyloids

    DEFF Research Database (Denmark)

    Risør, Michael Wulff

    2014-01-01

    Several human disorders are caused by a common general disease mechanism arising from abnormal folding and aggregation of the underlying protein. These include the prevalent dementias like Alzheimer’s and Parkinson’s, where accumulation of protein fibrillar structures, known as amyloid fibrils......, is a general hallmark. They also include the α1-antitrypsin deficiency, where disease-causing mutations in the serine protease inhibitor, α1-antitrypsin (α1AT), leads to accumulation of the aberrant protein in the liver of these patients. The native metastable structure of α1AT constitutes a molecular trap...... that inhibits its target protease through a large conformational change but mutations compromise this function and cause premature structural collapse into hyperstable polymers. Understanding the conformational disorders at a molecular level is not only important for our general knowledge on protein folding...

  1. Early Detection of Autism (ASD) by a Non-invasive Quick Measurement of Markedly Reduced Acetylcholine & DHEA and Increased β-Amyloid (1-42), Asbestos (Chrysotile), Titanium Dioxide, Al, Hg & often Coexisting Virus Infections (CMV, HPV 16 and 18), Bacterial Infections etc. in the Brain and Corresponding Safe Individualized Effective Treatment.

    Science.gov (United States)

    Omura, Yoshiaki; Lu, Dominic; Jones, Marilyn K; Nihrane, Ahdallah; Duvvi, Harsha; Shimotsuura, Yasuhiro; Ohki, Motomu

    2015-01-01

    A brief historical background on Autism & some of the important symptoms associated with Autism are summarized. Using strong Electro Magnetic Field Resonance Phenomenon between 2 identical molecules with identical weight (which received U.S. Patent) non-invasively & rapidly we can detect various molecules including neurotransmitters, bacteria, virus, fungus, metals & abnormal molecules. Simple non- invasive measurement of various molecules through pupils & head of diagnosed or suspected Autism patients indicated that in Autism patients following changes were often found: 1) Acetylcholine is markedly reduced; 2) Alzheimer's disease markers (i.e. β-Amyloid (1-42), Tau Protein, Apolipoprotein (Apo E4)) are markedly increased; 3) Chrysotile Asbestos is increased; 4) Titanium Dioxide (TiO2) is moderately increased; 5) Al is moderately increased; 6) Hg is moderately increased; 7) Dopamine, Serotonin & GABA are significantly reduced (up to about 1/10 of normal); 8) Often viral infections (such as CMV, HHV-6, HPV-16, HPV-18, etc.), and Bacterial infections (such as Chlamydia trachomatis, Mycobacterium TB, Borrelia Burgdorferi, etc.) coexist. Research by others on Autism spectrum disorder (ASD) shows that it is a group of complex neurodevelopmental disorders, with about 70% of ASD patients also suffering from gastro-intestinal problems. While Alzheimer disease (AD) is characterized by formation of 1) Amyloid plaques, 2) Neurofibrillary tangles inside of neurons, and 3) Loss of connections between neurons. More than 90% of AD develops in people over the age of 65. These 3 characteristics often progressively worsen over time. Although Autism Spectrum Disorder and Alzheimer's disease are completely different diseases they have some similar biochemical changes. Eight examples of such measurement & analysis are shown for comparison. Most of Autism patients improved significantly by removing the source or preventing intake of Asbestos, TiO2, Al & Hg or enhancing urinary output

  2. Towards a Pharmacophore for Amyloid

    Energy Technology Data Exchange (ETDEWEB)

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David (UCLA)

    2011-09-16

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of {beta}-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a

  3. A study of the cytoplasmic expression of a form of human prolactin and of its solubilization and renaturation from bacterial inclusion bodies

    International Nuclear Information System (INIS)

    Affonso, Regina

    2000-01-01

    Different vector elements, that can determine a high expression level of a form of human prolactin (taghPrl) in bacterial cytoplasm, were studied. Expression conditions were first optimized for a reference vector, which was used to transform different strains of E. coli: HB2151, RRI and RB791. The highest expression level (113 ±16 μg/mL.A 600 ) was obtained in HB2151, after activation with only 0.1 mM IPTG. At this point the influence of the transcription terminator (g32 from bacteriophage T4), of the translation enhancer (g10 from bacteriophage T7), of the promoter (λP L or tac) and of the antibiotic resistance gene (amp r or kan r ) were studied. The first three elements did not show any significant influence, at least in our systems. On the contrary, the analysis of the influence of amp r and kan r genes showed, unexpectedly, that the presence of the last one provides an approximately 5-fold higher expression for taghPrl in E. coli cytoplasm. Finally, an appropriate extraction, solubilization, renaturation and purification process, able to provide a monomeric form of taghPrl, was studied. A method utilizing urea and mercaptoethanol as solubilizing agents and a dialysis as a renaturation procedure, provided with some modifications, one of the highest yields ever reported in the literature: 35.4 ± 4.5% of total recovery. Moreover, the biological activity of the taghPrl obtained, when tested in the Nb2 cell proliferation assay, was of the same order of that shown by the International Standard of human prolactin of pituitary origin. These data show that the cytoplasmic expression system here described, which can provide an expression efficiency 50-100 - fold higher than the periplasmic expression, can represent a valid alternative for the production of this and of other hormones of pharmaceutical interest and grade. (author)

  4. Proteomic screening for amyloid proteins.

    Directory of Open Access Journals (Sweden)

    Anton A Nizhnikov

    Full Text Available Despite extensive study, progress in elucidation of biological functions of amyloids and their role in pathology is largely restrained due to the lack of universal and reliable biochemical methods for their discovery. All biochemical methods developed so far allowed only identification of glutamine/asparagine-rich amyloid-forming proteins or proteins comprising amyloids that form large deposits. In this article we present a proteomic approach which may enable identification of a broad range of amyloid-forming proteins independently of specific features of their sequences or levels of expression. This approach is based on the isolation of protein fractions enriched with amyloid aggregates via sedimentation by ultracentrifugation in the presence of strong ionic detergents, such as sarkosyl or SDS. Sedimented proteins are then separated either by 2D difference gel electrophoresis or by SDS-PAGE, if they are insoluble in the buffer used for 2D difference gel electrophoresis, after which they are identified by mass-spectrometry. We validated this approach by detection of known yeast prions and mammalian proteins with established capacity for amyloid formation and also revealed yeast proteins forming detergent-insoluble aggregates in the presence of human huntingtin with expanded polyglutamine domain. Notably, with one exception, all these proteins contained glutamine/asparagine-rich stretches suggesting that their aggregates arose due to polymerization cross-seeding by human huntingtin. Importantly, though the approach was developed in a yeast model, it can easily be applied to any organism thus representing an efficient and universal tool for screening for amyloid proteins.

  5. Porcine prion protein amyloid.

    Science.gov (United States)

    Hammarström, Per; Nyström, Sofie

    2015-01-01

    Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

  6. Inclusive pedagogy

    DEFF Research Database (Denmark)

    Korsgaard, Morten Timmermann; Skov Mortensen, Stig

    This article will present a case for a shift in perspective in inclusive education research towards a continentally inspired approach. Drawing on the age old distinction between continental and Anglo-American educational research the aim is to flesh out what a shift to a continental approach...... will entail, and why it might be beneficial to research in inclusive education...

  7. Social inclusion and inclusive education

    Directory of Open Access Journals (Sweden)

    Marsela Robo

    2014-07-01

    In line with global debate on social inclusion and exclusion, the author brings the way this debate has now pervaded both the official and development policy discourse in Albania.Social inclusion is considered as one of the priorities of the current government, with poverty reduction as its main focus, which will be ensured not only through economic development. In the end, the article focuses on the role of education as a very important and useful tool for ensuring social inclusion.Social inclusion through education, in particular through vocational education, considered by the author as the only way towards sustainable development of Albanian society.

  8. Exploring new biological functions of amyloids: bacteria cell agglutination mediated by host protein aggregation.

    Directory of Open Access Journals (Sweden)

    Marc Torrent

    Full Text Available Antimicrobial proteins and peptides (AMPs are important effectors of the innate immune system that play a vital role in the prevention of infections. Recent advances have highlighted the similarity between AMPs and amyloid proteins. Using the Eosinophil Cationic Protein as a model, we have rationalized the structure-activity relationships between amyloid aggregation and antimicrobial activity. Our results show how protein aggregation can induce bacteria agglutination and cell death. Using confocal and total internal reflection fluorescence microscopy we have tracked the formation in situ of protein amyloid-like aggregates at the bacteria surface and on membrane models. In both cases, fibrillar aggregates able to bind to amyloid diagnostic dyes were detected. Additionally, a single point mutation (Ile13 to Ala can suppress the protein amyloid behavior, abolishing the agglutinating activity and impairing the antimicrobial action. The mutant is also defective in triggering both leakage and lipid vesicle aggregation. We conclude that ECP aggregation at the bacterial surface is essential for its cytotoxicity. Hence, we propose here a new prospective biological function for amyloid-like aggregates with potential biological relevance.

  9. Functional Amyloid Formation within Mammalian Tissue.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

  10. Nanomechanical properties of single amyloid fibrils

    International Nuclear Information System (INIS)

    Sweers, K K M; Bennink, M L; Subramaniam, V

    2012-01-01

    Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils. (topical review)

  11. Functional amyloid formation within mammalian tissue.

    Directory of Open Access Journals (Sweden)

    Douglas M Fowler

    2006-01-01

    Full Text Available Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

  12. Terapeutika amyloidóz

    Czech Academy of Sciences Publication Activity Database

    Holubová, Monika; Hrubý, Martin

    2016-01-01

    Roč. 110, č. 12 (2016), s. 851-859 ISSN 0009-2770 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : amyloidosis * amyloid * Alzheimer's disease Subject RIV: CD - Macromolecular Chemistry Impact factor: 0.387, year: 2016 http://www.chemicke-listy.cz/common/article-vol_110-issue_12-page_851.html

  13. Inclusive pedagogy

    DEFF Research Database (Denmark)

    Korsgaard, Morten Timmermann; Mortensen, Stig Skov

    of education. The article explores the relationship between Continental and Anglo-American educational theory, and why they seem to have developed in such distinct directions. Beginning with the Anglo-American perspective it is outlined how pedagogy and the so called educational interest became replaced...... and the politicisation of inclusive education, and a positive aim in the form of an argument for a move towards constructing a pedagogical ideal of inclusion....

  14. Loss of metal ions, disulfide reduction and mutations related to familial ALS promote formation of amyloid-like aggregates from superoxide dismutase.

    Directory of Open Access Journals (Sweden)

    Zeynep A Oztug Durer

    Full Text Available Mutations in the gene encoding Cu-Zn superoxide dismutase (SOD1 are one of the causes of familial amyotrophic lateral sclerosis (FALS. Fibrillar inclusions containing SOD1 and SOD1 inclusions that bind the amyloid-specific dye thioflavin S have been found in neurons of transgenic mice expressing mutant SOD1. Therefore, the formation of amyloid fibrils from human SOD1 was investigated. When agitated at acidic pH in the presence of low concentrations of guanidine or acetonitrile, metalated SOD1 formed fibrillar material which bound both thioflavin T and Congo red and had circular dichroism and infrared spectra characteristic of amyloid. While metalated SOD1 did not form amyloid-like aggregates at neutral pH, either removing metals from SOD1 with its intramolecular disulfide bond intact or reducing the intramolecular disulfide bond of metalated SOD1 was sufficient to promote formation of these aggregates. SOD1 formed amyloid-like aggregates both with and without intermolecular disulfide bonds, depending on the incubation conditions, and a mutant SOD1 lacking free sulfhydryl groups (AS-SOD1 formed amyloid-like aggregates at neutral pH under reducing conditions. ALS mutations enhanced the ability of disulfide-reduced SOD1 to form amyloid-like aggregates, and apo-AS-SOD1 formed amyloid-like aggregates at pH 7 only when an ALS mutation was also present. These results indicate that some mutations related to ALS promote formation of amyloid-like aggregates by facilitating the loss of metals and/or by making the intramolecular disulfide bond more susceptible to reduction, thus allowing the conversion of SOD1 to a form that aggregates to form resembling amyloid. Furthermore, the occurrence of amyloid-like aggregates per se does not depend on forming intermolecular disulfide bonds, and multiple forms of such aggregates can be produced from SOD1.

  15. Amyloid Goiter Secondary to Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    Bunyamin Aydin

    2016-01-01

    Full Text Available Diffuse amyloid goiter (AG is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn’s disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis.

  16. inclusions revisited

    Directory of Open Access Journals (Sweden)

    S. Migórski

    1995-01-01

    Full Text Available In this paper we confirm the validity of some recent results of Hu, Lakshmikantham, Papageorgiou [4] and Papageorgiou [13] concerning the existence and relaxation for nonlinear evolution inclusions. We fill a gap in the proofs of these results due to the use of incorrect Nagy's compactness embedding theorem.

  17. Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review

    Directory of Open Access Journals (Sweden)

    Xinhua Zhan

    2018-02-01

    Full Text Available This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria could play a role in causing sporadic Alzheimer’s disease (AD. This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with β amyloid (Aβ and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM. These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Aβ levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Aβ1–42 is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram-negative bacteria might be treatment or prevention targets for sporadic AD.

  18. Experimental induction of chicken amyloid A amyloidosis in white layer chickens by inoculation with inactivated vaccines.

    Science.gov (United States)

    Habibi, Wazir Ahmad; Hirai, Takuya; Niazmand, Mohammad Hakim; Okumura, Naoko; Yamaguchi, Ryoji

    2017-10-01

    We investigated the amyloidogenic potential of inactivated vaccines and the localized production of serum amyloid A (SAA) at the injection site in white layer chickens. Hens in the treated group were injected intramuscularly three times with high doses of inactivated oil-emulsion Salmonella Enteritidis vaccine and multivalent viral and bacterial inactivated oil-emulsion vaccines at two-week intervals. Chickens in the control group did not receive any inoculum. In the treated group, emaciation and granulomas were present, while several chickens died between 4 and 6 weeks after the first injection. Hepatomegaly was seen at necropsy, and the liver parenchyma showed inconsistent discolouration with patchy green to yellowish-brown areas, or sometimes red-brown areas with haemorrhage. Amyloid deposition in the liver, spleen, duodenum, and at injection sites was demonstrated using haematoxylin and eosin staining, Congo red, and immunohistochemistry. The incidence of chicken amyloid A (AA) amyloidosis was 47% (28 of 60) in the treated group. In addition, RT-PCR was used to identify chicken SAA mRNA expression in the liver and at the injection sites. Furthermore, SAA mRNA was detected by in situ hybridization in fibroblasts at the injection sites, and also in hepatocytes. We believe that this is the first report of the experimental induction of systemic AA amyloidosis in white layer chickens following repeated inoculation with inactivated vaccines without the administration of amyloid fibrils or other amyloid-enhancing factors.

  19. Augmenting Amyloid PET Interpretations With Quantitative Information Improves Consistency of Early Amyloid Detection.

    Science.gov (United States)

    Harn, Nicholas R; Hunt, Suzanne L; Hill, Jacqueline; Vidoni, Eric; Perry, Mark; Burns, Jeffrey M

    2017-08-01

    Establishing reliable methods for interpreting elevated cerebral amyloid-β plaque on PET scans is increasingly important for radiologists, as availability of PET imaging in clinical practice increases. We examined a 3-step method to detect plaque in cognitively normal older adults, focusing on the additive value of quantitative information during the PET scan interpretation process. Fifty-five F-florbetapir PET scans were evaluated by 3 experienced raters. Scans were first visually interpreted as having "elevated" or "nonelevated" plaque burden ("Visual Read"). Images were then processed using a standardized quantitative analysis software (MIMneuro) to generate whole brain and region of interest SUV ratios. This "Quantitative Read" was considered elevated if at least 2 of 6 regions of interest had an SUV ratio of more than 1.1. The final interpretation combined both visual and quantitative data together ("VisQ Read"). Cohen kappa values were assessed as a measure of interpretation agreement. Plaque was elevated in 25.5% to 29.1% of the 165 total Visual Reads. Interrater agreement was strong (kappa = 0.73-0.82) and consistent with reported values. Quantitative Reads were elevated in 45.5% of participants. Final VisQ Reads changed from initial Visual Reads in 16 interpretations (9.7%), with most changing from "nonelevated" Visual Reads to "elevated." These changed interpretations demonstrated lower plaque quantification than those initially read as "elevated" that remained unchanged. Interrater variability improved for VisQ Reads with the addition of quantitative information (kappa = 0.88-0.96). Inclusion of quantitative information increases consistency of PET scan interpretations for early detection of cerebral amyloid-β plaque accumulation.

  20. Translating Inclusion

    DEFF Research Database (Denmark)

    Fallov, Mia Arp; Birk, Rasmus

    2018-01-01

    The purpose of this paper is to explore how practices of translation shape particular paths of inclusion for people living in marginalized residential areas in Denmark. Inclusion, we argue, is not an end-state, but rather something which must be constantly performed. Active citizenship, today......, is not merely a question of participation, but of learning to become active in all spheres of life. The paper draws on empirical examples from a multi-sited field work in 6 different sites of local community work in Denmark, to demonstrate how different dimensions of translation are involved in shaping active...... citizenship. We propose the following different dimensions of translation: translating authority, translating language, translating social problems. The paper takes its theoretical point of departure from assemblage urbanism, arguing that cities are heterogeneous assemblages of socio-material interactions...

  1. Why are Functional Amyloids Non-Toxic in Humans?

    Directory of Open Access Journals (Sweden)

    Matthew P. Jackson

    2017-09-01

    Full Text Available Amyloids were first identified in association with amyloidoses, human diseases in which proteins and peptides misfold into amyloid fibrils. Subsequent studies have identified an array of functional amyloid fibrils that perform physiological roles in humans. Given the potential for the production of toxic species in amyloid assembly reactions, it is remarkable that cells can produce these functional amyloids without suffering any obvious ill effect. Although the precise mechanisms are unclear, there are a number of ways in which amyloid toxicity may be prevented. These include regulating the level of the amyloidogenic peptides and proteins, minimising the production of prefibrillar oligomers in amyloid assembly reactions, sequestrating amyloids within membrane bound organelles, controlling amyloid assembly by other molecules, and disassembling the fibrils under physiological conditions. Crucially, a better understanding of how toxicity is avoided in the production of functional amyloids may provide insights into the prevention of amyloid toxicity in amyloidoses.

  2. Anti-amyloid treatments in Alzheimer's disease.

    Science.gov (United States)

    Sapra, Mamta; Kim, Kye Y

    2009-06-01

    Alzheimer's disease is one of the most challenging threats to the healthcare system in society. One of the main characteristic of Alzheimer's disease (AD) pathology is formation of amyloid plaques from accumulation of amyloid beta peptide. The therapeutic agents that are currently available for AD including acetylcholinesterase inhibitors (AchEIs) and the N-methyl-D-aspartate (NMDA) antagonist are focused on improving the symptoms and do not revert the progression of the disease. This limitation coupled with the burgeoning increase in the prevalence of AD and resultant impact on healthcare economics calls for more substantial treatments for AD. According to the leading amyloid hypothesis, cleavage of amyloid precursor protein to release amyloid beta peptide is the critical event in pathogenesis of Alzheimer's disease. Recently treatment strategies have been focused on modifying the formation, clearance and accumulation of neurotoxic amyloid beta peptide. This article reviews different therapeutic approaches that have been investigated to target amyloid beta ranging from secretase modulators, antiaggregation agents to amyloid immunotherapy. Authors review the different novel drugs which are in clinical trials.

  3. Carbon nanospecies affecting amyloid formation

    Czech Academy of Sciences Publication Activity Database

    Holubová, Monika; Konefal, Rafal; Morávková, Zuzana; Zhigunov, Alexander; Svoboda, Jan; Pop-Georgievski, Ognen; Hromádková, Jiřina; Groborz, Ondřej; Štěpánek, Petr; Hrubý, Martin

    2017-01-01

    Roč. 7, č. 85 (2017), s. 53887-53898 ISSN 2046-2069 R&D Projects: GA MŠk(CZ) LM2015064; GA MZd(CZ) NV16-30544A; GA ČR(CZ) GA16-03156S; GA TA ČR(CZ) TE01020118; GA MŠk(CZ) LO1507 Grant - others:OPPK(XE) CZ.2.16/3.1.00/21545 Program:OPPK Institutional support: RVO:61389013 Keywords : amyloid fibril * nanodiamond * fullerene Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 3.108, year: 2016

  4. Chiral recognition in amyloid fiber growth.

    Science.gov (United States)

    Torbeev, Vladimir; Grogg, Marcel; Ruiz, Jérémy; Boehringer, Régis; Schirer, Alicia; Hellwig, Petra; Jeschke, Gunnar; Hilvert, Donald

    2016-05-01

    Insoluble amyloid fibers represent a pathological signature of many human diseases. To treat such diseases, inhibition of amyloid formation has been proposed as a possible therapeutic strategy. d-Peptides, which possess high proteolytic stability and lessened immunogenicity, are attractive candidates in this context. However, a molecular understanding of chiral recognition phenomena for d-peptides and l-amyloids is currently incomplete. Here we report experiments on amyloid growth of individual enantiomers and their mixtures for two distinct polypeptide systems of different length and structural organization: a 44-residue covalently-linked dimer derived from a peptide corresponding to the [20-41]-fragment of human β2-microglobulin (β2m) and the 99-residue full-length protein. For the dimeric [20-41]β2m construct, a combination of electron paramagnetic resonance of nitroxide-labeled constructs and (13) C-isotope edited FT-IR spectroscopy of (13) C-labeled preparations was used to show that racemic mixtures precipitate as intact homochiral fibers, i.e. undergo spontaneous Pasteur-like resolution into a mixture of left- and right-handed amyloids. In the case of full-length β2m, the presence of the mirror-image d-protein affords morphologically distinct amyloids that are composed largely of enantiopure domains. Removal of the l-component from hybrid amyloids by proteolytic digestion results in their rapid transformation into characteristic long straight d-β2m amyloids. Furthermore, the full-length d-enantiomer of β2m was found to be an efficient inhibitor of l-β2m amyloid growth. This observation highlights the potential of longer d-polypeptides for future development into inhibitors of amyloid propagation. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  5. Amyloid beta peptide immunotherapy in Alzheimer disease.

    Science.gov (United States)

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  6. Cerebral amyloid angiopathy, blood-brain barrier disruption and amyloid accumulation in SAMP8 mice.

    Science.gov (United States)

    del Valle, Jaume; Duran-Vilaregut, Joaquim; Manich, Gemma; Pallàs, Mercè; Camins, Antoni; Vilaplana, Jordi; Pelegrí, Carme

    2011-01-01

    Cerebrovascular dysfunction and β-amyloid peptide deposition on the walls of cerebral blood vessels might be an early event in the development of Alzheimer's disease. Here we studied the time course of amyloid deposition in blood vessels and blood-brain barrier (BBB) disruption in the CA1 subzone of the hippocampus of SAMP8 mice and the association between these two variables. We also studied the association between the amyloid deposition in blood vessels and the recently described amyloid clusters in the parenchyma, as well as the association of these clusters with vessels in which the BBB is disrupted. SAMP8 mice showed greater amyloid deposition in blood vessels than age-matched ICR-CD1 control mice. Moreover, at 12 months of age the number of vessels with a disrupted BBB had increased in both strains, especially SAMP8 animals. At this age, all the vessels with amyloid deposition showed BBB disruption, but several capillaries with an altered BBB showed no amyloid on their walls. Moreover, amyloid clusters showed no spatial association with vessels with amyloid deposition, nor with vessels in which the BBB had been disrupted. Finally, we can conclude that vascular amyloid deposition seems to induce BBB alterations, but BBB disruption may also be due to other factors. Copyright © 2011 S. Karger AG, Basel.

  7. General amyloid inhibitors? A critical examination of the inhibition of IAPP amyloid formation by inositol stereoisomers.

    Directory of Open Access Journals (Sweden)

    Hui Wang

    Full Text Available Islet amyloid polypeptide (IAPP or amylin forms amyloid deposits in the islets of Langerhans; a process that is believed to contribute to the progression of type 2 diabetes and to the failure of islet transplants. An emerging theme in amyloid research is the hypothesis that the toxic species produced during amyloid formation by different polypeptides share common features and exert their effects by common mechanisms. If correct, this suggests that inhibitors of amyloid formation by one polypeptide might be effective against other amyloidogenic sequences. IAPP and Aβ, the peptide responsible for amyloid formation in Alzheimer's disease, are particularly interesting in this regard as they are both natively unfolded in their monomeric states and share some common characteristics. Comparatively little effort has been expended on the design of IAPP amyloid inhibitors, thus it is natural to inquire if Aβ inhibitors are effective against IAPP, especially since no IAPP inhibitors have been clinically approved. A range of compounds inhibit Aβ amyloid formation, including various stereoisomers of inositol. Myo-, scyllo-, and epi-inositol have been shown to induce conformational changes in Aβ and prevent Aβ amyloid fibril formation by stabilizing non-fibrillar β-sheet structures. We investigate the ability of inositol stereoisomers to inhibit amyloid formation by IAPP. The compounds do not induce a conformational change in IAPP and are ineffective inhibitors of IAPP amyloid formation, although some do lead to modest apparent changes in IAPP amyloid fibril morphology. Thus not all classes of Aβ inhibitors are effective against IAPP. This work provides a basis of comparison to work on polyphenol based inhibitors of IAPP amyloid formation and helps provide clues as to the features which render them effective. The study also helps provide information for further efforts in rational inhibitor design.

  8. Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation

    OpenAIRE

    Ribeiro, Diana; Horvath, Istvan; Heath, Nikki; Hicks, Ryan; Forslöw, Anna; Wittung-Stafshede, Pernilla

    2017-01-01

    Protein assembly into amyloid fibers underlies such neurodegenerative disorders as Alzheimer’s disease and Parkinson’s disease. Type 2 diabetes (T2D) also involves amyloid formation, although in the pancreas. Because there are no cures for amyloid diseases and T2D is on the rise due to an increasing prevalence of obesity, identifying involved mechanisms and control processes is of utmost importance. Extracellular vesicles (EVs) can mediate physiological and pathological communication both loc...

  9. Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins.

    Science.gov (United States)

    Flavin, William P; Bousset, Luc; Green, Zachary C; Chu, Yaping; Skarpathiotis, Stratos; Chaney, Michael J; Kordower, Jeffrey H; Melki, Ronald; Campbell, Edward M

    2017-10-01

    Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.

  10. Amyloid Imaging in Aging and Dementia: Testing the Amyloid Hypothesis In Vivo

    Directory of Open Access Journals (Sweden)

    G. D. Rabinovici

    2009-01-01

    Full Text Available Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET with ^{11}carbon-labelled Pittsburgh Compound-B (11C-PIB, the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Aβ deposits, and is a sensitive marker for Aβ pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI and Alzheimer’s disease (AD. PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.

  11. Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, P.N.; Lavender, J.P.; Myers, M.J.; Pepys, M.B.

    1988-06-25

    The specific molecular affinity of the normal plasma protein, serum amyloid P component (SAP), for all known types of amyloid fibrils was used to develop a new general diagnostic method for in-vivo radionuclide imaging of amyloid deposits. After intravenous injection of /sup 123/I-labelled purified human SAP there was specific uptake into amyloid deposits in all affected patients, 7 with systematic AL amyloid, 5 with AA amyloid, and 2 with ..beta../sub 2/M amyloid, in contrast to the complete absence of any tissue localisation in 5 control subjects. Distinctive high-resolution scintigraphic images, even of minor deposits in the carpal regions, bone marrow, or adrenals, were obtained. This procedure should yield much information on the natural history and the management of amyloidosis, the presence of which has hitherto been confirmed only by biopsy. Clearance and metabolic studies indicated that, in the presence of extensive amyloidosis, the rate of synthesis of SAP was greatly increased despite maintenance of normal plasma levels. Futhermore, once localised to amyloid deposits the /sup 123/I-SAP persisted for long periods and was apparently protected from its normal rapid degradation. These findings shed new light on the pathophysiology of amyloid and may have implications for therapeutic strategies based upon specific molecular targeting with SAP.

  12. beta. -Amyloid gene dosage in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Murdoch, G H; Manuelidis, L; Kim, J H; Manuelidis, E E

    1988-01-11

    The 4-5 kd amyloid ..beta..-peptide is a major constituent of the characteristic amyloid plaque of Alzheimer's disease. It has been reported that some cases of sporatic Alzheimer's disease are associated with at least a partial duplication of chromosome 21 containing the gene corresponding to the 695 residue precursor of this peptide. To contribute to an understanding of the frequency to such a duplication event in the overall Alzheimer's population, the authors have determined the gene dosage of the ..beta..-amyloid gene in this collection of cases. All cases had a clinical diagnosis of Alzheimer's confirmed neuropathologically. Each Alzheimer's case had an apparent normal diploid ..beta..-amyloid gene dosage, while control Down's cases had the expected triploid dosage. Thus partial duplication of chromosome 21 may be a rare finding in Alzheimer's disease. Similar conclusions were just reported in several studies of the Harvard Alzheimer collection.

  13. Bilateral metachronous periosteal tibial amyloid tumors

    International Nuclear Information System (INIS)

    Murata, H.; Kusuzaki, Katsuyuki; Hashiguchi, S.; Ueda, Hidetaka; Hirasawa, Yasusuke

    2000-01-01

    Localized primary periosteal amyloid tumors are extremely rare. A case of bilateral tibial amyloid tumor is presented. A 62-year-old woman initially presented with a painful mass in the anterior aspect of the right leg. There was no evidence of underlying systemic disease, including chronic infection or malignancy. Based on the results of resistance with Congo red staining to treatment with potassium permanganate and positivity for kappa light chain, we classified this particular case as AL-type amyloidosis. The patient noticed a swelling in the opposite leg 2 years later. The second tumor was also an AL-type amyloidoma. Amyloid tumors are generally solitary. This is the first case of bilateral periosteal amyloid tumors of the AL-type occurring in the tibiae. (orig.)

  14. Bacterial meningitis

    NARCIS (Netherlands)

    Roos, Karen L.; van de Beek, Diederik

    2010-01-01

    Bacterial meningitis is a neurological emergency. Empiric antimicrobial and adjunctive therapy should be initiated as soon as a single set of blood cultures has been obtained. Clinical signs suggestive of bacterial meningitis include fever, headache, meningismus, vomiting, photophobia, and an

  15. Calumenin interacts with serum amyloid P component

    DEFF Research Database (Denmark)

    Vorum, H; Jacobsen, Christian; Honoré, Bent

    2000-01-01

    with calumenin in the presence of Ca(2+). Amino acid sequencing identified this protein as serum amyloid P component (SAP). Furthermore, we verified and characterized the calumenin-SAP interaction by the surface plasmon resonance technique. The findings indicate that calumenin may participate...... in the immunological defense system and could be involved in the pathological process of amyloidosis that leads to formation of amyloid deposits seen in different types of tissues. Udgivelsesdato: 2000-Jan-14...

  16. Amyloid PET in neurodegenerative diseases with dementia.

    Science.gov (United States)

    Camacho, V; Gómez-Grande, A; Sopena, P; García-Solís, D; Gómez Río, M; Lorenzo, C; Rubí, S; Arbizu, J

    2018-05-15

    Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive decline and memory loss, and is the most common form of dementia. Amyloid plaques with neurofibrillary tangles are a neuropathological hallmark of AD that produces synaptic dysfunction and culminates later in neuronal loss. Amyloid PET is a useful, available and non-invasive technique that provides in vivo information about the cortical amyloid burden. In the latest revised criteria for the diagnosis of AD biomarkers were defined and integrated: pathological and diagnostic biomarkers (increased retention on fibrillar amyloid PET or decreased Aβ 1-42 and increased T-Tau or P-Tau in CSF) and neurodegeneration or topographical biomarkers (temporoparietal hypometabolism on 18 F-FDG PET and temporal atrophy on MRI). Recently specific recommendations have been created as a consensus statement on the appropriate use of the imaging biomarkers, including amyloid PET: early-onset cognitive impairment/dementia, atypical forms of AD, mild cognitive impairment with early age of onset, and to differentiate between AD and other neurodegenerative diseases that occur with dementia. Amyloid PET is also contributing to the development of new therapies for AD, as well as in research studies for the study of other neurodegenerative diseases that occur with dementia where the deposition of Aβ amyloid is involved in its pathogenesis. In this paper, we review some general concepts and study the use of amyloid PET in depth and its relationship with neurodegenerative diseases and other diagnostic techniques. Copyright © 2018 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. Luminescent conjugated oligothiophenes for sensitive fluorescent assignment of protein inclusion bodies.

    Science.gov (United States)

    Klingstedt, Therése; Blechschmidt, Cristiane; Nogalska, Anna; Prokop, Stefan; Häggqvist, Bo; Danielsson, Olof; Engel, W King; Askanas, Valerie; Heppner, Frank L; Nilsson, K Peter R

    2013-03-18

    Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Rehana Akter

    2016-01-01

    Full Text Available The hormone islet amyloid polypeptide (IAPP, or amylin plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.

  19. Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis.

    Science.gov (United States)

    Luo, Jinghui; Wärmländer, Sebastian K T S; Gräslund, Astrid; Abrahams, Jan Pieter

    2016-08-05

    Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-β (Aβ) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between Aβ and other amyloid proteins. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. IL-1β-Induced Accumulation of Amyloid: Macroautophagy in Skeletal Muscle Depends on ERK

    Directory of Open Access Journals (Sweden)

    Karsten Schmidt

    2017-01-01

    Full Text Available The pathology of inclusion body myositis (IBM involves an inflammatory response and β-amyloid deposits in muscle fibres. It is believed that MAP kinases such as the ERK signalling pathway mediate the inflammatory signalling in cells. Further, there is evidence that autophagic activity plays a crucial role in the pathogenesis of IBM. Using a well established in vitro model of IBM, the autophagic pathway, MAP kinases, and accumulation of β-amyloid were examined. We demonstrate that stimulation of muscle cells with IL-1β and IFN-γ led to an increased phosphorylation of ERK. The ERK inhibitor PD98059 diminished the expression of proinflammatory markers as well as the accumulation of β-amyloid. In addition, IL-1β and IFN-γ led to an increase of autophagic activity, upregulation of APP, and subsequent accumulation of β-sheet aggregates. Taken together, the data demonstrate that the ERK pathway contributes to formation of β-amyloid and regulation of autophagic activity in muscle cells exposed to proinflammatory cell stress. This suggests that ERK serves as an important mediator between inflammatory mechanisms and protein deposition in skeletal muscle and is a crucial element of the pathology of IBM.

  1. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    Science.gov (United States)

    Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

    2012-11-01

    The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  2. Confronting New Demands : Inclusive Growth, Inclusive Trade ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Confronting New Demands : Inclusive Growth, Inclusive Trade. Policymakers, businesspeople and civil society advocates need evidence-based research to react ... understood implications, such as labour standards and intellectual property; ...

  3. Adherence to the Mediterranean Diet Is not Related to Beta-Amyloid Deposition: Data from the Women's Healthy Ageing Project.

    Science.gov (United States)

    Hill, E; Szoeke, C; Dennerstein, L; Campbell, S; Clifton, P

    2018-01-01

    Research has indicated the neuroprotective potential of the Mediterranean diet. Adherence to the Mediterranean diet has shown preventative potential for Alzheimer's disease incidence and prevalence, yet few studies have investigated the impact of Mediterranean diet adherence on the hallmark protein; beta-amyloid. To investigate the association between Mediterranean diet adherence and beta-amyloid deposition in a cohort of healthy older Australian women. This study was a cross-sectional investigation of participants from the longitudinal, epidemiologically sourced Women's Healthy Ageing Project which is a follow-up of the Melbourne Women's Midlife Health Project. Assessments were conducted at the Centre for Medical Research, Royal Melbourne Hospital in Melbourne, Australia. F-18 Florbetaben positron emission tomography scanning was conducted at the Austin Centre for PET in Victoria, Australia. One hundred and eleven Women's Healthy Ageing Project participants were included in the study. Mediterranean diet adherence scores for all participants were calculated from the administration of a validated food frequency questionnaire constructed by the Cancer Council of Victoria. Beta-amyloid deposition was measured using positron emission tomography standardised uptake value ratios. Gamma regression analysis displayed no association between Mediterranean diet adherence and beta-amyloid deposition. This result was consistent across APOE-ε4 +/- cohorts and with the inclusion of covariates such as age, education, body mass index and cognition. This study found no association between adherence to the Mediterranean diet and beta-amyloid deposition in a cohort of healthy Australian women.

  4. Interaction of magnetic nanoparticles with lysozyme amyloid fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Gdovinová, Veronika [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Tomašovičová, Natália, E-mail: nhudak@saske.sk [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Batko, Ivan; Batková, Marianna; Balejčíková, Lucia [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Garamus, Vasyl M. [Helmholtz-Zentrum Geesthacht: Zentrum fr Material, und Kstenforschung GmbH, Max-Plank-Strae 1, Geesthacht 216502 (Germany); Petrenko, Viktor I. [Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Physics Department, Taras Shevchenko Kyiv National University, Volodymyrska Street 64, 01601 Kyiv (Ukraine); Avdeev, Mikhail V. [Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Kopčanský, Peter [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia)

    2017-06-01

    This work is devoted to the structural study of complex solutions of magnetic nanoparticles with lysozyme amyloid fibrils due to possible ordering of such system by applying the external magnetic field. The interaction of magnetic nanoparticles with amyloid fibrils has been followed by atomic force microscopy and small-angle X-ray scattering. It has been observed that magnetic nanoparticles (MNPs) adsorb to lysozyme amyloid fibrils. It was found that MNPs alter amyloids structures, namely the diameter of lysozyme amyloid fibrils is increased whereas the length of fibrils is decreased. In the same time MNPs do not change the helical pitch significantly. - Highlights: • Solution of MNPs with lysozyme amyloid fibrils was characterized by AFM and SAXS. • MNPs adsorb to lysozyme amyloid fibrils. • Diameter and size of lysozyme amyloid fibrils change due to doping with MNPs.

  5. Amyloid-degrading ability of nattokinase from Bacillus subtilis natto.

    Science.gov (United States)

    Hsu, Ruei-Lin; Lee, Kung-Ta; Wang, Jung-Hao; Lee, Lily Y-L; Chen, Rita P-Y

    2009-01-28

    More than 20 unrelated proteins can form amyloid fibrils in vivo which are related to various diseases, such as Alzheimer's disease, prion disease, and systematic amyloidosis. Amyloid fibrils are an ordered protein aggregate with a lamellar cross-beta structure. Enhancing amyloid clearance is one of the targets of the therapy of these amyloid-related diseases. Although there is debate on whether the toxicity is due to amyloids or their precursors, research on the degradation of amyloids may help prevent or alleviate these diseases. In this study, we explored the amyloid-degrading ability of nattokinase, a fibrinolytic subtilisin-like serine protease, and determined the optimal conditions for amyloid hydrolysis. This ability is shared by proteinase K and subtilisin Carlsberg, but not by trypsin or plasmin.

  6. Apolipoprotein E Regulates Amyloid Formation within Endosomes of Pigment Cells

    Directory of Open Access Journals (Sweden)

    Guillaume van Niel

    2015-10-01

    Full Text Available Accumulation of toxic amyloid oligomers is a key feature in the pathogenesis of amyloid-related diseases. Formation of mature amyloid fibrils is one defense mechanism to neutralize toxic prefibrillar oligomers. This mechanism is notably influenced by apolipoprotein E variants. Cells that produce mature amyloid fibrils to serve physiological functions must exploit specific mechanisms to avoid potential accumulation of toxic species. Pigment cells have tuned their endosomes to maximize the formation of functional amyloid from the protein PMEL. Here, we show that ApoE is associated with intraluminal vesicles (ILV within endosomes and remain associated with ILVs when they are secreted as exosomes. ApoE functions in the ESCRT-independent sorting mechanism of PMEL onto ILVs and regulates the endosomal formation of PMEL amyloid fibrils in vitro and in vivo. This process secures the physiological formation of amyloid fibrils by exploiting ILVs as amyloid nucleating platforms.

  7. Chirality and chiroptical properties of amyloid fibrils.

    Science.gov (United States)

    Dzwolak, Wojciech

    2014-09-01

    Chirality of amyloid fibrils-linear beta-sheet-rich aggregates of misfolded protein chains-often manifests in morphological traits such as helical twist visible in atomic force microscopy and in chiroptical properties accessible to vibrational circular dichroism (VCD). According to recent studies the relationship between molecular chirality of polypeptide building blocks and superstructural chirality of amyloid fibrils may be more intricate and less deterministic than previously assumed. Several puzzling experimental findings have put into question earlier intuitive ideas on: 1) the bottom-up chirality transfer upon amyloidogenic self-assembly, and 2) the structural origins of chiroptical properties of protein aggregates. For example, removal of a single amino acid residue from an amyloidogenic all-L peptide was shown to reverse handedness of fibrils. On the other hand, certain types of amyloid aggregates revealed surprisingly strong VCD spectra with the sign and shape dependent on the conditions of fibrillation. Hence, microscopic and chiroptical studies have highlighted chirality as one more aspect of polymorphism of amyloid fibrils. This brief review is intended to outline the current state of research on amyloid-like fibrils from the perspective of their structural and superstructural chirality and chiroptical properties. © 2014 Wiley Periodicals, Inc.

  8. Towards Alzheimer's beta-amyloid vaccination.

    Science.gov (United States)

    Frenkel, D; Solomon, B

    2001-01-01

    Beta-amyloid pathology, the main hallmark of Alzheimer's disease (AD), has been linked to its conformational status and aggregation. We recently showed that site-directed monoclonal antibodies (mAbs) towards the N-terminal region of the human beta-amyloid peptide bind to preformed beta-amyloid fibrils (Abeta), leading to disaggregation and inhibition of their neurotoxic effect. Here we report the development of a novel immunization procedure to raise effective anti-aggregating amyloid beta-protein (AbetaP) antibodies, using as antigen filamentous phages displaying the only EFRH peptide found to be the epitope of these antibodies. Due to the high antigenicity of the phage no adjuvant is required to obtain high affinity anti-aggregating IgG antibodies in animals model, that exhibit identity to human AbetaP. Such antibodies are able to sequester peripheral AbetaP, thus avoiding passage through the blood brain barrier (BBB) and, as recently shown in a transgenic mouse model, to cross the BBB and dissolve already formed beta-amyloid plaques. To our knowledge, this is the first attempt to use as a vaccine a self-anti-aggregating epitope displayed on a phage, and this may pave the way to treat abnormal accumulation-peptide diseases, such as Alzheimer's disease or other amyloidogenic diseases. Copyright 2001 The International Association for Biologicals.

  9. Tetrahydroxystilbene glucoside modulates amyloid precursor protein processing via activation of AKT-GSK3β pathway in cells and in APP/PS1 transgenic mice.

    Science.gov (United States)

    Yin, Xiaomin; Chen, Chen; Xu, Ting; Li, Lin; Zhang, Lan

    2018-01-01

    Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aβ) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3β pathway. We found GSK3β increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3β signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Halogenation dictates the architecture of amyloid peptide nanostructures.

    Science.gov (United States)

    Pizzi, Andrea; Pigliacelli, Claudia; Gori, Alessandro; Nonappa; Ikkala, Olli; Demitri, Nicola; Terraneo, Giancarlo; Castelletto, Valeria; Hamley, Ian W; Baldelli Bombelli, Francesca; Metrangolo, Pierangelo

    2017-07-20

    Amyloid peptides yield a plethora of interesting nanostructures though difficult to control. Here we report that depending on the number, position, and nature of the halogen atoms introduced into either one or both phenylalanine benzene rings of the amyloid β peptide-derived core-sequence KLVFF, four different architectures were obtained in a controlled manner. Our findings demonstrate that halogenation may develop as a general strategy to engineer amyloidal peptide self-assembly and obtain new amyloidal nanostructures.

  11. AL amyloid imaging and therapy with a monoclonal antibody to a cryptic epitope on amyloid fibrils.

    Directory of Open Access Journals (Sweden)

    Jonathan S Wall

    Full Text Available The monoclonal antibody 2A4 binds an epitope derived from a cleavage site of serum amyloid protein A (sAA containing a -Glu-Asp- amino acid pairing. In addition to its reactivity with sAA amyloid deposits, the antibody was also found to bind amyloid fibrils composed of immunoglobulin light chains. The antibody binds to synthetic fibrils and human light chain (AL amyloid extracts with high affinity even in the presence of soluble light chain proteins. Immunohistochemistry with biotinylated 2A4 demonstrated positive reaction with ALκ and ALλ human amyloid deposits in various organs. Surface plasmon resonance analyses using synthetic AL fibrils as a substrate revealed that 2A4 bound with a K(D of ∼10 nM. Binding was inhibited in the presence of the -Glu-Asp- containing immunogen peptide. Radiolabeled 2A4 specifically localized with human AL amyloid extracts implanted in mice (amyloidomas as evidenced by single photon emission (SPECT imaging. Furthermore, co-localization of the radiolabeled mAb with amyloid was shown in biodistribution and micro-autoradiography studies. Treatment with 2A4 expedited regression of ALκ amyloidomas in mice, likely mediated by the action of macrophages and neutrophils, relative to animals that received a control antibody. These data indicate that the 2A4 mAb might be of interest for potential imaging and immunotherapy in patients with AL amyloidosis.

  12. Amyloid in basal cell carcinoma and seborrheic keratosis

    DEFF Research Database (Denmark)

    Olsen, K E; Westermark, Per

    1994-01-01

    The frequency of amyloid substance was studied in two different types of skin tumours: basal cell carcinoma and seborrheic keratosis. In 9 out of 49 cases of seborrheic keratosis amyloid substance was found. In the basal cell carcinomas, 194 out of 260 cases showed amyloid deposits, a rate...

  13. The prion protein as a receptor for amyloid-beta

    NARCIS (Netherlands)

    Kessels, Helmut W.; Nguyen, Louis N.; Nabavi, Sadegh; Malinow, Roberto

    2010-01-01

    Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic

  14. Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

    Directory of Open Access Journals (Sweden)

    Langen Ralf

    2008-10-01

    Full Text Available Abstract Background The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD, age-related macular degeneration (AMD, atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins. Results We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation. Conclusion These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases.

  15. Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity

    Science.gov (United States)

    Du, Wen-Jie; Guo, Jing-Jing; Gao, Ming-Tao; Hu, Sheng-Quan; Dong, Xiao-Yan; Han, Yi-Fan; Liu, Fu-Feng; Jiang, Shaoyi; Sun, Yan

    2015-01-01

    Soluble amyloid β-protein (Aβ) oligomers, the main neurotoxic species, are predominantly formed from monomers through a fibril-catalyzed secondary nucleation. Herein, we virtually screened an in-house library of natural compounds and discovered brazilin as a dual functional compound in both Aβ42 fibrillogenesis inhibition and mature fibril remodeling, leading to significant reduction in Aβ42 cytotoxicity. The potent inhibitory effect of brazilin was proven by an IC50 of 1.5 +/- 0.3 μM, which was smaller than that of (-)-epigallocatechin gallate in Phase III clinical trials and about one order of magnitude smaller than those of curcumin and resveratrol. Most importantly, it was found that brazilin redirected Aβ42 monomers and its mature fibrils into unstructured Aβ aggregates with some β-sheet structures, which could prevent both the primary nucleation and the fibril-catalyzed secondary nucleation. Molecular simulations demonstrated that brazilin inhibited Aβ42 fibrillogenesis by directly binding to Aβ42 species via hydrophobic interactions and hydrogen bonding and remodeled mature fibrils by disrupting the intermolecular salt bridge Asp23-Lys28 via hydrogen bonding. Both experimental and computational studies revealed a different working mechanism of brazilin from that of known inhibitors. These findings indicate that brazilin is of great potential as a neuroprotective and therapeutic agent for Alzheimer's disease.

  16. Fibrillar dimer formation of islet amyloid polypeptides

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, Chi-cheng [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States); de Pablo, Juan J. [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  17. Cerebral hemorrhage caused by amyloid angiopathy

    International Nuclear Information System (INIS)

    Hanyu, Haruo; Tomonaga, Masanori; Yoshimura, Masahiro; Yamanouchi, Hiroshi; Shimada, Hiroyuki.

    1985-01-01

    Cerebral hemorrhage caused by amyloid angiopathy was studied clinicopathologically, with special attention given to the CT images. Cerebral hemorrhage caused by amyloid angiopathy is characterized, by a lobar-type hemorrhage involving the cortex, with direct extension into the subarachnoid space. Multiple hemorrhages are frequent, and cortical infarctions are present as complications in elderly patients without risk factors. CT scans taken in 5 cases demonstrated lobar hemorrhages in superficial locations, frequently in multiple sites or recurrently, with surrounding edema and mass effect. A subarachnoid extension of the hemorrhage through the superficial cortex, proven pathologically in all cases, was noted by CT in 4 of the 5 cases. However, cortical infarction was not detected by CT in any case. Therefore, CT is of value in the diagnosis of cerebral hemorrhage due to amyloid angiopathy based on distinctive findings such as a lobar hemorrhage in superficial regions, with extension into the subarachnoid space, frequently in multiple sites or recurrently. (author)

  18. Resveratrol and Amyloid-Beta: Mechanistic Insights

    Directory of Open Access Journals (Sweden)

    Yongming Jia

    2017-10-01

    Full Text Available The amyloid-beta (Aβ hypothesis that dyshomeostasis between Aβ production and clearance is a very early, key molecular factor in the etiology of Alzheimer’s disease (AD has been proposed and examined in the AD research field. Scientists have focused on seeking natural products or drugs to influence the dynamic equilibrium of Aβ, targeting production and clearance of Aβ. There is emerging evidence that resveratrol (Res, a naturally occurring polyphenol mainly found in grapes and red wine, acts on AD in numerous in vivo and in vitro models. Res decreases the amyloidogenic cleavage of the amyloid precursor protein (APP, enhances clearance of amyloid beta-peptides, and reduces Aβ aggregation. Moreover, Res also protects neuronal functions through its antioxidant properties. This review discusses the action of Res on Aβ production, clearance and aggregation and multiple potential mechanisms, providing evidence of the useful of Res for AD treatment.

  19. Case report 480: Periosteal amyloid tumor

    International Nuclear Information System (INIS)

    Yoshida, S.O.; Karjoo, R.; Johnstone, M.R.

    1988-01-01

    In summary, a 66-year-old woman presented with an asymptomatic left pretibial tumor of 7 years duration. Serial radiographs over this period demonstrated a slowly enlarging periosteal tumor with focal and increasing calcifications/ossifications. No involvement of the underlying medullary bone, as demonstrated by computed tomography was noted. Following the diagnosis by biopsy of an amyloid tumor, serum and urine electrophoreses, complete blood count, SMAC panel, erythrocyte sedimentation rate, and serum rheumatoid factor level were found to be within reference ranges. A needle biopsy of the abdominal wall failed to reveal amyloid in the fat by Congo-red staining. (orig.)

  20. Bone marrow amyloid spherulites in a case of AL amyloidosis.

    Science.gov (United States)

    Bommannan B K, Karthik; Sonai, Mukinkumar; Sachdeva, Man Updesh Singh

    2016-05-01

    Parallel arrangement of β-pleated sheets by amyloidogenic proteins is a well known phenomenon. Rarely, amyloid fibrils undergo radial orientation to form globular structures called spherulites. These amyloid spherulites show Maltese cross pattern under polarized microscopy. The clinical significance of amyloid spherulites is undetermined. Amyloidogenic proteins like insulin and β-lactoglobulin form spherulites in vitro. The senile plaques of Alzheimer's disease rarely form in vivo spherulites. Amyloid spherulites have been described in the liver and small intestine. For the first time, we document amyloid spherulite formation in the bone marrow biopsy of an AL amyloidosis patient. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Amyloid-β Peptide Induces Prion Protein Amyloid Formation: Evidence for Its Widespread Amyloidogenic Effect.

    Science.gov (United States)

    Honda, Ryo

    2018-04-12

    Transmissible spongiform encephalopathy is associated with misfolding of prion protein (PrP) into an amyloid β-rich aggregate. Previous studies have indicated that PrP interacts with Alzheimer's disease amyloid-β peptide (Aβ), but it remains elusive how this interaction impacts on the misfolding of PrP. This study presents the first in vitro evidence that Aβ induces PrP-amyloid formation at submicromolar concentrations. Interestingly, systematic mutagenesis of PrP revealed that Aβ requires no specific amino acid sequences in PrP, and induces the misfolding of other unrelated proteins (insulin and lysozyme) into amyloid fibrils in a manner analogous to PrP. This unanticipated nonspecific amyloidogenic effect of Aβ indicates that this peptide might be involved in widespread protein aggregation, regardless of the amino acid sequences of target proteins, and exacerbate the pathology of many neurodegenerative diseases. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Limits to Inclusion

    Science.gov (United States)

    Hansen, Janne Hedegaard

    2012-01-01

    In this article, I will argue that a theoretical identification of the limit to inclusion is needed in the conceptual identification of inclusion. On the one hand, inclusion is formulated as a vision that is, in principle, limitless. On the other hand, there seems to be an agreement that inclusion has a limit in the pedagogical practice. However,…

  3. Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

    OpenAIRE

    Hoyer, Wolfgang; Grönwall, Caroline; Jonsson, Andreas; Ståhl, Stefan; Härd, Torleif

    2008-01-01

    According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-β (Aβ) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Aβ assemblies is accompanied by a conformational change toward a high content of β-structure. Here, we report the solution structure of Aβ(1–40) in complex with the phage-display selected affibody protein ZAβ3, a binding protein of nanomolar affinity. Boun...

  4. Formation of amyloid fibers by monomeric light chain variable domains.

    Science.gov (United States)

    Brumshtein, Boris; Esswein, Shannon R; Landau, Meytal; Ryan, Christopher M; Whitelegge, Julian P; Phillips, Martin L; Cascio, Duilio; Sawaya, Michael R; Eisenberg, David S

    2014-10-03

    Systemic light chain amyloidosis is a lethal disease characterized by excess immunoglobulin light chains and light chain fragments composed of variable domains, which aggregate into amyloid fibers. These fibers accumulate and damage organs. Some light chains induce formation of amyloid fibers, whereas others do not, making it unclear what distinguishes amyloid formers from non-formers. One mechanism by which sequence variation may reduce propensity to form amyloid fibers is by shifting the equilibrium toward an amyloid-resistant quaternary structure. Here we identify the monomeric form of the Mcg immunoglobulin light chain variable domain as the quaternary unit required for amyloid fiber assembly. Dimers of Mcg variable domains remain stable and soluble, yet become prone to assemble into amyloid fibers upon disassociation into monomers. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Bacterial prostatitis.

    Science.gov (United States)

    Gill, Bradley C; Shoskes, Daniel A

    2016-02-01

    The review provides the infectious disease community with a urologic perspective on bacterial prostatitis. Specifically, the article briefly reviews the categorization of prostatitis by type and provides a distillation of new findings published on bacterial prostatitis over the past year. It also highlights key points from the established literature. Cross-sectional prostate imaging is becoming more common and may lead to more incidental diagnoses of acute bacterial prostatitis. As drug resistance remains problematic in this condition, the reemergence of older antibiotics such as fosfomycin, has proven beneficial. With regard to chronic bacterial prostatitis, no clear clinical risk factors emerged in a large epidemiological study. However, bacterial biofilm formation has been associated with more severe cases. Surgery has a limited role in bacterial prostatitis and should be reserved for draining of a prostatic abscess or the removal of infected prostatic stones. Prostatitis remains a common and bothersome clinical condition. Antibiotic therapy remains the basis of treatment for both acute and chronic bacterial prostatitis. Further research into improving prostatitis treatment is indicated.

  6. Organotypic vibrosections from whole brain adult Alzheimer mice (overexpressing amyloid-precursor-protein with the Swedish-Dutch-Iowa mutations as a model to study clearance of beta-amyloid plaques

    Directory of Open Access Journals (Sweden)

    Christian eHumpel

    2015-04-01

    Full Text Available Alzheimer´s disease is a severe neurodegenerative disorder of the brain, pathologically characterized by extracellular beta-amyloid plaques, intraneuronal Tau inclusions, inflammation, reactive glial cells, vascular pathology and neuronal cell death. The degradation and clearance of beta-amyloid plaques is an interesting therapeutic approach, and the proteases neprilysin (NEP, insulysin and matrix metalloproteinases (MMP are of particular interest. The aim of this project was to establish and characterize a simple in vitro model to study the degrading effects of these proteases. Organoytpic brain vibrosections (120 µm thick were sectioned from adult (9 month old wildtype and transgenic mice (expressing amyloid precursor protein (APP harboring the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations; APP_SDI and cultured for 2 weeks. Plaques were stained by immunohistochemistry for beta-amyloid and Thioflavin S. Our data show that plaques were evident in 2 week old cultures from 9 month old transgenic mice. These plaques were surrounded by reactive GFAP+ astroglia and Iba1+ microglia. Incubation of fresh slices for 2 weeks with 1-0.1-0.01 µg/ml of NEP, insulysin, MMP-2 or MMP-9 showed that NEP, insulysin and MMP-9 markedly degradeded beta-amyloid plaques but only at the highest concentration. Our data provide for the first time a potent and powerful living brain vibrosection model containing a high number of plaques, which allows to rapidly and simply study the degradation and clearance of beta-amyloid plaques in vitro.

  7. Nanoparticles and amyloid systems: A fatal encounter?

    Energy Technology Data Exchange (ETDEWEB)

    Abel, Bernd [Leibniz Institute of Surface Modification, Chemical Department, Permoserstr. 15, D-04318 Leipzig, Germany and Wilhelm-Ostwald-Institute for Physical and Theoretical Chemistry, Linnéstr. 3, D-04103 Leipzig (Germany)

    2014-10-06

    Nanoparticles (NPs) are used in many products of our daily life, however, there has been concern that they may also be harmful to human health. Recently NPs have been found to accelerate the fibrillation kinetics of amyloid systems. In the past this has been preliminarily attributed to a nucleation effect. Nanoparticle surfaces and interfaces appear to limit the degrees of freedom of amyloid systems (i.e., peptides and proteins) due to a phase space constraint such that rapid cross-beta structures are formed faster than without interface interactions and in turn fibril formation is enhanced significantly. Here we explore if lipid bilayers in the form of liposomes (140nm) also accelerate fibril formation for amyloid systems. We have investigated a fragment NNFGAIL of the Human islet amyloid polypeptide (hIAPP) in contact with 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) liposomes in aqueous solution. We found that the lipid bilayer vesicles do accelerate fibril formation in time-resolved off-line detected atomic force microscopy experiments. Characteristic Thioflavine-T fluorescence on the same structures verify that the structures consist of aggregated peptides in a typical cross-β-structure arrangement.

  8. A method for probing the mutational landscape of amyloid structure.

    Science.gov (United States)

    O'Donnell, Charles W; Waldispühl, Jérôme; Lis, Mieszko; Halfmann, Randal; Devadas, Srinivas; Lindquist, Susan; Berger, Bonnie

    2011-07-01

    Proteins of all kinds can self-assemble into highly ordered β-sheet aggregates known as amyloid fibrils, important both biologically and clinically. However, the specific molecular structure of a fibril can vary dramatically depending on sequence and environmental conditions, and mutations can drastically alter amyloid function and pathogenicity. Experimental structure determination has proven extremely difficult with only a handful of NMR-based models proposed, suggesting a need for computational methods. We present AmyloidMutants, a statistical mechanics approach for de novo prediction and analysis of wild-type and mutant amyloid structures. Based on the premise of protein mutational landscapes, AmyloidMutants energetically quantifies the effects of sequence mutation on fibril conformation and stability. Tested on non-mutant, full-length amyloid structures with known chemical shift data, AmyloidMutants offers roughly 2-fold improvement in prediction accuracy over existing tools. Moreover, AmyloidMutants is the only method to predict complete super-secondary structures, enabling accurate discrimination of topologically dissimilar amyloid conformations that correspond to the same sequence locations. Applied to mutant prediction, AmyloidMutants identifies a global conformational switch between Aβ and its highly-toxic 'Iowa' mutant in agreement with a recent experimental model based on partial chemical shift data. Predictions on mutant, yeast-toxic strains of HET-s suggest similar alternate folds. When applied to HET-s and a HET-s mutant with core asparagines replaced by glutamines (both highly amyloidogenic chemically similar residues abundant in many amyloids), AmyloidMutants surprisingly predicts a greatly reduced capacity of the glutamine mutant to form amyloid. We confirm this finding by conducting mutagenesis experiments. Our tool is publically available on the web at http://amyloid.csail.mit.edu/. lindquist_admin@wi.mit.edu; bab@csail.mit.edu.

  9. Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: A systematic critical update

    Directory of Open Access Journals (Sweden)

    Karim Farid

    2017-01-01

    Full Text Available Sporadic cerebral amyloid angiopathy (CAA is a very common small vessel disease of the brain, showing preferential and progressive amyloid-βdeposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. CAA now encompasses not only a specific cerebrovascular pathological trait, but also different clinical syndromes - including spontaneous lobar intracerebral haemorrhage (ICH, dementia and ‘amyloid spells’ - an expanding spectrum of brain parenchymal MRI lesions and a set of diagnostic criteria – the Boston criteria, which have resulted in increasingly detecting CAA during life. Although currently available validated diagnostic criteria perform well in multiple lobar ICH, a formal diagnosis is currently lacking unless a brain biopsy is performed. This is partly because in practice CAA MRI biomarkers provide only indirect evidence for the disease. An accurate diagnosis of CAA in different clinical settings would have substantial impact for ICH risk stratification and antithrombotic drug use in elderly people, but also for sample homogeneity in drug trials. It has recently been demonstrated that vascular (in addition to parenchymal amyloid-βdeposition can be detected and quantified in vivo by positron emission tomography (PET amyloid tracers. This non-invasive approach has the potential to provide a molecular signature of CAA, and could in turn have major clinical impact. However, several issues around amyloid-PET in CAA remain unsettled and hence its diagnostic utility is limited. In this article we systematically review and critically appraise the published literature on amyloid-PET (PiB and other tracers in sporadic CAA. We focus on two key areas: (a the diagnostic utility of amyloid-PET in CAA and (b the use of amyloid-PET as a window to understand pathophysiological mechanism of the disease. Key issues around amyloid-PET imaging in CAA, including relevant technical aspects are also covered in depth

  10. Bacterial Vaginosis

    Science.gov (United States)

    ... Archive STDs Home Page Bacterial Vaginosis (BV) Chlamydia Gonorrhea Genital Herpes Hepatitis HIV/AIDS & STDs Human Papillomavirus ( ... of getting other STDs, such as chlamydia and gonorrhea . These bacteria can sometimes cause pelvic inflammatory disease ( ...

  11. Social imaginaries and inclusion

    DEFF Research Database (Denmark)

    Hansen, Janne Hedegaard

    2016-01-01

    that inclusion on the one hand may be seen to be about human rights, solidarity, and democracy, and on the other hand, it is about ensuring the cohesion of neoliberal society by means of every person’s obligation to realize one’s potential through learning, development, and education regardless of one’s needs......, the development of inclusive schools and inclusive learning environments will involve both inclusion and exclusion processes. With this starting point, international educational research knowledge about inclusive schools and inclusive learning environments in general will be related to the fundamental dilemma...

  12. Nuclear imaging of amyloid deposits based upon thioflavins

    International Nuclear Information System (INIS)

    Wang Yanming; Wu Chunying; Wei Jinjun

    2005-01-01

    Alzheimer's Disease (AD) is a chronic neurodegenerative disorders characterized by the presence of amyloid deposits and neurofibrillar tangles in the brain. Direct assessment of local changes of amyloid deposits in vivo would greatly facilitate the diagnosis and therapeutic treatments of AD. The goal of this study is to develop small-molecule probes that can be used to follow amyloid deposition in vivo in patients with neurodegenerative diseases. Over the past years, we set out to develop a series of small molecules based on thioflavins as radiotracers for use in nuclear imaging modalities such as positron emission tomography and single photon emission computed tomography. The potential of these amyloid-imaging agents for in vivo studies of amyloid deposition has been evaluated based on the following methods: 1) spectrophotometric binding. assays with synthetic amyloid-β (Aβ) fibrils and AD brain homogenates; 2) fluorescent staining of brain tissue sections to evaluate specificity of binding to amyloid deposits; 3) fluorescent microscopy in mouse models to determine the brain permeability and characterize the binding specificity in vivo, and 4) PET studies in human subjects diagnosed with AD and age-matched control subjects. To date, we have identified some lead compounds as molecular probes with specificity towards amyloid deposits. The in vitro and in vivo binding properties of these compounds have been demonstrated in the following ways: 1) they selectively binds to Aβ fibrils; 2) they selectively stains amyloid deposits in AD brain tissue sections; 3) they readily penetrates the blood-brain barrier, selectively detects amyloid deposits in vivo iri living mice; and 4) One of these compounds, termed PIB, has been successfully used in PET studies in human subjects. In conclusion, amyloid-imaging probes have been developed that could be used to monitor amyloid load in vivo. Applications of the probes are under investigation for potential pathophysiology studies

  13. Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia

    Science.gov (United States)

    Santos-Santos, Miguel A.; Rabinovici, Gil D.; Iaccarino, Leonardo; Ayakta, Nagehan; Tammewar, Gautam; Lobach, Iryna; Henry, Maya L.; Hubbard, Isabel; Mandelli, Maria Luisa; Spinelli, Edoardo; Miller, Zachary A.; Pressman, Peter S.; O’Neil, James P.; Ghosh, Pia; Lazaris, Andreas; Meyer, Marita; Watson, Christa; Yoon, Soo Jin; Rosen, Howard J.; Grinberg, Lea; Seeley, William W.; Miller, Bruce L.; Jagust, William J.; Gorno-Tempini, Maria Luisa

    2018-01-01

    IMPORTANCE The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. OBJECTIVE To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). DESIGN, SETTING, AND PARTICIPANTS This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11–labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA. MAIN OUTCOMES AND MEASURES Clinical, cognitive, neuroimaging, and pathology results. RESULTS Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases

  14. Roadmap for Inclusive Innovation

    Data.gov (United States)

    Allegheny County / City of Pittsburgh / Western PA Regional Data Center — The Roadmap for Inclusive Innovation data set shares the status of action items under the Roadmap for Inclusive Innovation. Each action or project has been assigned...

  15. Teachers becoming inclusive practitioners

    African Journals Online (AJOL)

    , construct their identities in the light of inclusive education, and how they negotiate the tensions and contradictions emerging from the processof becoming inclusive practitioners. Central to this discussion is the understanding that teachers' ...

  16. Intracellular amyloid formation in muscle cells of Aβ-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification

    Directory of Open Access Journals (Sweden)

    Bush Ashley I

    2009-01-01

    Full Text Available Abstract Background The amyloid β-peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine Aβ aggregation in vivo are poorly understood, as well as the cellular meaning of this process itself. Genetic data as well as cell biological and biochemical evidence strongly support the hypothesis that Aβ is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that Aβ is involved in Inclusion Body Myositis, a common myopathy of the elderly in which the peptide accumulates intracellularly. Results In the present work, we found that intracellular Aβ aggregation in muscle cells of Caenorhabditis elegans overexpressing Aβ peptide is affected by two single amino acid substitutions, E22G (Arctic and V18A (NIC. Both variations show decrease intracellular amyloidogenesis compared to wild type Aβ. We show that intracellular amyloid aggregation of wild type Aβ is accelerated by Cu2+ and diminished by copper chelators. Moreover, we demonstrate through toxicity and behavioral assays that Aβ-transgenic worms display a higher tolerance to Cu2+ toxic effects and that this resistance may be linked to the formation of amyloid aggregates. Conclusion Our data show that intracellular Aβ amyloid aggregates may trap excess of free Cu2+ buffering its cytotoxic effects and that accelerated intracellular Aβ aggregation may be part of a cell protective mechanism.

  17. Chemical Methods to Knock Down the Amyloid Proteins

    Directory of Open Access Journals (Sweden)

    Na Gao

    2017-06-01

    Full Text Available Amyloid proteins are closely related with amyloid diseases and do tremendous harm to human health. However, there is still a lack of effective strategies to treat these amyloid diseases, so it is important to develop novel methods. Accelerating the clearance of amyloid proteins is a favorable method for amyloid disease treatment. Recently, chemical methods for protein reduction have been developed and have attracted much attention. In this review, we focus on the latest progress of chemical methods that knock down amyloid proteins, including the proteolysis-targeting chimera (PROTAC strategy, the “recognition-cleavage” strategy, the chaperone-mediated autophagy (CMA strategy, the selectively light-activatable organic and inorganic molecules strategy and other chemical strategies.

  18. Delimiting Inclusive Design

    DEFF Research Database (Denmark)

    Herriott, Richard

    2014-01-01

    This paper was written as an answer to the question raised by my PhD dissertation on accessibility through user-centred and Inclusive Design (ID) methods: can Inclusive Design be delimited? The literature on Inclusive Design deals almost entrirely with consumer product design and assistive...

  19. Footstep towards Inclusive Education

    Science.gov (United States)

    Abbas, Faiza; Zafar, Aneeka; Naz, Tayyaba

    2016-01-01

    Inclusive education is a rising trend in the world. The first step towards inclusive education is providing the awareness to the general education teachers. This study focused to investigate the general education teachers of primary and secondary level awareness about the special education and inclusive education. This study is descriptive method…

  20. Inclusion: Conceptualization and measurement

    NARCIS (Netherlands)

    Jansen, W.S.; Otten, S.; Van der Zee, K.I.; Jans, L.

    2014-01-01

    n the present research, we introduced a conceptual framework of inclusion and subsequently used this as a starting point to develop and validate a scale to measure perceptions of inclusion. Departing from existing work on inclusion and complementing this with theoretical insights from optimal

  1. Inclusion : Conceptualization and measurement

    NARCIS (Netherlands)

    Jansen, Wiebren S.; Otten, Sabine; van der Zee, Karen I.; Jans, Lise

    In the present research, we introduced a conceptual framework of inclusion and subsequently used this as a starting point to develop and validate a scale to measure perceptions of inclusion. Departing from existing work on inclusion and complementing this with theoretical insights from optimal

  2. Inclusion: Conceptualization and measurement

    NARCIS (Netherlands)

    Jansens, Wiebren S.; Otten, Sabine; van der Zee, Karen; Jans, Lise

    2014-01-01

    In the present research, we introduced a conceptual framework of inclusion and subsequently used this as a starting point to develop and validate a scale to measure perceptions of inclusion. Departing from existing work on inclusion and complementing this with theoretical insights from optimal

  3. BACTERIAL CONSORTIUM

    Directory of Open Access Journals (Sweden)

    Payel Sarkar

    2013-01-01

    Full Text Available Petroleum aromatic hydrocarbons like benzen e, toluene, ethyl benzene and xylene, together known as BTEX, has almost the same chemical structure. These aromatic hydrocarbons are released as pollutants in th e environment. This work was taken up to develop a solvent tolerant bacterial cons ortium that could degrade BTEX compounds as they all share a common chemical structure. We have isolated almost 60 different types of bacterial strains from different petroleum contaminated sites. Of these 60 bacterial strains almost 20 microorganisms were screene d on the basis of capability to tolerate high concentration of BTEX. Ten differe nt consortia were prepared and the compatibility of the bacterial strains within the consortia was checked by gram staining and BTEX tolerance level. Four successful mi crobial consortia were selected in which all the bacterial strains concomitantly grew in presence of high concentration of BTEX (10% of toluene, 10% of benzene 5% ethyl benzene and 1% xylene. Consortium #2 showed the highest growth rate in pr esence of BTEX. Degradation of BTEX by consortium #2 was monitored for 5 days by gradual decrease in the volume of the solvents. The maximum reduction observed wa s 85% in 5 days. Gas chromatography results also reveal that could completely degrade benzene and ethyl benzene within 48 hours. Almost 90% degradation of toluene and xylene in 48 hours was exhibited by consortium #2. It could also tolerate and degrade many industrial solvents such as chloroform, DMSO, acetonitrile having a wide range of log P values (0.03–3.1. Degradation of aromatic hydrocarbon like BTEX by a solvent tolerant bacterial consortium is greatly significant as it could degrade high concentration of pollutants compared to a bacterium and also reduces the time span of degradation.

  4. Calumenin interacts with serum amyloid P component

    DEFF Research Database (Denmark)

    Vorum, H; Jacobsen, Christian; Honoré, Bent

    2000-01-01

    We recently reported the identification of human calumenin, a novel Ca(2+) binding, transformation-sensitive and secreted protein [Vorum et al. (1998) Biochim. Biophys. Acta 1386, 121-131; Vorum et al. (1999) Exp. Cell Res. 248, 473-481] belonging to the family of multiple EF-hand proteins...... with calumenin in the presence of Ca(2+). Amino acid sequencing identified this protein as serum amyloid P component (SAP). Furthermore, we verified and characterized the calumenin-SAP interaction by the surface plasmon resonance technique. The findings indicate that calumenin may participate...... in the immunological defense system and could be involved in the pathological process of amyloidosis that leads to formation of amyloid deposits seen in different types of tissues. Udgivelsesdato: 2000-Jan-14...

  5. Strong transthyretin immunostaining: potential pitfall in cardiac amyloid typing.

    Science.gov (United States)

    Satoskar, Anjali A; Efebera, Yvonne; Hasan, Ayesha; Brodsky, Sergey; Nadasdy, Gyongyi; Dogan, Ahmet; Nadasdy, Tibor

    2011-11-01

    Although systemic amyloidosis commonly presents with renal disease, cardiac involvement usually determines the patient's prognosis. Cardiac involvement is seen in light chain amyloid and transthyretin amyloidosis. Distinguishing between these two is critical because prognosis and treatment differ. Our study demonstrates the unreliability of transthyretin immunostaining in subtyping cardiac amyloid. Between January 2003 and August 2010, we retrieved 229 native endomyocardial biopsies, of which 24 had amyloid. Immunohistochemistry for κ, λ, transthyretin, and serum amyloid A protein was performed on formalin-fixed, paraffin-embedded sections. Staining was graded as weak (trace to 1+) or strong (2 to 3+). Mass spectrometry (MS)-based proteomic typing of microdissected amyloid material was performed on selected cases. Fifteen patients had monoclonal gammopathy/plasma cell dyscrasia with cardiac amyloid. Eight of them (53%) showed strong transthyretin staining in the cardiac amyloid deposits. MS was performed in 5 of these 8 biopsies, and all 5 biopsies revealed light chain amyloid-type amyloid. Two of these 5 light chain amyloid biopsies did not even have concomitant strong staining for the appropriate light chain. Among the 15 cases with plasma cell dyscrasia, only 7 biopsies showed strong staining for the corresponding monoclonal light chain. Strong, false-positive immunostaining for transthyretin in cardiac amyloid is a potential pitfall, augmented by the frequent lack of staining for immunoglobulin light chains. Therefore, the presence of amyloid in the cardiac biopsy should prompt a search for plasma cell dyscrasia irrespective of transthyretin staining. Confirmation with MS should be sought, particularly if there is any discrepancy between κ/λ staining and serum immunofixation results.

  6. Amyloid PET in pseudotumoral multiple sclerosis.

    Science.gov (United States)

    Matías-Guiu, Jordi A; Cabrera-Martín, María Nieves; Cortés-Martínez, Ana; Pytel, Vanesa; Moreno-Ramos, Teresa; Oreja-Guevara, Celia; Carreras, José Luis; Matías-Guiu, Jorge

    2017-07-01

    Pseudotumoral multiple sclerosis is a rare form of demyelinating disease of the central nervous system. Positron emission tomography (PET) using amyloid-tracers has also been suggested as a marker of damage in white matter lesions in multiple sclerosis due to the nonspecific uptake of these tracers in white matter. We present the case of a 59 year-old woman with a pathological-confirmed pseudotumoral multiple sclerosis, who was studied with the amyloid tracer 18 F-florbetaben. The patient had developed word-finding difficulties and right hemianopia twelve years ago. In that time, MRI showed a lesion on the left hemisphere with an infiltrating aspect in frontotemporal lobes. Brain biopsy showed demyelinating areas and inflammation. During the following years, two new clinical relapses occurred. 18 F-florbetaben PET showed lower uptake in the white matter lesion visualized in the CT and MRI images. Decreased tracer uptake was also observed in a larger area of the left hemisphere beyond the lesions observed on MRI or CT. White matter lesion volume on FLAIR was 44.2mL, and tracer uptake change between damaged white matter and normal appearing white matter was - 40.5%. Standardized uptake value was inferior in the pseudotumoral lesion than in the other white matter lesions. We report the findings of amyloid PET in a patient with pseudotumoral multiple sclerosis. This case provides further evidence on the role of amyloid PET in the assessment of white matter and demyelinating diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Transbronchial biopsies safely diagnose amyloid lung disease

    Science.gov (United States)

    Govender, Praveen; Keyes, Colleen M.; Hankinson, Elizabeth A.; O’Hara, Carl J.; Sanchorawala, Vaishali; Berk, John L.

    2018-01-01

    Background Autopsy identifies lung involvement in 58–92% of patients with the most prevalent forms of systemic amyloidoses. In the absence of lung biopsies, amyloid lung disease often goes unrecognized. Report of a death following transbronchial biopsies in a patient with systemic amyloidosis cautioned against the procedure in this patient cohort. We reviewed our experience with transbronchial biopsies in patients with amyloidosis to determine the safety and utility of bronchoscopic lung biopsies. Methods We identified patients referred to the Amyloidosis Center at Boston Medical Center with lung amyloidosis diagnosed by transbronchial lung biopsies (TBBX). Amyloid typing was determined by immunohistochemistry or mass spectrometry. Standard end organ assessments, including pulmonary function test (PFT) and chest tomography (CT) imaging, and extra-thoracic biopsies established the extent of disease. Results Twenty-five (21.7%) of 115 patients with lung amyloidosis were diagnosed by TBBX. PFT classified 33.3% with restrictive physiology, 28.6% with obstructive disease, and 9.5% mixed physiology; 9.5% exhibited isolated diffusion defects while 19% had normal pulmonary testing. Two view chest or CT imaging identified focal opacities in 52% of cases and diffuse interstitial disease in 48%. Amyloid type and disease extent included 68% systemic AL disease, 16% localized (lung limited) AL disease, 12% ATTR disease, and 4% AA amyloidosis. Fluoroscopy was not used during biopsy. No procedure complications were reported. Conclusions Our case series of 25 patients supports the use of bronchoscopic transbronchial biopsies for diagnosis of parenchymal lung amyloidosis. Normal PFTs do not rule out the histologic presence of amyloid lung disease. PMID:28393574

  8. Transmission electron microscopy of amyloid fibrils.

    Science.gov (United States)

    Gras, Sally L; Waddington, Lynne J; Goldie, Kenneth N

    2011-01-01

    Transmission Electron Microscopy of negatively stained and cryo-prepared specimens allows amyloid fibrils to be visualised at high resolution in a dried or a hydrated state, and is an essential method for characterising the morphology of fibrils and pre-fibrillar species. We outline the key steps involved in the preparation and observation of samples using negative staining and cryo-electron preservation. We also discuss methods to measure fibril characteristics, such as fibril width, from electron micrographs.

  9. Beta-amyloid and cholinergic neurons

    Czech Academy of Sciences Publication Activity Database

    Doležal, Vladimír; Kašparová, Jana

    2003-01-01

    Roč. 28, 3-4 (2003), s. 499-506 ISSN 0364-3190 R&D Projects: GA ČR GA305/01/0283; GA AV ČR IAA5011206 Institutional research plan: CEZ:AV0Z5011922 Keywords : cholinergic neurons * AlzheimerŽs disease * beta-amyloid Subject RIV: FH - Neurology Impact factor: 1.511, year: 2003

  10. Isolation, characterization, and aggregation of a structured bacterial matrix precursor.

    Science.gov (United States)

    Chai, Liraz; Romero, Diego; Kayatekin, Can; Akabayov, Barak; Vlamakis, Hera; Losick, Richard; Kolter, Roberto

    2013-06-14

    Biofilms are surface-associated groups of microbial cells that are embedded in an extracellular matrix (ECM). The ECM is a network of biopolymers, mainly polysaccharides, proteins, and nucleic acids. ECM proteins serve a variety of structural roles and often form amyloid-like fibers. Despite the extensive study of the formation of amyloid fibers from their constituent subunits in humans, much less is known about the assembly of bacterial functional amyloid-like precursors into fibers. Using dynamic light scattering, atomic force microscopy, circular dichroism, and infrared spectroscopy, we show that our unique purification method of a Bacillus subtilis major matrix protein component results in stable oligomers that retain their native α-helical structure. The stability of these oligomers enabled us to control the external conditions that triggered their aggregation. In particular, we show that stretched fibers are formed on a hydrophobic surface, whereas plaque-like aggregates are formed in solution under acidic pH conditions. TasA is also shown to change conformation upon aggregation and gain some β-sheet structure. Our studies of the aggregation of a bacterial matrix protein from its subunits shed new light on assembly processes of the ECM within bacterial biofilms.

  11. Cerebral amyloid angiopathy: diagnosis and potential therapies.

    Science.gov (United States)

    Weber, Stewart A; Patel, Ranish K; Lutsep, Helmi L

    2018-06-01

    Cerebral amyloid angiopathy (CAA) is characterized by the pathologic deposition of amyloid-beta within cortical and leptomeningeal arteries, arterioles, capillaries and, in rare cases, the venules of the brain. It is often associated with the development of lobar intracerebral hemorrhages (ICHs) but may cause other neurologic symptoms or be asymptomatic. Magnetic resonance imaging characteristics, such as lobar microbleeds, support a diagnosis of CAA and assist with hemorrhage risk assessments. Immunosuppressants are used to treat rarer inflammatory forms of CAA. For the more common forms of CAA, the use of antihypertensive medications can prevent ICH recurrence while the use of antithrombotics may increase hemorrhage risk. Anti-amyloid approaches to treatment have not yet been investigated in phase 3 trials. Areas covered: A literature search was conducted using MEDLINE on the topics of imaging, biomarkers, ICH prevention and treatment trials in CAA, focusing on its current diagnosis and management and opportunities for future therapeutic approaches. Expert commentary: There is likely a significant unrecognized burden of CAA in the elderly population. Continued research efforts to discover biomarkers that allow the early diagnosis of CAA will enhance the opportunity to develop treatment interventions.

  12. Fibrillar dimer formation of islet amyloid polypeptides

    Directory of Open Access Journals (Sweden)

    Chi-cheng Chiu

    2015-09-01

    Full Text Available Amyloid deposits of human islet amyloid polypeptide (hIAPP, a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  13. Bacterial Adhesion & Blocking Bacterial Adhesion

    DEFF Research Database (Denmark)

    Vejborg, Rebecca Munk

    2008-01-01

    , which influence the transition from a planktonic lifestyle to a sessile lifestyle, have been studied. Protein conditioning film formation was found to influence bacterial adhesion and subsequent biofilm formation considerable, and an aqueous extract of fish muscle tissue was shown to significantly...... tract to the microbial flocs in waste water treatment facilities. Microbial biofilms may however also cause a wide range of industrial and medical problems, and have been implicated in a wide range of persistent infectious diseases, including implantassociated microbial infections. Bacterial adhesion...... is the first committing step in biofilm formation, and has therefore been intensely scrutinized. Much however, still remains elusive. Bacterial adhesion is a highly complex process, which is influenced by a variety of factors. In this thesis, a range of physico-chemical, molecular and environmental parameters...

  14. Bacterial meningitis

    NARCIS (Netherlands)

    Heckenberg, Sebastiaan G. B.; Brouwer, Matthijs C.; van de Beek, Diederik

    2014-01-01

    Bacterial meningitis is a neurologic emergency. Vaccination against common pathogens has decreased the burden of disease. Early diagnosis and rapid initiation of empiric antimicrobial and adjunctive therapy are vital. Therapy should be initiated as soon as blood cultures have been obtained,

  15. Bacterial lipases

    NARCIS (Netherlands)

    Jaeger, Karl-Erich; Ransac, Stéphane; Dijkstra, Bauke W.; Colson, Charles; Heuvel, Margreet van; Misset, Onno

    Many different bacterial species produce lipases which hydrolyze esters of glycerol with preferably long-chain fatty acids. They act at the interface generated by a hydrophobic lipid substrate in a hydrophilic aqueous medium. A characteristic property of lipases is called interfacial activation,

  16. Bacterial stress

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. Bacterial stress. Physicochemical and chemical parameters: temperature, pressure, pH, salt concentration, oxygen, irradiation. Nutritional depravation: nutrient starvation, water shortage. Toxic compounds: Antibiotics, heavy metals, toxins, mutagens. Interactions with other cells: ...

  17. Hyperforin prevents beta-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-beta-deposits.

    Science.gov (United States)

    Dinamarca, M C; Cerpa, W; Garrido, J; Hancke, J L; Inestrosa, N C

    2006-11-01

    The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid beta-peptide (Abeta). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Abeta-induced spatial memory impairments and on Abeta neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Abeta-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Abeta oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Abeta aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.

  18. Foresighting for Inclusive Development

    DEFF Research Database (Denmark)

    Andersen, Allan Dahl; Andersen, Per Dannemand

    2017-01-01

    of policymaking processes affects the actual process with a focus on inclusion, and we discuss how it affects policy effectiveness and innovation system transformation. Our argument is that processes of policymaking must be inclusive to affect and transform innovation systems because a set of distributed actors...... in foresight cases in two emerging economies: Brazil and South Korea. We conclude that better systemic and innovation oriented foresight is needed to enhance inclusive development....

  19. INCLUSIVE EDUCATION IN ITALY

    OpenAIRE

    Voitkāne, Vita

    2017-01-01

    European member States implement Inclusive Education policies thus contributing to a sustainable, inclusive society, although each country is at a different stage in this process. Italy, one of the first countries to launch integrative learning, has set an example since the 1970s, although the quality of inclusive education is unpredictable due to many issues. Authors Cantoni and Panetta (2006) emphasize that, although the culture of integration in Italy exists, much needs to be done to impro...

  20. SUPPORT IN INCLUSIVE EDUCATION

    OpenAIRE

    Belma Čičkušić; Ševala Tulumović; Selma Bakić; Salem Bakić

    2016-01-01

    In order for inclusive class to be successful, associates are of great help to teachers. Besides associates, teachers' specialization can be accomplished through educational seminars on the inclusion topic. However, information about inclusion, working with children with special needs, can also be found in scientific journals that offer more information on methods of working with children with special needs, didactic materials customized according to abilities of children. Aim of ...

  1. [Bacterial vaginosis].

    Science.gov (United States)

    Romero Herrero, Daniel; Andreu Domingo, Antonia

    2016-07-01

    Bacterial vaginosis (BV) is the main cause of vaginal dysbacteriosis in the women during the reproductive age. It is an entity in which many studies have focused for years and which is still open for discussion topics. This is due to the diversity of microorganisms that cause it and therefore, its difficult treatment. Bacterial vaginosis is probably the result of vaginal colonization by complex bacterial communities, many of them non-cultivable and with interdependent metabolism where anaerobic populations most likely play an important role in its pathogenesis. The main symptoms are an increase of vaginal discharge and the unpleasant smell of it. It can lead to serious consequences for women, such as an increased risk of contracting sexually transmitted infections including human immunodeficiency virus and upper genital tract and pregnancy complications. Gram stain is the gold standard for microbiological diagnosis of BV, but can also be diagnosed using the Amsel clinical criteria. It should not be considered a sexually transmitted disease but it is highly related to sex. Recurrence is the main problem of medical treatment. Apart from BV, there are other dysbacteriosis less characterized like aerobic vaginitis of which further studies are coming slowly but are achieving more attention and consensus among specialists. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  2. Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy

    NARCIS (Netherlands)

    van Veluw, Susanne J.; Kuijf, Hugo J.; Charidimou, Andreas; Viswanathan, Anand; Biessels, Geert Jan; Rozemuller, Annemieke J M; Frosch, Matthew P.; Greenberg, Steven M.

    Microhemorrhages are strongly associated with advanced cerebral amyloid angiopathy (CAA). Although it has been frequently proposed that the deposition of Aβ in the walls of cortical vessels directly causes microhemorrhages, this has not been studied in great detail, mainly because the ruptured

  3. Prevalence of cerebral amyloid pathology in persons without dementia

    DEFF Research Database (Denmark)

    Jansen, Willemijn J; Ossenkoppele, Rik; Knol, Dirk L

    2015-01-01

    IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies...

  4. Prevalence of amyloid PET positivity in dementia syndromes

    DEFF Research Database (Denmark)

    Ossenkoppele, Rik; Jansen, Willemijn J; Rabinovici, Gil D

    2015-01-01

    IMPORTANCE: Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. OBJECTIVE: To use...

  5. FKBP12 regulates the localization and processing of amyloid ...

    Indian Academy of Sciences (India)

    2014-01-27

    Jan 27, 2014 ... One of the pathological hallmarks of Alzheimer's disease is the presence of insoluble extracellular amyloid plaques. These plaques ... The proteolytic cleavage of amyloid precursor protein (APP) ..... lower sAPPα/sAPPs ratio, which may lead to an increase in ..... spine density in healthy adult mouse brain.

  6. Ligand-binding sites in human serum amyloid P component

    DEFF Research Database (Denmark)

    Heegaard, N.H.H.; Heegaard, Peter M. H.; Roepstorff, P.

    1996-01-01

    Amyloid P component (AP) is a naturally occurring glycoprotein that is found in serum and basement membranes, AP is also a component of all types of amyloid, including that found in individuals who suffer from Alzheimer's disease and Down's syndrome. Because AP has been found to bind strongly...

  7. Collapsed state of polyglutamic acid results in amyloid spherulite formation.

    Science.gov (United States)

    Stehli, Daniel; Mulaj, Mentor; Miti, Tatiana; Traina, Joshua; Foley, Joseph; Muschol, Martin

    2015-01-01

    Self-assembly of proteins and peptides into amyloid fibrils involves multiple distinct intermediates and late-stage fibrillar polymorphs. Understanding the conditions and mechanisms that promote the formation of one type of intermediate and polymorph over the other represents a fundamental challenge. Answers to this question are also of immediate biomedical relevance since different amyloid aggregate species have been shown to have distinct pathogenic potencies. One amyloid polymorph that has received comparatively little attention are amyloid spherulites. Here we report that self-assembly of the intrinsically disordered polymer poly(L-glutamic) acid (PLE) can generate amyloid spherulites. We characterize spherulite growth kinetics, as well as the morphological, optical and tinctorial features of this amyloid polymorph previously unreported for PLE. We find that PLE spherulites share both tinctorial and structural characteristics with their amyloid fibril counterparts. Differences in PLE's molecular weight, polydispersity or chemistry could not explain the selective propensity toward either fibril or spherulite formation. Instead, we provide evidence that PLE polymers can exist in either a collapsed globule or an extended random coil conformation. The collapsed globule consistently produces spherulites while the extended coil assembles into disordered fibril bundles. This results suggests that these 2 PLE conformers directly affect the morphology of the resulting macroscopic amyloid assembly.

  8. A Peptide-Fc Opsonin with Pan-Amyloid Reactivity

    Directory of Open Access Journals (Sweden)

    James S. Foster

    2017-09-01

    Full Text Available There is a continuing need for therapeutic interventions for patients with the protein misfolding disorders that result in systemic amyloidosis. Recently, specific antibodies have been employed to treat AL amyloidosis by opsonizing tissue amyloid deposits thereby inducing cell-mediated dissolution and organ improvement. To develop a pan-amyloid therapeutic agent, we have produced an Fc-fusion product incorporating a peptide, p5, which binds many if not all forms of amyloid. This protein, designated Fcp5, expressed in mammalian cells, forms the desired bivalent dimer structure and retains pan-amyloid reactivity similar to the p5 peptide as measured by immunosorbent assays, immunohistochemistry, surface plasmon resonance, and pulldown assays using radioiodinated Fcp5. Additionally, Fcp5 was capable of opsonizing amyloid fibrils in vitro using a pH-sensitive fluorescence assay of phagocytosis. In mice,125 I-labeled Fcp5 exhibited an extended serum circulation time, relative to the p5 peptide. It specifically bound AA amyloid deposits in diseased mice, as evidenced by biodistribution and microautoradiographic methods, which coincided with an increase in active, Iba-1-positive macrophages in the liver at 48 h postinjection of Fcp5. In healthy mice, no specific tissue accumulation was observed. The data indicate that polybasic, pan-amyloid-targeting peptides, in the context of an Fc fusion, can yield amyloid reactive, opsonizing reagents that may serve as next-generation immunotherapeutics.

  9. Cardiac resynchronization therapy in a patient with amyloid cardiomyopathy.

    Science.gov (United States)

    Zizek, David; Cvijić, Marta; Zupan, Igor

    2013-06-01

    Cardiac involvement in systemic light chain amyloidosis carries poor prognosis. Amyloid deposition in the myocardium can alter regional left ventricular contraction and cause dyssynchrony. Cardiac resynchronization therapy (CRT) is an effective treatment strategy for patients with advanced heart failure and echocardiographic dyssynchrony. We report a clinical and echocardiographic response of a patient with amyloid cardiomyopathy, treated with a combination of chemotherapy and CRT.

  10. Collapsed state of polyglutamic acid results in amyloid spherulite formation

    Science.gov (United States)

    Stehli, Daniel; Mulaj, Mentor; Miti, Tatiana; Traina, Joshua; Foley, Joseph; Muschol, Martin

    2015-01-01

    Self-assembly of proteins and peptides into amyloid fibrils involves multiple distinct intermediates and late-stage fibrillar polymorphs. Understanding the conditions and mechanisms that promote the formation of one type of intermediate and polymorph over the other represents a fundamental challenge. Answers to this question are also of immediate biomedical relevance since different amyloid aggregate species have been shown to have distinct pathogenic potencies. One amyloid polymorph that has received comparatively little attention are amyloid spherulites. Here we report that self-assembly of the intrinsically disordered polymer poly(L-glutamic) acid (PLE) can generate amyloid spherulites. We characterize spherulite growth kinetics, as well as the morphological, optical and tinctorial features of this amyloid polymorph previously unreported for PLE. We find that PLE spherulites share both tinctorial and structural characteristics with their amyloid fibril counterparts. Differences in PLE's molecular weight, polydispersity or chemistry could not explain the selective propensity toward either fibril or spherulite formation. Instead, we provide evidence that PLE polymers can exist in either a collapsed globule or an extended random coil conformation. The collapsed globule consistently produces spherulites while the extended coil assembles into disordered fibril bundles. This results suggests that these 2 PLE conformers directly affect the morphology of the resulting macroscopic amyloid assembly. PMID:28232889

  11. Amyloid goitre following chronic osteomyelitis: case report and ...

    African Journals Online (AJOL)

    Amyloid goitre following chronic osteomyelitis: case report and review of literature. AZ Mohammed, ST Edino, O Ochicha. Abstract. Amyloid Goitre is a rare clinical entity associated with systemic amyloidosis. It poses a significant diagnostic and therapeutic challenge and may be confused with a neoplastic goiter. We present ...

  12. The Tubular Sheaths Encasing Methanosaeta thermophila Filaments Are Functional Amyloids.

    Science.gov (United States)

    Dueholm, Morten S; Larsen, Poul; Finster, Kai; Stenvang, Marcel R; Christiansen, Gunna; Vad, Brian S; Bøggild, Andreas; Otzen, Daniel E; Nielsen, Per Halkjær

    2015-08-14

    Archaea are renowned for their ability to thrive in extreme environments, although they can be found in virtually all habitats. Their adaptive success is linked to their unique cell envelopes that are extremely resistant to chemical and thermal denaturation and that resist proteolysis by common proteases. Here we employ amyloid-specific conformation antibodies and biophysical techniques to show that the extracellular cell wall sheaths encasing the methanogenic archaea Methanosaeta thermophila PT are functional amyloids. Depolymerization of sheaths and subsequent MS/MS analyses revealed that the sheaths are composed of a single major sheath protein (MspA). The amyloidogenic nature of MspA was confirmed by in vitro amyloid formation of recombinant MspA under a wide range of environmental conditions. This is the first report of a functional amyloid from the archaeal domain of life. The amyloid nature explains the extreme resistance of the sheath, the elastic properties that allow diffusible substrates to penetrate through expandable hoop boundaries, and how the sheaths are able to split and elongate outside the cell. The archaeal sheath amyloids do not share homology with any of the currently known functional amyloids and clearly represent a new function of the amyloid protein fold. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Conformational dynamics of amyloid proteins at the aqueous interface

    Science.gov (United States)

    Armbruster, Matthew; Horst, Nathan; Aoki, Brendy; Malik, Saad; Soto, Patricia

    2013-03-01

    Amyloid proteins is a class of proteins that exhibit distinct monomeric and oligomeric conformational states hallmark of deleterious neurological diseases for which there are not yet cures. Our goal is to examine the extent of which the aqueous/membrane interface modulates the folding energy landscape of amyloid proteins. To this end, we probe the dynamic conformational ensemble of amyloids (monomer prion protein and Alzheimer's Ab protofilaments) interacting with model bilayers. We will present the results of our coarse grain molecular modeling study in terms of the existence of preferential binding spots of the amyloid to the bilayer and the response of the bilayer to the interaction with the amyloid. NSF Nebraska EPSCoR First Award

  14. Metastable Amyloid Phases and their Conversion to Mature Fibrils

    Science.gov (United States)

    Muschol, Martin; Miti, Tatiana; Mulaj, Mentor; Schmit, Jeremy

    Self-assembly of proteins into amyloid fibrils plays a key role in both functional biological responses and pathogenic disorders which include Alzheimer's disease and type II diabetes. Amyloid fibril assembly frequently generates compact oligomeric and curvilinear polymeric intermediates which are implicated to be toxic to cells. Yet, the relation between these early-stage oligomeric aggregates and late-stage rigid fibrils, which are the hallmark structure of amyloid plaques, has remained unclear. Our measurements indicate that lysozyme amyloid oligomers and their curvilinear fibrils only form after crossing a salt and protein concentration dependent threshold. These oligomeric aggregates are structurally distinct from rigid fibrils and are metastable against nucleation and growth of rigid fibrils. Our experimental transition boundaries match well with colloidal model predictions accounting for salt-modulated charge repulsion. We also report our preliminary findings on the mechanism by which these metastable oligomeric phases are converted into stable amyloid fibrils.

  15. Development of (F-18)-Labeled Amyloid Imaging Agents for PET

    International Nuclear Information System (INIS)

    Mathis, C.A.

    2007-01-01

    The applicant proposes to design and synthesize a series of fluorine-18-labeled radiopharmaceuticals to be used as amyloid imaging agents for positron emission tomography (PET). The investigators will conduct comprehensive iterative in vitro and in vivo studies based upon well defined acceptance criteria in order to identify lead agents suitable for human studies. The long term goals are to apply the selected radiotracers as potential diagnostic agents of Alzheimer's disease (AD), as surrogate markers of amyloid in the brain to determine the efficacy of anti-amyloid therapeutic drugs, and as tools to help address basic scientific questions regarding the progression of the neuropathology of AD, such as testing the 'amyloid cascade hypothesis' which holds that amyloid accumulation is the primary cause of AD.

  16. Preparation of Amyloid Fibrils Seeded from Brain and Meninges.

    Science.gov (United States)

    Scherpelz, Kathryn P; Lu, Jun-Xia; Tycko, Robert; Meredith, Stephen C

    2016-01-01

    Seeding of amyloid fibrils into fresh solutions of the same peptide or protein in disaggregated form leads to the formation of replicate fibrils, with close structural similarity or identity to the original fibrillar seeds. Here we describe procedures for isolating fibrils composed mainly of β-amyloid (Aβ) from human brain and from leptomeninges, a source of cerebral blood vessels, for investigating Alzheimer's disease and cerebral amyloid angiopathy. We also describe methods for seeding isotopically labeled, disaggregated Aβ peptide solutions for study using solid-state NMR and other techniques. These methods should be applicable to other types of amyloid fibrils, to Aβ fibrils from mice or other species, tissues other than brain, and to some non-fibrillar aggregates. These procedures allow for the examination of authentic amyloid fibrils and other protein aggregates from biological tissues without the need for labeling the tissue.

  17. Design and Construction of Large Amyloid Fibers

    OpenAIRE

    Ridgley, Devin M.; Rippner, Caitlin M. W.; Barone, Justin R.

    2015-01-01

    Mixtures of “template” and “adder” proteins self-assemble into large amyloid fibers of varying morphology and modulus. Fibers range from low modulus, rectangular cross-sectioned tapes to high modulus, circular cross-sectioned cylinders. Varying the proteins in the mixture can elicit “in-between” morphologies, such as elliptical cross-sectioned fibers and twisted tapes, both of which have moduli in-between rectangular tapes and cylindrical fibers. Experiments on mixtures of proteins of known a...

  18. Inclusive Services Innovation Configuration

    Science.gov (United States)

    Holdheide, Lynn R.; Reschly, Daniel J.

    2011-01-01

    Teacher preparation to deliver inclusive services to students with disabilities is increasingly important because of changes in law and policy emphasizing student access to, and achievement in, the general education curriculum. This innovation configuration identifies the components of inclusive services that should be incorporated in teacher…

  19. Testing and Inclusive Schooling

    DEFF Research Database (Denmark)

    Morin, Anne; Hamre, Bjørn; Ydesen, Christian

    Testing and Inclusive Schooling provides a comparative on seemingly incompatible global agendas and efforts to include all children in the general school system, Thus reducing exclusion. With an examination of the international testing culture and the politics of inclusion currently permeating...

  20. Understanding Inclusion in Cyprus

    Science.gov (United States)

    Mamas, Christoforos

    2013-01-01

    This paper provides a framework for understanding inclusion in Cyprus. The evidence base is the result of a six-month qualitative research study in five Cypriot mainstream primary schools. Despite the rhetoric in favour of inclusion, it seems that the Cypriot educational system is still highly segregating in its philosophy and does not fully…

  1. Jet inclusive cross sections

    International Nuclear Information System (INIS)

    Del Duca, V.

    1992-11-01

    Minijet production in jet inclusive cross sections at hadron colliders, with large rapidity intervals between the tagged jets, is evaluated by using the BFKL pomeron. We describe the jet inclusive cross section for an arbitrary number of tagged jets, and show that it behaves like a system of coupled pomerons

  2. Bacterial mitosis

    DEFF Research Database (Denmark)

    Møller-Jensen, Jakob; Borch, Jonas; Dam, Mette

    2003-01-01

    Bacterial DNA segregation takes place in an active and ordered fashion. In the case of Escherichia coli plasmid R1, the partitioning system (par) separates paired plasmid copies and moves them to opposite cell poles. Here we address the mechanism by which the three components of the R1 par system...... act together to generate the force required for plasmid movement during segregation. ParR protein binds cooperatively to the centromeric parC DNA region, thereby forming a complex that interacts with the filament-forming actin-like ParM protein in an ATP-dependent manner, suggesting that plasmid...

  3. Human serum amyloid genes--molecular characterization

    International Nuclear Information System (INIS)

    Sack, G.H.; Lease, J.J.

    1986-01-01

    Three clones containing human genes for serum amyloid A protein (SAA) have been isolated and characterized. Each of two clones, GSAA 1 and 2 (of 12.8 and 15.9 kilobases, respectively), contains two exons, accouting for amino acids 12-58 and 58-103 of mature SAA; the extreme 5' termini and 5' untranslated regions have not yet been defined but are anticipated to be close based on studies of murine SAA genes. Initial amino acid sequence comparisons show 78/89 identical residues. At 4 of the 11 discrepant residues, the amino acid specified by the codon is the same as the corresponding residue in murine SAA. Identification of regions containing coding regions has permitted use of selected subclones for blot hybridization studies of larger human SAA chromosomal gene organization. The third clone, GSAA 3 also contains SAA coding information by DNA sequence analysis but has a different organization which has not yet been fully described. We have reported the isolation of clones of human DNA hybridizing with pRS48 - a plasmid containing a complementary DNA (cDNA) clone for murine serum amyloid A (SAA; 1, 2). We now present more detailed data confirming the identity and defining some of the organizational features of these clones

  4. Recent progress on understanding the mechanisms of amyloid nucleation.

    Science.gov (United States)

    Chatani, Eri; Yamamoto, Naoki

    2018-04-01

    Amyloid fibrils are supramolecular protein assemblies with a fibrous morphology and cross-β structure. The formation of amyloid fibrils typically follows a nucleation-dependent polymerization mechanism, in which a one-step nucleation scheme has widely been accepted. However, a variety of oligomers have been identified in early stages of fibrillation, and a nucleated conformational conversion (NCC) mechanism, in which oligomers serve as a precursor of amyloid nucleation and convert to amyloid nuclei, has been proposed. This development has raised the need to consider more complicated multi-step nucleation processes in addition to the simplest one-step process, and evidence for the direct involvement of oligomers as nucleation precursors has been obtained both experimentally and theoretically. Interestingly, the NCC mechanism has some analogy with the two-step nucleation mechanism proposed for inorganic and organic crystals and protein crystals, although a more dramatic conformational conversion of proteins should be considered in amyloid nucleation. Clarifying the properties of the nucleation precursors of amyloid fibrils in detail, in comparison with those of crystals, will allow a better understanding of the nucleation of amyloid fibrils and pave the way to develop techniques to regulate it.

  5. Kinetically controlled thermal response of beta2-microglobulin amyloid fibrils.

    Science.gov (United States)

    Sasahara, Kenji; Naiki, Hironobu; Goto, Yuji

    2005-09-23

    Calorimetric measurements were carried out using a differential scanning calorimeter in the temperature range from 10 to 120 degrees C for characterizing the thermal response of beta2-microglobulin amyloid fibrils. The thermograms of amyloid fibril solution showed a remarkably large decrease in heat capacity that was essentially released upon the thermal unfolding of the fibrils, in which the magnitude of negative heat capacity change was not explicable in terms of the current accessible surface area model of protein structural thermodynamics. The heat capacity-temperature curve of amyloid fibrils prior to the fibril unfolding exhibited an unusual dependence on the fibril concentration and the heating rate. Particularly, the heat needed to induce the thermal response was found to be linearly dependent on the heating rate, indicating that its thermal response is under a kinetic control and precluding the interpretation in terms of equilibrium thermodynamics. Furthermore, amyloid fibrils of amyloid beta peptides also exhibited a heating rate-dependent exothermic process before the fibril unfolding, indicating that the kinetically controlled thermal response may be a common phenomenon to amyloid fibrils. We suggest that the heating rate-dependent negative change in heat capacity is coupled to the association of amyloid fibrils with characteristic hydration pattern.

  6. Stable, metastable, and kinetically trapped amyloid aggregate phases.

    Science.gov (United States)

    Miti, Tatiana; Mulaj, Mentor; Schmit, Jeremy D; Muschol, Martin

    2015-01-12

    Self-assembly of proteins into amyloid fibrils plays a key role in a multitude of human disorders that range from Alzheimer's disease to type II diabetes. Compact oligomeric species, observed early during amyloid formation, are reported as the molecular entities responsible for the toxic effects of amyloid self-assembly. However, the relation between early-stage oligomeric aggregates and late-stage rigid fibrils, which are the hallmark structure of amyloid plaques, has remained unclear. We show that these different structures occupy well-defined regions in a peculiar phase diagram. Lysozyme amyloid oligomers and their curvilinear fibrils only form after they cross a salt and protein concentration-dependent threshold. We also determine a boundary for the onset of amyloid oligomer precipitation. The oligomeric aggregates are structurally distinct from rigid fibrils and are metastable against nucleation and growth of rigid fibrils. These experimentally determined boundaries match well with colloidal model predictions that account for salt-modulated charge repulsion. The model also incorporates the metastable and kinetic character of oligomer phases. Similarities and differences of amyloid oligomer assembly to metastable liquid-liquid phase separation of proteins and to surfactant aggregation are discussed.

  7. Fish β-parvalbumin acquires allergenic properties by amyloid assembly.

    Science.gov (United States)

    Martínez, Javier; Sánchez, Rosa; Castellanos, Milagros; Fernández-Escamilla, Ana M; Vázquez-Cortés, Sonia; Fernández-Rivas, Montserrat; Gasset, María

    2015-01-01

    Amyloids are highly cross-β-sheet-rich aggregated states that confer protease resistance, membrane activity and multivalence properties to proteins, all essential features for the undesired preservation of food proteins transiting the gastrointestinal tract and causing type I allergy. Amyloid propensity of β-parvalbumin, the major fish allergen, was theoretically analysed and assayed under gastrointestinal-relevant conditions using the binding of thioflavin T, the formation of sodium dodecyl sulphate- (SDS-) resistant aggregates, circular dichroism spectroscopy and atomic force microscopy fibril imaging. Impact of amyloid aggregates on allergenicity was assessed with dot blot. Sequences of β-parvalbumin from species with commercial value contain several adhesive hexapeptides capable of driving amyloid formation. Using Atlantic cod β-parvalbumin (rGad m 1) displaying high IgE cross-reactivity, we found that formation of amyloid fibres under simulated gastrointestinal conditions accounts for the resistance to acid and neutral proteases, for the presence of membrane active species under gastrointestinal relevant conditions and for the IgE-recognition in the sera of allergic patients. Incorporation of the anti-amyloid compound epigallocatechin gallate prevents rGad m 1 fibrillation, facilitates its protease digestion and impairs its recognition by IgE. the formation of amyloid by rGad m 1 explains its degradation resistance, its facilitated passage across the intestinal epithelial barrier and its epitope architecture as allergen.

  8. Amyloid plaque imaging in vivo: current achievement and future prospects

    International Nuclear Information System (INIS)

    Nordberg, Agneta

    2008-01-01

    Alzheimer's disease (AD) is a very complex neurodegenerative disorder, the exact cause of which is still not known. The major histopathological features, amyloid plaques and neurofibrillary tangles, already described by Alois Alzheimer, have been the focus in research for decades. Despite a probable whole cascade of events in the brain leading to impairment of cognition, amyloid is still the target for diagnosis and treatment. The rapid development of molecular imaging techniques now allows imaging of amyloid plaques in vivo in Alzheimer patients by PET amyloid ligands such as Pittsburgh compound B (PIB). Studies so far have revealed high 11 C-PIB retention in brain at prodromal stages of AD and a possibility to discriminate AD from other dementia disorders by 11 C-PIB. Ongoing studies are focussing to understand the relationship between brain and CSF amyloid processes and cognitive processes. In vivo imaging of amyloid will be important for early diagnosis and evaluation of new anti-amyloid therapies in AD. (orig.)

  9. Inclusion in Elementary Schools

    Directory of Open Access Journals (Sweden)

    Susan Allan Galis

    1995-10-01

    Full Text Available This study of reform policy focused on inclusive education in the 1990s in the state of Georgia, United States of America. Program modifications including, individualizing instructional methods, adapting the instructional environment, and lowering maximum class size emerged as significant issues. We found that policies related to these areas were compounded by the less experienced educators not readily accepting change strategies for serving students. Apparently younger educators are engrossed in surviving daily routine and have difficulty coping with the complex demands of change. Regular education teachers have difficulty with the idea of inclusion. Legal aspects dealing inclusion need clarification, especially for regular education teachers.

  10. Assessment of inclusive education

    DEFF Research Database (Denmark)

    Miller, Tanja

    2014-01-01

    The focus of this paper is on the way teachers, in teams can work with assessing the inclusive practice in their own classes. In 2012 a joint effort between CEPRA, teachers and school administrators from the municipality of Hjørring developed a dialog based model for continually assessing...... the quality of the learning environment in regard to inclusion – this model draws heavily on the logic and mindset of ECERS (Early child environment program). This article will relate the rationale of the assessment model called “Dialoger om Kvalitet” (dialogues on quality) to LSP’s definition of inclusion...

  11. Fluid inclusion geothermometry

    Science.gov (United States)

    Cunningham, C.G.

    1977-01-01

    Fluid inclusions trapped within crystals either during growth or at a later time provide many clues to the histories of rocks and ores. Estimates of fluid-inclusion homogenization temperature and density can be obtained using a petrographic microscope with thin sections, and they can be refined using heating and freezing stages. Fluid inclusion studies, used in conjunction with paragenetic studies, can provide direct data on the time and space variations of parameters such as temperature, pressure, density, and composition of fluids in geologic environments. Changes in these parameters directly affect the fugacity, composition, and pH of fluids, thus directly influencing localization of ore metals. ?? 1977 Ferdinand Enke Verlag Stuttgart.

  12. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    Directory of Open Access Journals (Sweden)

    Yazan S. Batarseh

    2016-03-01

    Full Text Available Amyloid-β (Aβ pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer’s disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia.

  13. Proteomics with Mass Spectrometry Imaging: Beyond Amyloid Typing.

    Science.gov (United States)

    Lavatelli, Francesca; Merlini, Giampaolo

    2018-04-01

    Detection and typing of amyloid deposits in tissues are two crucial steps in the management of systemic amyloidoses. The presence of amyloid deposits is routinely evaluated through Congo red staining, whereas proteomics is now a mainstay in the identification of the deposited proteins. In article number 1700236, Winter et al. [Proteomics 2017, 17, Issue 22] describe a novel method based on MALDI-MS imaging coupled to ion mobility separation and peptide filtering, to detect the presence of amyloid in histology samples and to identify its composition, while preserving the spatial distribution of proteins in tissues. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Inhibition of Alzheimer amyloid {beta} aggregation by polyvalent trehalose

    Energy Technology Data Exchange (ETDEWEB)

    Miura, Yoshiko; You, Chouga [School of Materials Science, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa 923-1292 (Japan); Ohnishi, Reiko [Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603 (Japan)], E-mail: miuray@jaist.ac.jp

    2008-04-15

    A glycopolymer carrying trehalose was found to suppress the formation of amyloid fibrils from the amyloid {beta} peptide (1-42) (A{beta}), as evaluated by thioflavin T assay and atomic force microscopy. Glycopolymers carrying sugar alcohols also changed the aggregation properties of A{beta}, and the inhibitory effect depended on the type of sugar and alkyl side chain. Neutralization activity was confirmed by in vitro assay using HeLa cells. The glycopolymer carrying trehalose strongly inhibited amyloid formation and neutralized cytotoxicity.

  15. Bacterial Ecology

    DEFF Research Database (Denmark)

    Fenchel, Tom

    2011-01-01

    compounds these must first be undergo extracellular hydrolysis. Bacteria have a great diversity with respect to types of metabolism that far exceeds the metabolic repertoire of eukaryotic organisms. Bacteria play a fundamental role in the biosphere and certain key processes such as, for example......, the production and oxidation of methane, nitrate reduction and fixation of atmospheric nitrogen are exclusively carried out by different groups of bacteria. Some bacterial species – ‘extremophiles’ – thrive in extreme environments in which no eukaryotic organisms can survive with respect to temperature, salinity...... biogeochemical processes are carried exclusively by bacteria. * Bacteria play an important role in all types of habitats including some that cannot support eukaryotic life....

  16. Can we build inclusion?

    DEFF Research Database (Denmark)

    Kirkeby, Inge Mette; Grangaard, Sidse

    2016-01-01

    of some children with special needs. Hence the title – can we build inclusion? In the literature of Universal Design, accommodation and design features seldom reflect the less visible disabilities. The paper is based on a research project initiated to investigate how more or less space influences daily......Inclusion of children with special needs in kindergartens and preschools may be approached from different angles. This paper raises the question of whether the physical framework of kindergartens makes any difference for daily life at the kindergarten at all, and whether it can support inclusion...... on the answers in the interviews, we found support for answering the question in the title in the affirmative; we can build inclusion! This is because the teachers' experience indicated that, if there was sufficient space per child, there were fewer conflicts and the children managed to stay in the same activity...

  17. Evidence on Inclusion

    DEFF Research Database (Denmark)

    Dyssegaard, Camilla Brørup; Larsen, Michael Søgaard

    The purpose of this publication is to examine existing research on inclusion to identify strategies of inclusion that have generated positive effects. To do so it is necessary to understand the effect of the applied strategies. One approach, which is being discussed, is to use evidence to determine...... which methods have proven more effective than others. The desire to gain insight into research on inclusion forms the basis of the current systematic review. The task was to determine which strategies primary research has found to be most effective for inclusion purposes. We have solved this task...... by addressing the existing research with the following question: What is the effect of including children with special needs in mainstream teaching in basic school, and which of the applied educational methods have proved to have a positive effect?...

  18. Melt inclusions: Chapter 6

    Science.gov (United States)

    ,; Lowenstern, J. B.

    2014-01-01

    Melt inclusions are small droplets of silicate melt that are trapped in minerals during their growth in a magma. Once formed, they commonly retain much of their initial composition (with some exceptions) unless they are re-opened at some later stage. Melt inclusions thus offer several key advantages over whole rock samples: (i) they record pristine concentrations of volatiles and metals that are usually lost during magma solidification and degassing, (ii) they are snapshots in time whereas whole rocks are the time-integrated end products, thus allowing a more detailed, time-resolved view into magmatic processes (iii) they are largely unaffected by subsolidus alteration. Due to these characteristics, melt inclusions are an ideal tool to study the evolution of mineralized magma systems. This chapter first discusses general aspects of melt inclusions formation and methods for their investigation, before reviewing studies performed on mineralized magma systems.

  19. Bacterial Actins.

    Science.gov (United States)

    Izoré, Thierry; van den Ent, Fusinita

    2017-01-01

    A diverse set of protein polymers, structurally related to actin filaments contributes to the organization of bacterial cells as cytomotive or cytoskeletal filaments. This chapter describes actin homologs encoded by bacterial chromosomes. MamK filaments, unique to magnetotactic bacteria, help establishing magnetic biological compasses by interacting with magnetosomes. Magnetosomes are intracellular membrane invaginations containing biomineralized crystals of iron oxide that are positioned by MamK along the long-axis of the cell. FtsA is widespread across bacteria and it is one of the earliest components of the divisome to arrive at midcell, where it anchors the cell division machinery to the membrane. FtsA binds directly to FtsZ filaments and to the membrane through its C-terminus. FtsA shows altered domain architecture when compared to the canonical actin fold. FtsA's subdomain 1C replaces subdomain 1B of other members of the actin family and is located on the opposite side of the molecule. Nevertheless, when FtsA assembles into protofilaments, the protofilament structure is preserved, as subdomain 1C replaces subdomain IB of the following subunit in a canonical actin filament. MreB has an essential role in shape-maintenance of most rod-shaped bacteria. Unusually, MreB filaments assemble from two protofilaments in a flat and antiparallel arrangement. This non-polar architecture implies that both MreB filament ends are structurally identical. MreB filaments bind directly to membranes where they interact with both cytosolic and membrane proteins, thereby forming a key component of the elongasome. MreB filaments in cells are short and dynamic, moving around the long axis of rod-shaped cells, sensing curvature of the membrane and being implicated in peptidoglycan synthesis.

  20. Specific localization and imaging of amyloid deposits in vivo using 123I-labeled serum amyloid P component

    International Nuclear Information System (INIS)

    Hawkins, P.N.; Myers, M.J.; Epenetos, A.A.; Caspi, D.; Pepys, M.B.

    1988-01-01

    Highly specific, high-resolution scintigraphic images of amyloid-laden organs in mice with experimentally induced amyloid A protein (AA) amyloidosis were obtained after intravenous injection of 123 I-labeled serum amyloid P component (SAP). Interestingly, a much higher proportion (up to 40%) of the injected dose of heterologous human SAP localized to amyloid and was retained there than was the case with isologous mouse SAP, indicating that human SAP binds more avidly to mouse AA fibrils than does mouse SAP. Specificity of SAP localization was established by the failure of the related proteins, human C-reactive protein and Limulus C-reactive protein, to deposit significantly in amyloid and by the absence of human SAP deposition in nonamyloidotic organs. However, only partial correlations were observed between the quantity of SAP localized and two independent estimates, histology and RIA for AA of the amount of amyloid in particular organs. It is not clear which of the three methods used reflects better the extent or clinical significance of the amyloid deposits but in vivo localization of radiolabeled SAP, detectable and quantifiable by gamma camera imaging, is apparently extremely sensitive. These findings establish the use of labeled SAP as a noninvasive in vivo diagnostic probe in experimental amyloidosis, potentially capable of revealing the natural history of the condition, and suggest that it may also be applicable generally as a specific targeting agent for diagnostic and even therapeutic purposes in clinical amyloidosis

  1. RISKS OF INCLUSIVE EDUCATION

    OpenAIRE

    M. R. Husnutdinova

    2017-01-01

    Introduction. Inclusion is a new and unfamiliar phenomenon for most of the Russians which is treated as ensuring equal access to education for all students taking into account a variety of their special educational needs and individual capabilities. Inclusive educational model began to take root in Russia without a broad public debate and today’s parents and teachers were not ready to the cardinal changes caused by transition to the new model of education. In this regard, the studying of dire...

  2. Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation.

    Science.gov (United States)

    Pilkington, Emily H; Lai, May; Ge, Xinwei; Stanley, William J; Wang, Bo; Wang, Miaoyi; Kakinen, Aleksandr; Sani, Marc-Antonie; Whittaker, Michael R; Gurzov, Esteban N; Ding, Feng; Quinn, John F; Davis, Thomas P; Ke, Pu Chun

    2017-12-11

    Protein aggregation into amyloid fibrils is a ubiquitous phenomenon across the spectrum of neurodegenerative disorders and type 2 diabetes. A common strategy against amyloidogenesis is to minimize the populations of toxic oligomers and protofibrils by inhibiting protein aggregation with small molecules or nanoparticles. However, melanin synthesis in nature is realized by accelerated protein fibrillation to circumvent accumulation of toxic intermediates. Accordingly, we designed and demonstrated the use of star-shaped poly(2-hydroxyethyl acrylate) (PHEA) nanostructures for promoting aggregation while ameliorating the toxicity of human islet amyloid polypeptide (IAPP), the peptide involved in glycemic control and the pathology of type 2 diabetes. The binding of PHEA elevated the β-sheet content in IAPP aggregates while rendering a new morphology of "stelliform" amyloids originating from the polymers. Atomistic molecular dynamics simulations revealed that the PHEA arms served as rodlike scaffolds for IAPP binding and subsequently accelerated IAPP aggregation by increased local peptide concentration. The tertiary structure of the star nanoparticles was found to be essential for driving the specific interactions required to impel the accelerated IAPP aggregation. This study sheds new light on the structure-toxicity relationship of IAPP and points to the potential of exploiting star polymers as a new class of therapeutic agents against amyloidogenesis.

  3. Yeast and Fungal Prions: Amyloid-Handling Systems, Amyloid Structure, and Prion Biology.

    Science.gov (United States)

    Wickner, R B; Edskes, H K; Gorkovskiy, A; Bezsonov, E E; Stroobant, E E

    2016-01-01

    Yeast prions (infectious proteins) were discovered by their outré genetic properties and have become important models for an array of human prion and amyloid diseases. A single prion protein can become any of many distinct amyloid forms (called prion variants or strains), each of which is self-propagating, but with different biological properties (eg, lethal vs mild). The folded in-register parallel β sheet architecture of the yeast prion amyloids naturally suggests a mechanism by which prion variant information can be faithfully transmitted for many generations. The yeast prions rely on cellular chaperones for their propagation, but can be cured by various chaperone imbalances. The Btn2/Cur1 system normally cures most variants of the [URE3] prion that arise. Although most variants of the [PSI+] and [URE3] prions are toxic or lethal, some are mild in their effects. Even the most mild forms of these prions are rare in the wild, indicating that they too are detrimental to yeast. The beneficial [Het-s] prion of Podospora anserina poses an important contrast in its structure, biology, and evolution to the yeast prions characterized thus far. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Interaction between amyloid beta peptide and an aggregation blocker peptide mimicking islet amyloid polypeptide.

    Directory of Open Access Journals (Sweden)

    Nasrollah Rezaei-Ghaleh

    Full Text Available Assembly of amyloid-beta peptide (Aβ into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD and interfering with Aβ aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of Aβ. Here we investigate the interaction of IAPP-GI with Aβ40 and Aβ42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide. On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates.

  5. Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

    Science.gov (United States)

    Hoyer, Wolfgang; Grönwall, Caroline; Jonsson, Andreas; Ståhl, Stefan; Härd, Torleif

    2008-01-01

    According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-β (Aβ) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Aβ assemblies is accompanied by a conformational change toward a high content of β-structure. Here, we report the solution structure of Aβ(1–40) in complex with the phage-display selected affibody protein ZAβ3, a binding protein of nanomolar affinity. Bound Aβ(1–40) features a β-hairpin comprising residues 17–36, providing the first high-resolution structure of Aβ in β conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar Aβ. ZAβ3 stabilizes the β-sheet by extending it intermolecularly and by burying both of the mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity. Consequently, ZAβ3 acts as a stoichiometric inhibitor of Aβ fibrillation. The selected Aβ conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates. PMID:18375754

  6. Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Payel Das

    Full Text Available Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.

  7. Limitations of inclusive fitness.

    Science.gov (United States)

    Allen, Benjamin; Nowak, Martin A; Wilson, Edward O

    2013-12-10

    Until recently, inclusive fitness has been widely accepted as a general method to explain the evolution of social behavior. Affirming and expanding earlier criticism, we demonstrate that inclusive fitness is instead a limited concept, which exists only for a small subset of evolutionary processes. Inclusive fitness assumes that personal fitness is the sum of additive components caused by individual actions. This assumption does not hold for the majority of evolutionary processes or scenarios. To sidestep this limitation, inclusive fitness theorists have proposed a method using linear regression. On the basis of this method, it is claimed that inclusive fitness theory (i) predicts the direction of allele frequency changes, (ii) reveals the reasons for these changes, (iii) is as general as natural selection, and (iv) provides a universal design principle for evolution. In this paper we evaluate these claims, and show that all of them are unfounded. If the objective is to analyze whether mutations that modify social behavior are favored or opposed by natural selection, then no aspect of inclusive fitness theory is needed.

  8. A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies.

    Science.gov (United States)

    Lathuilière, Aurélien; Laversenne, Vanessa; Astolfo, Alberto; Kopetzki, Erhard; Jacobsen, Helmut; Stampanoni, Marco; Bohrmann, Bernd; Schneider, Bernard L; Aebischer, Patrick

    2016-05-01

    Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. RISKS OF INCLUSIVE EDUCATION

    Directory of Open Access Journals (Sweden)

    M. R. Husnutdinova

    2017-01-01

    Full Text Available Introduction. Inclusion is a new and unfamiliar phenomenon for most of the Russians which is treated as ensuring equal access to education for all students taking into account a variety of their special educational needs and individual capabilities. Inclusive educational model began to take root in Russia without a broad public debate and today’s parents and teachers were not ready to the cardinal changes caused by transition to the new model of education. In this regard, the studying of directly educational process by consequences of inclusive training and education is urgent now.The aims of the research are the following: to identify the major risks that characterize the current stage of the implementation process of inclusion in the Russian educational organizations; to consider the main causes that lead to their occurrence; to present a comparative analysis of the views of respondents in comprehensive, inclusive and correctional schools. Methodology and research methods. The Sector Monitoring Studies of Moscow State University of Psychology & Education in 2010 and 2014 implemented a sociological study on the process of introduction of inclusion in the Russian schools. 200 teachers and 244 parents were interviewed in 2010; in 2014, in addition, 178 teachers and 386 parents were interviewed; 47 senior students including those with disabilities were interviewed too.Results. According to the results, the main concerns of the parents of students of comprehensive, inclusive and correctional schools are reduced to a few basic risks: lack of individual approach while teaching children with different educational needs, increased emotional pressure on the child, and child’s perception of the complexity of disability as an equal. These risks arise primarily because of the acute shortage of especially prepared-governmental teachers and socio-cultural, psychological unpreparedness of most contemporary children with disabilities to the perception of

  10. The proton-pump inhibitor lansoprazole enhances amyloid beta production.

    Science.gov (United States)

    Badiola, Nahuai; Alcalde, Victor; Pujol, Albert; Münter, Lisa-Marie; Multhaup, Gerd; Lleó, Alberto; Coma, Mireia; Soler-López, Montserrat; Aloy, Patrick

    2013-01-01

    A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

  11. Amyloid goiter in a child - US, CT and MR evaluation

    International Nuclear Information System (INIS)

    Perez Fontan, F.J.; Mosquera Oses, J.; Pombo Felipe, F.; Rodriguez Sanchez, I.; Arnaiz Pena, S.

    1992-01-01

    There are few radiological descriptions of amyloid goiter, basically in adult patients or oriental origin. We present a ten-year-old boy with Still's disease and secondary thyroid amyloidosis, describing the US, CT and MR findings. (orig.)

  12. In situ analysis of Bacillus licheniformis biofilms: amyloid-like polymers and eDNA are involved in the adherence and aggregation of the extracellular matrix.

    Science.gov (United States)

    Randrianjatovo-Gbalou, I; Rouquette, P; Lefebvre, D; Girbal-Neuhauser, E; Marcato-Romain, C-E

    2017-05-01

    This study attempts to determine which of the exopolymeric substances are involved in the adherence and aggregation of a Bacillus licheniformis biofilm. The involvement of extracellular proteins and eDNA were particularly investigated using DNase and proteinase K treatment. The permeability of the biofilms increased fivefold after DNase I treatment. The quantification of the matrix components showed that, irrespective to the enzyme tested, eDNA and amyloid-like polymers were removed simultaneously. Size-exclusion chromatography analyses supported these observations and revealed the presence of associated nucleic acid and protein complexes in the biofilm lysates. These data suggest that some extracellular DNA and amyloid-like proteins were closely interlaced within the matrix. Finally, confocal laser scanning microscopy imaging gave supplementary clues about the 3D organization of the biofilms, confirming that eDNA and exoproteins were essentially layered under and around the bacterial cells, whereas the amyloid-like fractions were homogeneously distributed within the matrix. These results confirm that some DNA-amyloid complexes play a key role in the modulation of the mechanical resistance of B. licheniformis biofilms. The study highlights the need to consider the whole structure of biofilms and to target the interactions between matrix components. A better understanding of B. licheniformis biofilm physiology and the structural organization of the matrix will strengthen strategies of biofilm control. © 2017 The Society for Applied Microbiology.

  13. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Helen P McWilliams-Koeppen

    Full Text Available Light chain (AL amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(PH-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. These data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.

  14. Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis

    Directory of Open Access Journals (Sweden)

    Tanya L. Poshusta

    2013-11-01

    Full Text Available Light chain (AL amyloidosis is a devastating disease characterized by amyloid deposits formed by immunoglobulin light chains. Current available treatments involve conventional chemotherapy and autologous stem cell transplant. We have recently concluded a phase III trial comparing these two treatments. AL amyloidosis patients who achieve hematological complete response (CR do not necessarily achieve organ response regardless of the treatment they received. In order to investigate the possible correlation between amyloid formation kinetics and organ response, we selected AL amyloidosis patients from the trial with kidney involvement and CR after treatment. Six patients were selected and their monoclonal immunoglobulin light chains were characterized. The proteins showed differences in their stability and their kinetics of amyloid formation. A correlation was detected at pH 7.4, showing that less stable proteins are more likely to form amyloid fibrils. AL-T03 is too unstable to form amyloid fibrils at pH 7.4. This protein was found in the only patient in the study that had organ response, suggesting that partially folded species are required for amyloid formation to occur in AL amyloidosis.

  15. Cooperative structural transitions in amyloid-like aggregation

    Science.gov (United States)

    Steckmann, Timothy; Bhandari, Yuba R.; Chapagain, Prem P.; Gerstman, Bernard S.

    2017-04-01

    Amyloid fibril aggregation is associated with several horrific diseases such as Alzheimer's, Creutzfeld-Jacob, diabetes, Parkinson's, and others. Although proteins that undergo aggregation vary widely in their primary structure, they all produce a cross-β motif with the proteins in β-strand conformations perpendicular to the fibril axis. The process of amyloid aggregation involves forming myriad different metastable intermediate aggregates. To better understand the molecular basis of the protein structural transitions and aggregation, we report on molecular dynamics (MD) computational studies on the formation of amyloid protofibrillar structures in the small model protein ccβ, which undergoes many of the structural transitions of the larger, naturally occurring amyloid forming proteins. Two different structural transition processes involving hydrogen bonds are observed for aggregation into fibrils: the breaking of intrachain hydrogen bonds to allow β-hairpin proteins to straighten, and the subsequent formation of interchain H-bonds during aggregation into amyloid fibrils. For our MD simulations, we found that the temperature dependence of these two different structural transition processes results in the existence of a temperature window that the ccβ protein experiences during the process of forming protofibrillar structures. This temperature dependence allows us to investigate the dynamics on a molecular level. We report on the thermodynamics and cooperativity of the transformations. The structural transitions that occurred in a specific temperature window for ccβ in our investigations may also occur in other amyloid forming proteins but with biochemical parameters controlling the dynamics rather than temperature.

  16. Towards Prebiotic Catalytic Amyloids Using High Throughput Screening.

    Directory of Open Access Journals (Sweden)

    Michael P Friedmann

    Full Text Available Enzymes are capable of directing complex stereospecific transformations and of accelerating reaction rates many orders of magnitude. As even the simplest known enzymes comprise thousands of atoms, the question arises as to how such exquisite catalysts evolved. A logical predecessor would be shorter peptides, but they lack the defined structure and size that are apparently necessary for enzyme functions. However, some very short peptides are able to assemble into amyloids, thereby forming a well-defined tertiary structure called the cross-β-sheet, which bestows unique properties upon the peptides. We have hypothesized that amyloids could have been the catalytically active precursor to modern enzymes. To test this hypothesis, we designed an amyloid peptide library that could be screened for catalytic activity. Our approach, amenable to high-throughput methodologies, allowed us to find several peptides and peptide mixtures that form amyloids with esterase activity. These results indicate that amyloids, with their stability in a wide range of conditions and their potential as catalysts with low sequence specificity, would indeed be fitting precursors to modern enzymes. Furthermore, our approach can be efficiently expanded upon in library size, screening conditions, and target activity to yield novel amyloid catalysts with potential applications in aqueous-organic mixtures, at high temperature and in other extreme conditions that could be advantageous for industrial applications.

  17. Novel β-amyloid aggregation inhibitors possessing a turn mimic.

    Science.gov (United States)

    Hamada, Yoshio; Miyamoto, Naoko; Kiso, Yoshiaki

    2015-04-01

    Amyloid β peptide, the main component of senile plaques found in the brain of Alzheimer disease (AD) patients, is a molecular target for AD therapeutic intervention. A number of potential AD therapeutics have been reported, including inhibitors of β-secretase, γ-secretase, and Aβ aggregation, and anti-amyloid agents, such as neprilysin, insulin degrading enzyme (IDE), and Aβ antibodies. Recently, we reported potent small-sized β-secretase (BACE1) inhibitors, which could serve as anti-AD drugs. However AD is a progressive disorder, where dementia symptoms gradually worsen over several decades, and therefore may require many years to get cured. One possible way to achieve a greater therapeutic effect is through simultaneous administration of multiple drugs, similar to those used in Highly Active Anti-Retroviral Therapy (HAART) used to treat AIDS. In order to overcome AD, we took a drug discovery approach to evaluate, novel β-amyloid aggregation inhibitors. Previously, we reported that a tong-type compound possessing a turn mimic as the inhibitor of HIV-1 protease dimerization. Oligomerized amyloid β peptides contain a turn structure within the molecule. Here, we designed and synthesized novel β-amyloid aggregation inhibitors with a turn-mimic template, based on the turn conformer of the oligomerized amyloid β peptides. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Amyloid Imaging: Poised for Integration into Medical Practice.

    Science.gov (United States)

    Anand, Keshav; Sabbagh, Marwan

    2017-01-01

    Amyloid imaging represents a significant advance as an adjunct in the diagnosis of Alzheimer's disease (AD) because it is the first imaging modality that identifies in vivo changes known to be associated with the pathogenesis. Initially, 11 C-PIB was developed, which was the prototype for many 18 F compounds, including florbetapir, florbetaben, and flutemetamol, among others. Despite the high sensitivity and specificity of amyloid imaging, it is not commonly used in clinical practice, mainly because it is not reimbursed under current Center for Medicare and Medicaid Services guidelines in the USA. To guide the field in who would be most appropriate for the utility of amyloid positron emission tomography, current studies are underway [Imaging Dementia Evidence for Amyloid Scanning (IDEAS) Study] that will inform the field on the utilization of amyloid positron emission tomography in clinical practice. With the advent of monoclonal antibodies that specifically target amyloid antibody, there is an interest, possibly a mandate, to screen potential treatment recipients to ensure that they are suitable for treatment. In this review, we summarize progress in the field to date.

  19. Multilingualism and Social Inclusion

    DEFF Research Database (Denmark)

    2017-01-01

    This is a thematic issue on the relation between multilingualism and social inclusion. Due to globalization, Europeanization, supranational and transnational regulations linguistic diversity and multilingualism are on the rise. Migration and old and new forms of mobility play an important role...... in these processes. As a consequence, English as the only global language is spreading around the world, including Europe and the European Union. Social and linguistic inclusion was accounted for in the pre-globalization age by the nation-state ideology implementing the ‘one nation-one people-one language’ doctrine...... in governance and daily life protected by a legal framework. This does not mean that there is full equality of languages. This carries over to the fair and just social inclusion of the speakers of these weaker, dominated languages as well. There is always a power question related to multilingualism. The ten...

  20. TOWARDS AN INCLUSIVE SCHOOL

    Directory of Open Access Journals (Sweden)

    Lucía López Menéndez

    2015-06-01

    Full Text Available Nowadays schools have to direct all efforts towards the comprehensive development of all students whatever their individual characteristics and their environment; they have to give a quality educational attention a qualified educational attention to the diversity in all their schools. This article presents an approach on the possibilities of developing a self-assessment using the Guide: "Index for Inclusion": “Index for Inclusion” published in the United kingdom by Centre for Studies on Inclusive Education (CSIE Tony Booth - Mel Ainscow (2002. This guide is a simple tool intended for schools to evaluate their reality in relation to important aspects of school organization and teaching-learning from the perspective of inclusion. From this self-assessment they can design specific programs to guide their educacional practice.

  1. Inclusive Education in Israel

    OpenAIRE

    O. V. Mayzel

    2013-01-01

    To get acquainted with the practice of inclusive education in mainstream schools, with professionals who work with special children, to visit the specialist centers to share experiences - all of this was part of an internship program «Early Childhood Education for Children with Special Needs», held in Israel (April 8 -02 May 2013) this year. The country has been selected for an internship, because the practice of inclusive education has been used for over 20 years in Israel. Moreover, a lot ...

  2. Creative activity and inclusion

    Directory of Open Access Journals (Sweden)

    Shemanov A.Yu.

    2013-09-01

    Full Text Available The aim of the article was to analyze the inclusion potential of art creative activity, namely of theatre performance, in people with disabilities. The article provides examples of disagreements in understanding the significance of these art activities for exercising the rights of people with disabilities to contribute to culture and art and some problems arising here. The conclusion is made that theatre art performed by people with disabilities is gradually changing its function: from being a means of self-affirmation to the determination of its specific place in overall theatre process. These changes confirm the inclusion potential of theatre art activity.

  3. Lead inclusions in aluminium

    International Nuclear Information System (INIS)

    Johnson, E.; Johansen, A.; Sarholt-Kristensen, L.; Andersen, H.H.; Grabaek, L.; Bohr, J.

    1990-01-01

    Ion implantation at room temperature of lead into aluminum leads to spontaneous phase separation and formation of lead precipitates growing topotactically with the matrix. Unlike the highly pressurized (∼ 1-5 GPa) solid inclusions formed after noble gas implantations, the pressure in the lead precipitates is found to be less than 0.12 GPa. Recently the authors have observed the result that the lead inclusions in aluminum exhibit both superheating and supercooling. In this paper they review and elaborate on these results. Small implantation-induced lead precipitates embedded in an aluminum matrix were studied by x-ray diffraction

  4. Lack of evidence for protein AA reactivity in amyloid deposits of lattice corneal dystrophy and amyloid corneal degeneration.

    Science.gov (United States)

    Gorevic, P D; Rodrigues, M M; Krachmer, J H; Green, C; Fujihara, S; Glenner, G G

    1984-08-15

    Amyloid fibrils occurring in primary and myeloma-associated (AL), secondary (AA), and certain neuropathic hereditary forms of systemic amyloidosis can be distinguished biochemically or immunohistologically as being composed of immunoglobulin light chain, protein AA, or prealbumin respectively. All types of systemic and several localized forms of amyloidosis contain amyloid P component (protein AP). We studied formalin-fixed tissue from eight cases of lattice corneal dystrophy by the immunoperoxidase method using antisera to proteins AA and AP, to normal serum prealbumin and prealbumin isolated from a case of hereditary amyloidosis, and to light-chain determinants; additional cases were examined by indirect immunofluorescence of fresh-frozen material. We found weak (1:10 dilution) staining with anti-AP, but no reactivity with other antisera. Congo red staining was resistant to pretreatment of sections with potassium permanganate, a characteristic of non-AA amyloid. Two-dimensional gels of solubilized proteins from frozen tissue from two cases of lattice corneal dystrophy resembled those obtained from normal human cornea. Western blots of two cases of polymorphous amyloid degeneration and solubilized protein from normal cornea did not react with radioactive iodine-labeled anti-AA or anti-AP with purified protein AP and unfixed protein AA amyloid tissue as controls. We were unable to corroborate the presence of protein AA in the amyloid deposits of lattice corneal dystrophy. Although staining with antiserum to protein AP was demonstrable, the molecular configuration of this protein in stromal deposits remains to be defined.

  5. Imaging β-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization

    International Nuclear Information System (INIS)

    Shoghi-Jadid, Kooresh; Barrio, Jorge R.; Kepe, Vladimir; Wu, H.-M.; Small, Gary W.; Phelps, Michael E.; Huang, S.-C.

    2005-01-01

    The polymerization of β-amyloid (Aβ) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. Aβ molecular imaging probes (Aβ-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of Aβ with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of Aβ-MIPs with fibrils. Subsequently, we hypothesize four Aβ-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B max and K D to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions

  6. Developing a financial inclusion index and inclusive growth in India

    OpenAIRE

    Susanta Kumar SETHY

    2016-01-01

    Financial inclusion is one of the systems through which Inclusive Growth can be achieved in developing countries like India where large sections are unable or hopeless to contribute in the financial system. An inclusive financial system mobilizes more resources for productive purposes leading to higher economic growth, better opportunities and reduction of poverty. This study, proposed an Index of financial inclusion – a multidimensional measure. The Financial Inclusion Index c...

  7. Linguistic Diversity and Social Inclusion

    Science.gov (United States)

    Piller, Ingrid; Takahashi, Kimie

    2011-01-01

    This introduction provides the framework for the special issue by describing the social inclusion agenda of neoliberal market democracies. While the social inclusion agenda has been widely adopted, social inclusion policies are often blind to the ways in which language proficiency and language ideologies mediate social inclusion in linguistically…

  8. Relationships in Inclusive Classrooms

    Science.gov (United States)

    Santos, Graça Duarte; Sardinha, Susana; Reis, Silvia

    2016-01-01

    Climate in the classroom is one of the determining factors in the development of practices in Inclusive Education. Many factors contribute to the climate in the classroom. However, there are predominance on affective-relational factors, with impact on action, norms and values, social interactions and learning processes. In this paper, the authors…

  9. Inclusion on the Bookshelf

    Science.gov (United States)

    Jackson, Camille

    2009-01-01

    Three decades have passed since federal law mandated inclusion--ending, officially at least, a system that segregated students with disabilities from the rest of the student population. The publishing world has yet to catch up. In children's books, characters with disabilities often inhabit their own separate world, where disability is the only…

  10. Mathematics Teaching and Inclusion

    DEFF Research Database (Denmark)

    This volume contains the proceedings of the 3rd Nordic Research Conference on Special Needs Education in Mathematics, which took place in Rebild organised by Aalborg University in November 23-25, 2005. The theme of the conference was Mathematics Education and Inclusion. The conference theme...

  11. Multilingualism and social inclusion

    NARCIS (Netherlands)

    Marácz, L.; Adamo, S.

    2017-01-01

    This is a thematic issue on the relation between multilingualism and social inclusion. Due to globalization, Europeanization, supranational and transnational regulations linguistic diversity and multilingualism are on the rise. Migration and old and new forms of mobility play an important role in

  12. Inclusion's Confusion in Alberta

    Science.gov (United States)

    Gilham, Chris; Williamson, W. John

    2014-01-01

    This hermeneutic paper interprets a recent series of reforms to inclusive education policy undertaken by the ministry of education in the province of Alberta, Canada. A 2007 Alberta Education review of the 16,000 student files in the province that school boards had claimed met the criteria for severe disability codification status -- the level of…

  13. High prevalence of biofilm synergy among bacterial soil isolates in cocultures indicates bacterial interspecific cooperation

    DEFF Research Database (Denmark)

    Ren, Dawei; Madsen, Jonas Stenløkke; Sørensen, Søren Johannes

    2015-01-01

    of single-species biofilms, indicating that all the individual strains benefit from inclusion in the multispecies community. Our results show a high prevalence of synergy in biofilm formation in multispecies consortia isolated from a natural bacterial habitat and suggest that interspecific cooperation...

  14. The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia

    Directory of Open Access Journals (Sweden)

    Brian A. Gordon

    2015-01-01

    Conclusions: The amount of amyloid deposition and white matter damage independently predicts cognitive impairment. This suggests a diagnostic utility of qualitative white matter scales in addition to measuring amyloid levels.

  15. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    Energy Technology Data Exchange (ETDEWEB)

    Okumura, Hisashi [Research Center for Computational Science, Institute for Molecular Science, Okazaki, Aichi 444-8585 (Japan); Department of Structural Molecular Science, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8585 (Japan)

    2015-12-31

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly.

  16. Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces

    NARCIS (Netherlands)

    van Veluw, Susanne J; Biessels, Geert Jan; Bouvy, Willem H; Spliet, Wim Gm; Zwanenburg, Jaco Jm; Luijten, Peter R; Macklin, Eric A; Rozemuller, Annemieke Jm; Gurol, M Edip; Greenberg, Steven M; Viswanathan, Anand; Martinez-Ramirez, Sergi

    2016-01-01

    Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not

  17. Key aromatic/hydrophobic amino acids controlling a cross-amyloid peptide interaction versus amyloid self-assembly.

    Science.gov (United States)

    Bakou, Maria; Hille, Kathleen; Kracklauer, Michael; Spanopoulou, Anna; Frost, Christina V; Malideli, Eleni; Yan, Li-Mei; Caporale, Andrea; Zacharias, Martin; Kapurniotu, Aphrodite

    2017-09-01

    The interaction of the intrinsically disordered polypeptide islet amyloid polypeptide (IAPP), which is associated with type 2 diabetes (T2D), with the Alzheimer's disease amyloid-β (Aβ) peptide modulates their self-assembly into amyloid fibrils and may link the pathogeneses of these two cell-degenerative diseases. However, the molecular determinants of this interaction remain elusive. Using a systematic alanine scan approach, fluorescence spectroscopy, and other biophysical methods, including heterocomplex pulldown assays, far-UV CD spectroscopy, the thioflavin T binding assay, transmission EM, and molecular dynamics simulations, here we identified single aromatic/hydrophobic residues within the amyloid core IAPP region as hot spots or key residues of its cross-interaction with Aβ40(42) peptide. Importantly, we also find that none of these residues in isolation plays a key role in IAPP self-assembly, whereas simultaneous substitution of four aromatic/hydrophobic residues with Ala dramatically impairs both IAPP self-assembly and hetero-assembly with Aβ40(42). Furthermore, our experiments yielded several novel IAPP analogs, whose sequences are highly similar to that of IAPP but have distinct amyloid self- or cross-interaction potentials. The identified similarities and major differences controlling IAPP cross-peptide interaction with Aβ40(42) versus its amyloid self-assembly offer a molecular basis for understanding the underlying mechanisms. We propose that these insights will aid in designing intervention strategies and novel IAPP analogs for the management of type 2 diabetes, Alzheimer's disease, or other diseases related to IAPP dysfunction or cross-amyloid interactions. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Amyloid PET in European and North American cohorts; and exploring age as a limit to clinical use of amyloid imaging

    Energy Technology Data Exchange (ETDEWEB)

    Chiotis, Konstantinos [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); Carter, Stephen F. [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); University of Manchester, Wolfson Molecular Imaging Centre, Institute of Brain, Behaviour and Mental Health, Manchester (United Kingdom); Farid, Karim [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); APHP, Hotel-Dieu Hospital, Department of Nuclear Medicine, Paris (France); Savitcheva, Irina [Karolinska University Hospital Huddinge, Department of Radiology, Stockholm (Sweden); Nordberg, Agneta [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden); Collaboration: for the Diagnostic Molecular Imaging (DiMI) network and the Alzheimer' s Disease Neuroimaging Initiative

    2015-09-15

    Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively). These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients. (orig.)

  19. Amyloid PET in European and North American cohorts; and exploring age as a limit to clinical use of amyloid imaging

    International Nuclear Information System (INIS)

    Chiotis, Konstantinos; Carter, Stephen F.; Farid, Karim; Savitcheva, Irina; Nordberg, Agneta

    2015-01-01

    Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively). These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients. (orig.)

  20. Accumulation of murine amyloid-β mimics early Alzheimer's disease.

    Science.gov (United States)

    Krohn, Markus; Bracke, Alexander; Avchalumov, Yosef; Schumacher, Toni; Hofrichter, Jacqueline; Paarmann, Kristin; Fröhlich, Christina; Lange, Cathleen; Brüning, Thomas; von Bohlen Und Halbach, Oliver; Pahnke, Jens

    2015-08-01

    Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for patients with Alzheimer's disease. The inherited form is even regarded a 'rare' disease according to the regulations for funding of the European Union (www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-β-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-β clearance from the brain, develop various aspects of sporadic Alzheimer's disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows investigations

  1. Imaging and quantification of amyloid fibrillation in the cell nucleus.

    Science.gov (United States)

    Arnhold, Florian; Scharf, Andrea; von Mikecz, Anna

    2015-01-01

    Xenobiotics, as well as intrinsic processes such as cellular aging, contribute to an environment that constantly challenges nuclear organization and function. While it becomes increasingly clear that proteasome-dependent proteolysis is a major player, the topology and molecular mechanisms of nuclear protein homeostasis remain largely unknown. We have shown previously that (1) proteasome-dependent protein degradation is organized in focal microenvironments throughout the nucleoplasm and (2) heavy metals as well as nanoparticles induce nuclear protein fibrillation with amyloid characteristics. Here, we describe methods to characterize the landscape of intranuclear amyloid on the global and local level in different systems such as cultures of mammalian cells and the soil nematode Caenorhabditis elegans. Application of discrete mathematics to imaging data is introduced as a tool to develop pattern recognition of intracellular protein fibrillation. Since stepwise fibrillation of otherwise soluble proteins to insoluble amyloid-like protein aggregates is a hallmark of neurodegenerative protein-misfolding disorders including Alzheimer's disease, CAG repeat diseases, and the prion encephalopathies, investigation of intracellular amyloid may likewise aid to a better understanding of the pathomechanisms involved. We consider aggregate profiling as an important experimental approach to determine if nuclear amyloid has toxic or protective roles in various disease processes.

  2. Safety of disclosing amyloid status in cognitively normal older adults.

    Science.gov (United States)

    Burns, Jeffrey M; Johnson, David K; Liebmann, Edward P; Bothwell, Rebecca J; Morris, Jill K; Vidoni, Eric D

    2017-09-01

    Disclosing amyloid status to cognitively normal individuals remains controversial given our lack of understanding the test's clinical significance and unknown psychological risk. We assessed the effect of amyloid status disclosure on anxiety and depression before disclosure, at disclosure, and 6 weeks and 6 months postdisclosure and test-related distress after disclosure. Clinicians disclosed amyloid status to 97 cognitively normal older adults (27 had elevated cerebral amyloid). There was no difference in depressive symptoms across groups over time. There was a significant group by time interaction in anxiety, although post hoc analyses revealed no group differences at any time point, suggesting a minimal nonsustained increase in anxiety symptoms immediately postdisclosure in the elevated group. Slight but measureable increases in test-related distress were present after disclosure and were related to greater baseline levels of anxiety and depression. Disclosing amyloid imaging results to cognitively normal adults in the clinical research setting with pre- and postdisclosure counseling has a low risk of psychological harm. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  3. New Insights in the Amyloid-Beta Interaction with Mitochondria

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2012-01-01

    Full Text Available Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD. Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

  4. Amyloid Structure and Assembly: Insights from Scanning Transmission Electron Microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Goldsbury, C.; Wall, J.; Baxa, U.; Simon, M. N.; Steven, A. C.; Engel, A.; Aebi, U.; Muller, S. A.

    2011-01-01

    Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer's disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).

  5. A Novel Small Molecule Modulator of Amyloid Pathology.

    Science.gov (United States)

    Lovell, Mark A; Lynn, Bert C; Fister, Shuling; Bradley-Whitman, Melissa; Murphy, M Paul; Beckett, Tina L; Norris, Christopher M

    2016-05-04

    Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer's disease.

  6. MR Microimaging of amyloid plaques in Alzheimer's disease transgenic mice

    International Nuclear Information System (INIS)

    Wengenack, Thomas M.; Poduslo, Joseph F.; Jack, Clifford R.; Garwood, Michael

    2008-01-01

    Alzheimer's disease (AD) is the most prevalent neurological condition affecting industrialized nations and will rapidly become a healthcare crisis as the population ages. Currently, the post-mortem histological observation of amyloid plaques and neurofibrillary tangles is the only definitive diagnosis available for AD. A pre-mortem biological or physiological marker specific for AD used in conjunction with current neurological and memory testing could add a great deal of confidence to the diagnosis of AD and potentially allow therapeutic intervention much earlier in the disease process. Our group has developed MRI techniques to detect individual amyloid plaques in AD transgenic mouse brain in vivo. We are also developing contrast-enhancing agents to increase the specificity of detection of amyloid plaques. Such in vivo imaging of amyloid plaques will also allow the evaluation of anti-amyloid therapies being developed by the pharmaceutical industry in pre-clinical trials of AD transgenic mice. This short review briefly discusses our progress in these areas. (orig.)

  7. Concordance Between Different Amyloid Immunoassays and Visual Amyloid Positron Emission Tomographic Assessment.

    Science.gov (United States)

    Janelidze, Shorena; Pannee, Josef; Mikulskis, Alvydas; Chiao, Ping; Zetterberg, Henrik; Blennow, Kaj; Hansson, Oskar

    2017-12-01

    Visual assessment of amyloid positron emission tomographic (PET) images has been approved by regulatory authorities for clinical use. Several immunoassays have been developed to measure β-amyloid (Aβ) 42 in cerebrospinal fluid (CSF). The agreement between CSF Aβ42 measures from different immunoassays and visual PET readings may influence the use of CSF biomarkers and/or amyloid PET assessment in clinical practice and trials. To determine the concordance between CSF Aβ42 levels measured using 5 different immunoassays and visual amyloid PET analysis. The study included 262 patients with mild cognitive impairment or subjective cognitive decline from the Swedish BioFINDER (Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably) cohort (recruited from September 1, 2010, through December 31, 2014) who had undergone flutemetamol F 18 ([18F]flutemetamol)-labeled PET. Levels of CSF Aβ42 were analyzed using the classic INNOTEST and the newer modified INNOTEST, fully automated Lumipulse (FL), EUROIMMUN (EI), and Meso Scale Discovery (MSD) assays. Concentrations of CSF Aβ were assessed using an antibody-independent mass spectrometry-based reference measurement procedure. The concordance of CSF Aβ42 levels and Aβ42:Aβ40 and Aβ42:tau ratios with visual [18F]flutemetamol PET status. Of 262 participants (mean [SD] age, 70.9 [5.5] years), 108 were women (41.2%) and 154 were men (58.8%). The mass spectrometry-derived Aβ42 values showed higher correlations with the modified Aβ42-INNOTEST (r = 0.97), Aβ42-FL (r = 0.93), Aβ42-EI (r = 0.93), and Aβ42-MSD (r = 0.95) assays compared with the classic Aβ42-INNOTEST assay (r = 0.88; P ≤ .01). The signal in the classic Aβ42-INNOTEST assay was partly quenched by recombinant Aβ1-40 peptide. However, the classic Aβ42-INNOTEST assay showed better concordance with visual [18F]flutemetamol PET status (area under the receiver operating characteristic curve [AUC], 0.92) compared with the

  8. Inclusive Physical Education

    DEFF Research Database (Denmark)

    Østergaard, Charlotte; Rostbøll, Solveig Fogh

    2015-01-01

    EN317 - Inclusive Physical Education - with a focus on active and successful participation Charlotte Østergaard, Solveig Fogh Rostbøll, Department of School and Learning, Metropolitan University College (DK) chao@phmetropol.dk The Danish School Reform 2014 intends to raise the amount and intensity...... and is often a bad experience for students who do not have the required skills or the necessary competitive mentality. The purpose of the study is to generate increased knowledge of how to work with inclusive education in PE in schools. The aims of the study are to identify groups of “outsiders” and to find...... and ability to participate in PE must be understood in specific socio-cultural and socio-economic conditions. The hypothesis of the study is that the experience of being acknowledged for your efforts in physical education by significant others can form the basis for the construction of physical capital. EN323...

  9. Inclusive differentiated instruction

    Directory of Open Access Journals (Sweden)

    Jerković Ljiljana S.

    2017-01-01

    Full Text Available Inclusive differentiated instruction is a new model of didactic instruction, theoretically described and established in this paper for the first time, after being experimentally verified through teaching of the mother tongue (instruction in reading and literature. Inclusive individually planned instruction is based on a phenomenological and constructivist didactic instructional paradigm. This type of teaching is essentially developmental and person-oriented. The key stages of inclusive differentiated instruction of literature are: 1 recognition of individual students' potential and educational needs regarding reading and work on literary texts; 2 planning and preparation of inclusive individually planned instruction in reading and literature; 3 actual class teaching of lessons thus prepared; and 4 evaluation of the student achievement following inclusive differentiated instruction in reading and literature. A highly important element of the planning and preparation of inclusive differentiated instruction is the creation of student profiles and inclusive individualized syllabi. Individualized syllabi specify the following: 1. a brief student profile; 2. the student position on the continuum of the learning outcomes of instruction in the Serbian language; 3. reverse-engineered macro-plan stages of instruction in the Serbian language (3.1. identifying expected outcomes and fundamental qualities of learners' work, 3.2. defining acceptable proofs of their realisation, 3.3. planning learning and teaching experiences, and 3.4. providing material and technical requisites for teaching; 4 the contents and procedure of individualized lessons targeting the student; 5 a plan of syllabus implementation monitoring and evaluation. The continuum of the learning outcomes of inclusive differentiated instruction in literature exists at three main levels, A, B and C. The three levels are: A reading techniques and learning about the main literary theory concepts; B

  10. Inclusive Flavour Tagging Algorithm

    International Nuclear Information System (INIS)

    Likhomanenko, Tatiana; Derkach, Denis; Rogozhnikov, Alex

    2016-01-01

    Identifying the flavour of neutral B mesons production is one of the most important components needed in the study of time-dependent CP violation. The harsh environment of the Large Hadron Collider makes it particularly hard to succeed in this task. We present an inclusive flavour-tagging algorithm as an upgrade of the algorithms currently used by the LHCb experiment. Specifically, a probabilistic model which efficiently combines information from reconstructed vertices and tracks using machine learning is proposed. The algorithm does not use information about underlying physics process. It reduces the dependence on the performance of lower level identification capacities and thus increases the overall performance. The proposed inclusive flavour-tagging algorithm is applicable to tag the flavour of B mesons in any proton-proton experiment. (paper)

  11. Can We Build Inclusion?

    Science.gov (United States)

    Kirkeby, Inge Mette; Grangaard, Sidse

    2016-01-01

    Inclusion of children with special needs in kindergartens and preschools may be approached from different angles. This paper raises the question of whether the physical framework of kindergartens makes any difference for daily life at the kindergarten at all, and whether it can support inclusion of some children with special needs. Hence the title - can we build inclusion? In the literature of Universal Design, accommodation and design features seldom reflect the less visible disabilities. The paper is based on a research project initiated to investigate how more or less space influences daily pedagogical practice in general. Twelve interviews were conducted with experienced teachers from twelve different kindergartens with different amounts of space, varying from a ratio of 2.1 m2 play area per child to 5.5 m2. The results indicated that, for a group of children with special needs in particular, the amount of space is crucial. This group consisted of children who were socially very extrovert, and who maybe were noisy, easily provoked, and quick to get involved in arguments with other children. Alternatively, children in the group were very restrained and withdrawn in social interaction. Based on the answers in the interviews, we found support for answering the question in the title in the affirmative; we can build inclusion! This is because the teachers' experience indicated that, if there was sufficient space per child, there were fewer conflicts and the children managed to stay in the same activity for a much longer period. Sufficient space made it possible to divide the children into smaller groups, and use any secluded space. Therefore, it was much easier for other children to include some children with special needs. Accordingly, we can say that, sufficient space per child and an adequate layout and furnishing of the kindergarten is an advantage for all children. This is a clear example of Universal Design in which architectural solutions that are good for

  12. Foresighting for Inclusive Development

    DEFF Research Database (Denmark)

    Dahl Andersen, Allan; Andersen, Per Dannemand

    and transform innovation systems because a set of distributed actors, rather than ministries and innovation agencies, is the gatekeepers of change. From this perspective, inclusion is a precondition rather than an obstacle for transformation. We develop a conceptual framework and use it to study design...... and processes in two foresight cases in two emerging economies - Brazil and South Korea. Although the research is exploratory and the results tentative, the empirical studies support our main propositions....

  13. Inclusion body myositis.

    OpenAIRE

    Garlepp, M J; Mastaglia, F L

    1996-01-01

    The idiopathic inflammatory myopathies (IIM) are a heterogenous group of rare disorders that share many similarities. In addition to sporadic inclusion body myositis (IBM), these include dematomyositis (DM), polymyositis (PM), and autoimmune necrotizing myopathy (NM). For discussion of later three disorders, the reader is referred to the IIM review in this issue. IBM is the most common IIM after age 50. It typically presents with chronic insidious proximal leg and/or distal arm asymmetric mus...

  14. Identification of a Common Binding Mode for Imaging Agents to Amyloid Fibrils from Molecular Dynamics Simulations

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby; Sørensen, Jesper; Schiøtt, Birgit

    2013-01-01

    experimentally due to the insoluble nature of amyloid fibrils. This study uses molecular dynamics simulations to investigate the interactions between 13 aromatic amyloid imaging agents, entailing 4 different organic scaffolds, and a model of an amyloid fibril. Clustering analysis combined with free energy...

  15. Modeling the Aggregation Propensity and Toxicity of Amyloid-β Variants

    DEFF Research Database (Denmark)

    Tiwari, Manish Kumar; Kepp, Kasper Planeta

    2015-01-01

    Protein aggregation is a hallmark of many neurodegenerative disorders. Alzheimer’s disease (AD) is directly linked to deposits of amyloid-β (Aβ) derived from the amyloid-β protein precursor (AβPP), and multiple experimental studies have investigated the aggregation behavior of these amyloids...

  16. Whole body amyloid deposition imaging by 123I-SAP scintigraphy

    NARCIS (Netherlands)

    van Rheenen, Ronald; Glaudemans, Andor; Hazenberg, Bouke

    2011-01-01

    Amyloidosis is the name of a group of diseases characterized by extracellular deposition of amyloid fibrils. Deposition of amyloid can be localized or systemic. The 123I-SAP-scan can be used to image extent and distribution of amyloid deposition in patients with systemic AA, AL and ATTR amyloidosis.

  17. Trifluoroethanol modulates α-synuclein amyloid-like aggregate formation, stability and dissolution

    DEFF Research Database (Denmark)

    Di Carlo, Maria Giovanna; Vetri, Valeria; Buscarino, Gianpiero

    2016-01-01

    The conversion of proteins into amyloid fibrils and other amyloid-like aggregates is closely connected to the onset of a series of age-related pathologies. Upon changes in environmental conditions, amyloid-like aggregates may also undergo disassembly into oligomeric aggregates, the latter being r...

  18. Novel squarylium dyes for detection of amyloid fibrils in vitro

    Directory of Open Access Journals (Sweden)

    K. O. Vus

    2015-04-01

    Full Text Available A series of novel symmetrical and asymmetrical squarylium dyes with the different substituents in the donor moieties have been tested for their ability to detect and characterize insulin and lysozyme amyloid fibrils prepared in acidic buffer at elevated temperature. The dye-protein binding parameters were estimated in terms of the one-site Langmuir adsorption model using the data of direct and reverse fluorimetric titrations. By comparing the dye quantum yields, binding affinities, and extents of the fluorescence enhancement in the protein-bound state, G6 and G7 were selected as the most prospective amyloid tracers. Furthermore, these probes provided evidence for the lower polarity of the lysozyme fibrillar grooves compared to insulin aggregates. The novel dyes G6 and G7 were recommended for amyloid fibril detection and characterization in the near-infrared region.

  19. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease.

    Science.gov (United States)

    Barage, Sagar H; Sonawane, Kailas D

    2015-08-01

    Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. Various therapeutic approaches are being used to improve the cholinergic neurotransmission, but their role in AD pathogenesis is still unknown. Although, an increase in tau protein concentration in CSF has been described in AD, but several issues remains unclear. Extensive and accurate analysis of CSF could be helpful to define presence of tau proteins in physiological conditions, or released during the progression of neurodegenerative disease. The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aβ) plaques in various areas of the brain. The amyloid hypothesis has continued to gain support over the last two decades, particularly from genetic studies. Therefore, current research progress in several areas of therapies shall provide an effective treatment to cure this devastating disease. This review critically evaluates general biochemical and physiological functions of Aβ directed therapeutics and their relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Computational Modelling of the Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby

    2014-01-01

    to interpret results correctly. Computational studies and molecular dynamics (MD) simulations in particular have become important tools in the effort to understand biological mechanisms. The strength of these methods is the high resolution in time and space, and the ability to specifically design the system....... Using MD simulations we have investigated the binding of 13 different imaging agents to a fibril segment. Using clustering analysis and binding energy calculations we have identified a common binding mode for the 13 agents in the surface grooves of the fibril, which are present on all amyloid fibrils....... This information combined with specific knowledge about the AD amyloid fibril is the building block for the design of highly specific amyloid imaging agents. We have also used MD simulations to study the interaction between hIAPP and a phospholipid membrane. At neutral pH, we find that the attraction is mainly...

  1. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

    KAUST Repository

    Demetrius, Lloyd A.; Magistretti, Pierre J.; Pellerin, Luc

    2015-01-01

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

  2. Analysis of amyloid fibrils in the cheetah (Acinonyx jubatus).

    Science.gov (United States)

    Bergström, Joakim; Ueda, Mitsuharu; Une, Yumi; Sun, Xuguo; Misumi, Shogo; Shoji, Shozo; Ando, Yukio

    2006-06-01

    Recently, a high prevalence of amyloid A (AA) amyloidosis has been documented among captive cheetahs worldwide. Biochemical analysis of amyloid fibrils extracted from the liver of a Japanese captive cheetah unequivocally showed that protein AA was the main fibril constituent. Further characterization of the AA fibril components by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis revealed three main protein AA bands with approximate molecular weights of 8, 10 and 12 kDa. Mass spectrometry analysis of the 12-kDa component observed in SDS-PAGE and Western blotting confirmed the molecular weight of a 12,381-Da peak. Our finding of a 12-kDa protein AA component provides evidence that the cheetah SAA sequence is longer than the previously reported 90 amino acid residues (approximately 10 kDa), and hence SAA is part of the amyloid fibril.

  3. Are Amyloid Fibrils RNA-Traps? A Molecular Dynamics Perspective

    Directory of Open Access Journals (Sweden)

    Massimiliano Meli

    2018-06-01

    Full Text Available The self-assembly of proteins and peptides into amyloids is a key feature of an increasing number of diseases. Amyloid fibrils display a unique surface reactivity endowing the sequestration of molecules such as MicroRNAs, which can be the active moiety of the toxic action. To test this hypothesis we studied the recognition between a model RNA and two different steric zipper spines using molecular dynamics simulations. We found that the interaction occurs and displays peptide-sequence dependence. Interestingly, interactions with polar zipper surfaces such as the formed by SNQNNF are more stable and favor the formation of β-barrel like complexes resembling the structures of toxic oligomers. These sequence-structure-recognition relationships of the two different assemblies may be exploited for the design of compounds targeting the fibers or competing with RNA-amyloid attachment

  4. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

    KAUST Repository

    Demetrius, Lloyd A.

    2015-01-14

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer\\'s disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

  5. Inclusive Education in Italy: Description and Reflections on Full Inclusion

    Science.gov (United States)

    Anastasiou, Dimitris; Kauffman, James M.; Di Nuovo, Santo

    2015-01-01

    Inclusion of students with disabilities when appropriate is an important goal of special education for students with special needs. Full inclusion, meaning no education for any child in a separate setting, is held to be desirable by some, and Italy is likely the nation with an education system most closely approximating full inclusion on the…

  6. Perforin Promotes Amyloid Beta Internalisation in Neurons.

    Science.gov (United States)

    Lana, Erica; Khanbolouki, Mahbod; Degavre, Charline; Samuelsson, Eva-Britt; Åkesson, Elisabet; Winblad, Bengt; Alici, Evren; Lithner, Christina Unger; Behbahani, Homira

    2017-03-01

    Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ 40 and Aβ 42 were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ 40 (250 nM) compared with Aβ 42 (100 nM). The internalised Aβ 40 showed a dot-like pattern of distribution whereas Aβ 42 accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ 40 and Aβ 42 co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ 40 ) and 50 (Aβ 42 ) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ enters the cells. In addition, the internalisation of Aβ 42 , but not Aβ 40 , was reduced by 55 % by blocking RAGE. Finally, for the first time we showed that pore formation in cell membranes by perforin led to Aβ internalisation in hPCN. Understanding how Aβ is internalised sheds light on the pathological role of Aβ and provides further ideas of inhibitory strategies for preventing Aβ internalisation and the spreading of neurodegeneration in AD.

  7. BETASCAN: probable beta-amyloids identified by pairwise probabilistic analysis.

    Directory of Open Access Journals (Sweden)

    Allen W Bryan

    2009-03-01

    Full Text Available Amyloids and prion proteins are clinically and biologically important beta-structures, whose supersecondary structures are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Recent work has indicated the utility of pairwise probabilistic statistics in beta-structure prediction. We develop here a new strategy for beta-structure prediction, emphasizing the determination of beta-strands and pairs of beta-strands as fundamental units of beta-structure. Our program, BETASCAN, calculates likelihood scores for potential beta-strands and strand-pairs based on correlations observed in parallel beta-sheets. The program then determines the strands and pairs with the greatest local likelihood for all of the sequence's potential beta-structures. BETASCAN suggests multiple alternate folding patterns and assigns relative a priori probabilities based solely on amino acid sequence, probability tables, and pre-chosen parameters. The algorithm compares favorably with the results of previous algorithms (BETAPRO, PASTA, SALSA, TANGO, and Zyggregator in beta-structure prediction and amyloid propensity prediction. Accurate prediction is demonstrated for experimentally determined amyloid beta-structures, for a set of known beta-aggregates, and for the parallel beta-strands of beta-helices, amyloid-like globular proteins. BETASCAN is able both to detect beta-strands with higher sensitivity and to detect the edges of beta-strands in a richly beta-like sequence. For two proteins (Abeta and Het-s, there exist multiple sets of experimental data implying contradictory structures; BETASCAN is able to detect each competing structure as a potential structure variant. The ability to correlate multiple alternate beta-structures to experiment opens the possibility of computational investigation of prion strains and structural heterogeneity of amyloid

  8. Inclusion-Body Myositis: Diagnosis

    Science.gov (United States)

    ... for MDA Blog Donate Search MDA.org Close Inclusion-Body Myositis (IBM) Diagnosis As with other muscle diseases, a doctor diagnoses inclusion-body myositis (IBM) by considering the individual’s personal ...

  9. Stop-and-go kinetics in amyloid fibrillation

    DEFF Research Database (Denmark)

    Ferkinghoff-Borg, Jesper; Fonslet, Jesper; Andersen, Christian Beyschau

    2010-01-01

    Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow in an intermi......Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow...

  10. Native human serum amyloid P component is a single pentamer

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH

    1995-01-01

    Serum amyloid P component (SAP) and C-reactive protein (CRP) are members of the pentraxin protein family. SAP is the precursor protein to amyloid P component present in all forms of amyloidosis. The prevailing notion is that SAP in circulation has the form of a double pentameric molecule (decamer...... by rocket immunoelectrophoresis and electron microscopy. Thus, electron micrographs of purified SAP showed a predominance of decamers. However, the decamer form of SAP reversed to single pentamers when purified SAP was incorporated into SAP-depleted serum....

  11. New fluorescent probes for detection and characterization of amyloid fibrils

    Science.gov (United States)

    Gorbenko, Galyna; Trusova, Valeriya; Kirilova, Elena; Kirilov, Georgiy; Kalnina, Inta; Vasilev, Aleksey; Kaloyanova, Stefka; Deligeorgiev, Todor

    2010-08-01

    The applicability of the novel fluorescent probes, aminoderivative of benzanthrone ABM, squaraine dye SQ-1 and polymethine dye V2 to identification and structural analysis of amyloid fibrils has been evaluated using the lysozyme model system in which fibrillar aggregates have been formed in concentrated ethanol solution. The association constant, binding stoichiometry and molar fluorescence of the bound dye have been determined. ABM was found to surpass classical amyloid marker ThT in the sensitivity to the presence of fibrillar aggregates. Resonance energy transfer measurements involving ABM-SQ-1 and SQ-1-V2 donor-acceptor pairs yielded the limits for fractal-like dimension of lysozyme fibrils.

  12. Financial inclusion: Policies and practices

    OpenAIRE

    Thankom Arun; Rajalaxmi Kamath

    2015-01-01

    As a key enabler for development, financial inclusion is firmly placed on the agenda of most governments as a key policy priority. Against this background, this round table provides a global and regional perspective on the policies and practices of financial inclusion. Using macro data, the collection reveals the diversity in the efforts towards achieving financial inclusion and the need for a progressive approach in financial inclusion. Further to this, the round table provides the regional ...

  13. Removal of inclusions from silicon

    Science.gov (United States)

    Ciftja, Arjan; Engh, Thorvald Abel; Tangstad, Merete; Kvithyld, Anne; Øvrelid, Eivind Johannes

    2009-11-01

    The removal of inclusions from molten silicon is necessary to satisfy the purity requirements for solar grade silicon. This paper summarizes two methods that are investigated: (i) settling of the inclusions followed by subsequent directional solidification and (infiltration by ceramic foam filters. Settling of inclusions followed by directional solidification is of industrial importance for production of low-cost solar grade silicon. Filtration is reported as the most efficient method for removal of inclusions from the top-cut silicon scrap.

  14. Supporting Teachers in Inclusive Education

    Directory of Open Access Journals (Sweden)

    Alekhina S.V.

    2015-03-01

    Full Text Available The article regards the issues of support provision to teachers involved in inclusive education as the main requirement for successful realization of inclusion. The methodological framework used in the study is a resource approach. The article describes the ways of extending the means of supporting teachers. The article also arguments for consolidating all the educators of inclusive schools into inclusive teams equally interested in joint work of administration and educators of intervention programs.

  15. Singing and social inclusion

    Science.gov (United States)

    Welch, Graham F.; Himonides, Evangelos; Saunders, Jo; Papageorgi, Ioulia; Sarazin, Marc

    2014-01-01

    There is a growing body of neurological, cognitive, and social psychological research to suggest the possibility of positive transfer effects from structured musical engagement. In particular, there is evidence to suggest that engagement in musical activities may impact on social inclusion (sense of self and of being socially integrated). Tackling social exclusion and promoting social inclusion are common concerns internationally, such as in the UK and the EC, and there are many diverse Government ministries and agencies globally that see the arts in general and music in particular as a key means by which social needs can be addressed. As part of a wider evaluation of a national, Government-sponsored music education initiative for Primary-aged children in England (“Sing Up”), opportunity was taken by the authors, at the request of the funders, to assess any possible relationship between (a) children's developing singing behavior and development and (b) their social inclusion (sense of self and of being socially integrated). Subsequently, it was possible to match data from n = 6087 participants, drawn from the final 3 years of data collection (2008–2011), in terms of each child's individually assessed singing ability (based on their singing behavior of two well-known songs to create a “normalized singing score”) and their written responses to a specially-designed questionnaire that included a set of statements related to children's sense of being socially included to which the children indicated their level of agreement on a seven-point Likert scale. Data analyses suggested that the higher the normalized singing development rating, the more positive the child's self-concept and sense of being socially included, irrespective of singer age, sex and ethnicity. PMID:25120514

  16. Singing and social inclusion.

    Science.gov (United States)

    Welch, Graham F; Himonides, Evangelos; Saunders, Jo; Papageorgi, Ioulia; Sarazin, Marc

    2014-01-01

    There is a growing body of neurological, cognitive, and social psychological research to suggest the possibility of positive transfer effects from structured musical engagement. In particular, there is evidence to suggest that engagement in musical activities may impact on social inclusion (sense of self and of being socially integrated). Tackling social exclusion and promoting social inclusion are common concerns internationally, such as in the UK and the EC, and there are many diverse Government ministries and agencies globally that see the arts in general and music in particular as a key means by which social needs can be addressed. As part of a wider evaluation of a national, Government-sponsored music education initiative for Primary-aged children in England ("Sing Up"), opportunity was taken by the authors, at the request of the funders, to assess any possible relationship between (a) children's developing singing behavior and development and (b) their social inclusion (sense of self and of being socially integrated). Subsequently, it was possible to match data from n = 6087 participants, drawn from the final 3 years of data collection (2008-2011), in terms of each child's individually assessed singing ability (based on their singing behavior of two well-known songs to create a "normalized singing score") and their written responses to a specially-designed questionnaire that included a set of statements related to children's sense of being socially included to which the children indicated their level of agreement on a seven-point Likert scale. Data analyses suggested that the higher the normalized singing development rating, the more positive the child's self-concept and sense of being socially included, irrespective of singer age, sex and ethnicity.

  17. Singing and social inclusion

    Directory of Open Access Journals (Sweden)

    Graham Frederick Welch

    2014-07-01

    Full Text Available There is a growing body of neurological, cognitive and social psychological research to suggest the possibility of positive transfer effects from structured musical engagement. In particular, there is evidence to suggest that engagement in musical activities may impact on social inclusion (sense of self and of being socially integrated. Tackling social exclusion and promoting social inclusion are common concerns internationally, such as in the UK and the EC, and there are many diverse Government ministries and agencies globally that see the arts in general and music in particular as a key means by which social needs can be addressed. As part of a wider evaluation of a national, Government-sponsored music education initiative for Primary-aged children in England (‘Sing Up’, opportunity was taken by the authors, at the request of the funders, to assess any possible relationship between (a children’s developing singing behaviour and development and (b their social inclusion (sense of self and of being socially integrated. Subsequently, it was possible to match data from n=6087 participants, drawn from the final three years of data collection (2008-2011, in terms of each child’s individually assessed singing ability (based on their singing behaviour of two well-known songs to create a 'normalised singing score' and their written responses to a specially-designed questionnaire that included a set of statements related to children’s sense of being socially included to which the children indicated their level of agreement on a seven-point Likert scale. Data analyses suggested that the higher the normalized singing development rating, the more positive the child’s self-concept and sense of being socially included, irrespective of singer age, sex and ethnicity.

  18. Designing Inclusive Spaces

    DEFF Research Database (Denmark)

    Colfelt, Solvej

    2012-01-01

    CWUAAT -6.TH CAMBRIDGE WORKSHOP – 2012 Designing inclusive systems for real-world applications Abstracht: Denmark has planned huge investments in development in healthcare systems. Nearly 50 billion danish krones has been set aside on the stately budget for this purpose to be spent over the next 10...... hospital complexes ? The article will explore the fundament of wayshowing on the basis of prior research as well as on the basis of the results of a case study in a large existing danish hospital complex. The result points to signage being an inevitable factor but also that it is a factor that is not very...

  19. Inclusion body myositis.

    Science.gov (United States)

    Dimachkie, Mazen M; Barohn, Richard J

    2014-08-01

    The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare disorders that share many similarities. In addition to sporadic inclusion body myositis (IBM), these include dermatomyositis, polymyositis, and autoimmune necrotizing myopathy. IBM is the most common IIM after age 50 years. Muscle histopathology shows endomysial inflammatory exudates surrounding and invading nonnecrotic muscle fibers often accompanied by rimmed vacuoles and protein deposits. It is likely that IBM is has a prominent degenerative component. This article reviews the evolution of knowledge in IBM, with emphasis on recent developments in the field, and discusses ongoing clinical trials. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Designing Inclusive Spaces

    DEFF Research Database (Denmark)

    Colfelt, Solvej

    2012-01-01

    CWUAAT -6.TH CAMBRIDGE WORKSHOP – 2012 Designing inclusive systems for real-world applications Abstracht: Denmark has planned huge investments in development in healthcare systems. Nearly 50 billion danish krones has been set aside on the stately budget for this purpose to be spent over the next 10...... in existing hospital complexes only half the size of these new ones is already recognized as a big problem: How can we avoid the wayfinding-problem of the new complexes to grow to the double with the doubling of the complex size ? What kind of design application can improve the accessibility of future...

  1. Inclusive Education in South Korea

    Science.gov (United States)

    Kim, Yong-Wook

    2014-01-01

    The purpose of this paper is to examine the current implementation of inclusive education in South Korea and discuss its challenges. The history of special education is first described followed by an introduction to policies relevant to special and inclusive education. Next, a critical discussion of the state of inclusive education follows built…

  2. Inclusive Education under Collectivistic Culture

    Science.gov (United States)

    Futaba, Yasuko

    2016-01-01

    This paper addresses how inclusive education under collective culture is possible. Inclusive education, which more-or-less involves changing the current schools, has been denied, doubted or distorted by both policy-makers and practitioners of general and special education in Japan. Main reason for the setback in inclusive education can be…

  3. Neuroinflammation and common mechanism in Alzheimer's disease and prion amyloidosis: amyloid-associated proteins, neuroinflammation and neurofibrillary degeneration

    NARCIS (Netherlands)

    Rozemuller, A.J.M.; Jansen, C.; Carrano, A.; van Haastert, E.S.; Hondius, D.; van der Vies, S.M.; Hoozemans, J.J.M.

    2012-01-01

    Background: In cases with a long (>1 year) clinical duration of prion disease, the prion protein can form amyloid deposits. These cases do not show accumulation of 4-kDa β-amyloid, which is observed in amyloid deposits in Alzheimer's disease (AD). In AD, amyloid is associated with inflammation and

  4. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Weiner, H L; Lemere, C A; Maron, R

    2000-01-01

    Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated ......Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease...... cerebral Abeta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD....

  5. Core cerebrospinal fluid biomarker profile in cerebral amyloid angiopathy: A meta-analysis.

    Science.gov (United States)

    Charidimou, Andreas; Friedrich, Jan O; Greenberg, Steven M; Viswanathan, Anand

    2018-02-27

    To perform a meta-analysis of 4 core CSF biomarkers (β-amyloid [Aβ]42, Aβ40, total tau [t-tau], and phosphorylated tau [p-tau]) to assess which of these are most altered in sporadic cerebral amyloid angiopathy (CAA). We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting amyloid precursor protein metabolism (Aβ42, Aβ40), neurodegeneration (t-tau), and tangle pathology (p-tau) in symptomatic sporadic CAA cohorts vs controls and patients with Alzheimer disease (AD). Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations: (1) in patients with CAA vs healthy controls and (2) in patients with CAA vs patients with AD. RoM >1 indicates higher biomarker concentration in patients with CAA vs comparison population and RoM <1 indicates higher concentration in comparison groups. Three studies met inclusion criteria. These comprised 5 CAA patient cohorts (n = 59 patients) vs healthy controls (n = 94 cases) and AD cohorts (n = 158). Three core biomarkers differentiated CAA from controls: CSF Aβ42 (RoM 0.49, 95% confidence interval [CI] 0.38-0.64, p < 0.003), Aβ40 (RoM 0.70, 95% CI 0.63-0.78, p < 0.0001), and t-tau (RoM 1.54, 95% CI 1.15-2.07, p = 0.004); p-tau was marginal (RoM 1.24, 95% CI 0.99-1.54, p = 0.062). Differentiation between CAA and AD was strong for CSF Aβ40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001), but not Aβ42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For t-tau and p-tau, average CSF ratios in patients with CAA vs patients with AD were 0.63 (95% CI 0.54-0.74, p < 0.0001) and 0.60 (95% CI 0.50-0.71, p < 0.0001), respectively. Specific CSF patterns of Aβ42, Aβ40, t-tau, and p-tau might serve as molecular biomarkers of CAA, but analyses in larger CAA cohorts are needed. © 2018 American Academy of Neurology.

  6. Financial inclusion: Policies and practices

    Directory of Open Access Journals (Sweden)

    Thankom Arun

    2015-12-01

    Full Text Available As a key enabler for development, financial inclusion is firmly placed on the agenda of most governments as a key policy priority. Against this background, this round table provides a global and regional perspective on the policies and practices of financial inclusion. Using macro data, the collection reveals the diversity in the efforts towards achieving financial inclusion and the need for a progressive approach in financial inclusion. Further to this, the round table provides the regional perspectives on the policies and practices of financial inclusion in India, South Africa, and Australia.

  7. Establishing and validating the fluorescent amyloid ligand h-FTAA (heptamer formyl thiophene acetic acid) to identify transthyretin amyloid deposits in carpal tunnel syndrome.

    Science.gov (United States)

    Hahn, Katharina; Nilsson, K Peter R; Hammarström, Per; Urban, Peter; Meliss, Rolf Rüdiger; Behrens, Hans-Michael; Krüger, Sandra; Röcken, Christoph

    2017-06-01

    Transthyretin-derived (ATTR) amyloidosis is a frequent finding in carpal tunnel syndrome. We tested the following hypotheses: the novel fluorescent amyloid ligand heptameric formic thiophene acetic acid (h-FTAA) has a superior sensitivity for the detection of amyloid compared with Congo red-staining; Amyloid load correlates with patient gender and/or patient age. We retrieved 208 resection specimens obtained from 184 patients with ATTR amyloid in the carpal tunnel. Serial sections were stained with Congo red, h-FTAA and an antibody directed against transthyretin (TTR). Stained sections were digitalized and forwarded to computational analyses. The amount of amyloid was correlated with patient demographics. Amyloid stained intensely with h-FTAA and an anti-TTR-antibody. Congo red-staining combined with fluorescence microscopy was significantly less sensitive than h-FTAA-fluorescence and TTR-immunostaining: the highest percentage area was found in TTR-immunostained sections, followed by h-FTAA and Congo red. The Pearson correlation coefficient was .8 (Congo red vs. h-FTAA) and .9 (TTR vs. h-FTAA). Amyloid load correlated with patient gender, anatomical site and patient age. h-FTAA is a highly sensitive method to detect even small amounts of ATTR amyloid in the carpal tunnel. The staining protocol is easy and h-FTAA may be a much more sensitive procedure to detect amyloid at an earlier stage.

  8. Kinetics of human serum amyloid A

    International Nuclear Information System (INIS)

    Rosenthal, C.J.; Martin, M.E.; Solomon, N.

    1986-01-01

    In order to better understand the pathogenetic role of serum amyloid A (SAA) we studied the kinetics of 131 I radiolabelled pure SAA, extracted from 400 ml serum of a human volunteer. 50 microCi of 131 I SAA and 15 microCi 125 I labelled sodium iodide were administered i.v. on two occasions at 6 month intervals. Serum and plasma samples were collected at 10-20 min intervals x 10, then once daily x 10; lymphocytes were separated from monocytes and granulocytes. Counts per minute of 131 I and 125 I were measured in each sample in the serum, in serum precipitates resulting after addition of a rabbit anti-SAA antibody and of TCA and in various cell subpopulations as well as in the whole urine and TCA precipitated urine from each micturition. The 131 I disappearance curves from the plasma and serum precipitates were semilogarithmically plotted; cumulative 131 I cpm in plasma, cells and urine at various intervals were determined. Body scanning was performed at 2, 16, and 48 h. The results of the two experiments were very similar. The curve of 131 I SAA in plasma TCA precipitates indicated the existence of 4 compartments likely due to uptake of 131 I SAA by some plasma proteins, circulating cells and other tissues; later release from tissues started at 6 h. The 131 I SAA half-life time in these compartments was found to be 35, 170, 255, and 550 min, respectively. Tissue binding of 131 I was also suggested by a rising of the 125 I: 131 I ratio with time and by a 26% release of 131 I in the urine at 15 h which could not account for its plasma disappearance. Scanning, except for 131 I uptake in the spleen at 2 h likely due to blood activity, showed no organ concentration. 92% of the injected 131 I was found in the urine but only 6.2% of 131 I SAA was accounted for in urine precicipitates

  9. Beta-amyloid, cholinergní neurony a Alzheimerova choroba

    Czech Academy of Sciences Publication Activity Database

    Kašparová, Jana; Doležal, Vladimír

    2002-01-01

    Roč. 51, č. 2 (2002), s. 82-94 ISSN 0009-0557 R&D Projects: GA MZd NF5183; GA ČR GA305/01/0283 Institutional research plan: CEZ:AV0Z5011922 Keywords : Alzheimer 's disease * beta-amyloid * cholinergic neurons Subject RIV: FR - Pharmacology ; Medidal Chemistry

  10. Effects of diet-induced hypercholesterolemia on amyloid ...

    Indian Academy of Sciences (India)

    2012-10-27

    Oct 27, 2012 ... A central hypothesis in the study of Alzheimer's disease (AD) is the accumulation and aggregation of β-amyloid ... protein (APP) and estrogen has been implicated in the pre- .... inant in HCL in the intensity of the expression was lower ..... estrogen replacement therapy of the Women's Health Initiative.

  11. Elasticity in Physically Cross-Linked Amyloid Fibril Networks

    Science.gov (United States)

    Cao, Yiping; Bolisetty, Sreenath; Adamcik, Jozef; Mezzenga, Raffaele

    2018-04-01

    We provide a constitutive model of semiflexible and rigid amyloid fibril networks by combining the affine thermal model of network elasticity with the Derjaguin-Landau-Vervey-Overbeek (DLVO) theory of electrostatically charged colloids. When compared to rheological experiments on β -lactoglobulin and lysozyme amyloid networks, this approach provides the correct scaling of elasticity versus both concentration (G ˜c2.2 and G ˜c2.5 for semiflexible and rigid fibrils, respectively) and ionic strength (G ˜I4.4 and G ˜I3.8 for β -lactoglobulin and lysozyme, independent from fibril flexibility). The pivotal role played by the screening salt is to reduce the electrostatic barrier among amyloid fibrils, converting labile physical entanglements into long-lived cross-links. This gives a power-law behavior of G with I having exponents significantly larger than in other semiflexible polymer networks (e.g., actin) and carrying DLVO traits specific to the individual amyloid fibrils.

  12. Visuospatial Functioning in Cerebral Amyloid Angiopathy : A Pilot Study

    NARCIS (Netherlands)

    Valenti, Raffaella; Charidimou, Andreas; Xiong, Li; Boulouis, Gregoire; Fotiadis, Panagiotis; Ayres, Alison; Riley, Grace; Kuijf, Hugo J.; Reijmer, Yael D.; Pantoni, Leonardo; Gurol, M. Edip; Davidsdottir, Sigurros; Greenberg, Steven M.; Viswanathan, Anand

    2017-01-01

    Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitive

  13. Renal amyloid A amyloidosis as a complication of hidradenitis suppurativa

    DEFF Research Database (Denmark)

    Schandorff, Kristine D; Miller, Iben M; Krustrup, Dorrit

    2016-01-01

    Rheumatic disease is the dominant cause of amyloid A (AA) amyloidosis, but other chronic inflammatory diseases may have similar consequences. Hidradenitis suppurativa (HS) is a relatively common, but little known skin disease characterized by chronic inflammation. Here we present a case of chronic...

  14. Two-Step Amyloid Aggregation: Sequential Lag Phase Intermediates

    Science.gov (United States)

    Castello, Fabio; Paredes, Jose M.; Ruedas-Rama, Maria J.; Martin, Miguel; Roldan, Mar; Casares, Salvador; Orte, Angel

    2017-01-01

    The self-assembly of proteins into fibrillar structures called amyloid fibrils underlies the onset and symptoms of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. However, the molecular basis and mechanism of amyloid aggregation are not completely understood. For many amyloidogenic proteins, certain oligomeric intermediates that form in the early aggregation phase appear to be the principal cause of cellular toxicity. Recent computational studies have suggested the importance of nonspecific interactions for the initiation of the oligomerization process prior to the structural conversion steps and template seeding, particularly at low protein concentrations. Here, using advanced single-molecule fluorescence spectroscopy and imaging of a model SH3 domain, we obtained direct evidence that nonspecific aggregates are required in a two-step nucleation mechanism of amyloid aggregation. We identified three different oligomeric types according to their sizes and compactness and performed a full mechanistic study that revealed a mandatory rate-limiting conformational conversion step. We also identified the most cytotoxic species, which may be possible targets for inhibiting and preventing amyloid aggregation.

  15. Rational heterodoxy: cholesterol reformation of the amyloid doctrine.

    Science.gov (United States)

    Castello, Michael A; Soriano, Salvador

    2013-01-01

    According to the amyloid cascade hypothesis, accumulation of the amyloid peptide Aβ, derived by proteolytic processing from the amyloid precursor protein (APP), is the key pathogenic trigger in Alzheimer's disease (AD). This view has led researchers for more than two decades and continues to be the most influential model of neurodegeneration. Nevertheless, close scrutiny of the current evidence does not support a central pathogenic role for Aβ in late-onset AD. Furthermore, the amyloid cascade hypothesis lacks a theoretical foundation from which the physiological generation of Aβ can be understood, and therapeutic approaches based on its premises have failed. We present an alternative model of neurodegeneration, in which sustained cholesterol-associated neuronal distress is the most likely pathogenic trigger in late-onset AD, directly causing oxidative stress, inflammation and tau hyperphosphorylation. In this scenario, Aβ generation is part of an APP-driven adaptive response to the initial cholesterol distress, and its accumulation is neither central to, nor a requirement for, the initiation of the disease. Our model provides a theoretical framework that places APP as a regulator of cholesterol homeostasis, accounts for the generation of Aβ in both healthy and demented brains, and provides suitable targets for therapeutic intervention. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Amyloid-β positron emission tomography imaging probes

    DEFF Research Database (Denmark)

    Kepe, Vladimir; Moghbel, Mateen C; Långström, Bengt

    2013-01-01

    , a number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate...

  17. Raman optical activity study on insulin amyloid- and prefibril intermediate

    Czech Academy of Sciences Publication Activity Database

    Yamamoto, Shigeki; Watarai, H.

    2012-01-01

    Roč. 24, č. 2 (2012), s. 97-103 ISSN 0899-0042 Institutional research plan: CEZ:AV0Z40550506 Keywords : raman optical activity * amyloid * fibril * intermediate * insulin Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 1.718, year: 2012

  18. Aggregation properties of a short peptide that mediates amyloid fibril ...

    Indian Academy of Sciences (India)

    Short peptides have been identified from amyloidogenic proteins that form amyloid fibrils in isolation. The ... proteins. These peptide fibrils have the conformational features of β-structure that .... water and immediately deposited on freshly cleaved surface of mica .... with the peptide via electrostatic interactions. NaCl would.

  19. Quantification of amyloid-beta 40 in cerebrospinal fluid

    NARCIS (Netherlands)

    Verwey, N.A.; Veerhuis, R.; Twaalfhoven, H.A.M.; Wouters, D.; Hoozemans, J.J.M.; Bollen, Y.J.M.; Killestein, J.; Bibl, M.; Wiltfang, J.; Hack, C.E.; Scheltens, P.; Blankenstein, M.A.

    2009-01-01

    Background: Truncated forms and full-length forms of the amyloid-beta 40 (Aβ40) are key molecules in the pathogenesis of dementia, and are detectable in CSF. Reliable methods to detect these biomarkers in CSF are of great importance for understanding the disease mechanisms and for diagnostic

  20. INCLUSION BODY MYOSITIS

    Directory of Open Access Journals (Sweden)

    Luh Yeni Laksmini

    2014-09-01

    Full Text Available Inclusion body myositis (IBM merupakan penyakit inflamasi pada otot yang bersifat progresif dengan penyebab yang tidak diketahui dan tidak menunjukkan respon yang baik terhadap berbagai terapi. Gambaran histopatologi IBM ditandai dengan infiltrat sel-sel limfosit diantara ruangan endomisial, di dalam otot dan di sekitar otot dengan fokus-fokus inklusi di dalam miosit (rimmed vacuole serta beberapa serat otot terlihat atrofi dan nekrosis. Dilaporkan wanita, usia 46 tahun dengan IBM. Keluhan utama pasien berupa kelemahan pada kedua tangan, kaki kanan terasa berat jika diangkat sehingga susah berjalan. Pemeriksaan saraf sensorik ekstremitas dekstra dan sinistra dalam batas normal. Pemeriksaan enzim cretinine kinase meningkat secara dramatik. Pemeriksaan histopatologi dari biospi otot gastrocnemius menunjukkan gambaran yang sesuai untuk IBM dan telah dilakukan penanganan dengan pemberian oral methilprednisolon 3x32 mg dan mecobalmin 1x500ìg intravena, namun tidak menunjukkan respon yang baik terhadap terapi dan akhirnya pasien meninggal. [MEDICINA 2013;44:118-123].

  1. IPads in Inclusive Classrooms

    DEFF Research Database (Denmark)

    Meyer, Bente Tobiesen

    2015-01-01

    This paper builds on data from a research project where iPads were used in a lower secondary school in Denmark to support school development and inclusive learning environments. The paper explores how iPads enter into and work as part of an ecology of learning resources in five classes in lower...... secondary school. I conceptualize the systems of related technologies observed in this school as ecologies of learning resources as they present themselves as carefully balanced systems in which educational resources circulate in different ways that make sense for learners’ needs. Inspired by Actor...... in by pupils the paper argues that we should disengage approaches to the iPad in education from ideas of what the properties of these technologies are, and see the device as a more relational and situated actor, avoiding the definition of properties of technologies outside the contexts specific to their use....

  2. Between psychopathology and inclusion

    DEFF Research Database (Denmark)

    Hedegaard-Sørensen, Lotte; Hamre, Bjørn Frithiof

    2017-01-01

    and social pedagogy. We thus enquire into how the rise of diagnostics and medicalisation affects our understanding of children’s difficulties. We discuss a paradox that is present in Denmark and other countries. As educational policies emphasise inclusion, the field of schooling experiences a huge rise......This article reports on a Danish study on interprofessional collaboration between child psychiatrists and educational psychologists concerning children who are categorised as being at risk. Methodologically, the analysis is grounded in qualitative interviews with psychologists. A Foucauldian...... approach is applied to narratives and experiences that occur within these interviews concerning external collaboration with child psychiatrists. The article is informed by the research tradition that has problematised the significance of psychiatry and diagnoses in the field of special needs education...

  3. Patterns of inclusion

    DEFF Research Database (Denmark)

    Pedersen, Alex Young; Nørgård, Rikke Toft; Köppe, Christian

    2018-01-01

    Reconsidering the concept of digital citizenship and the essential component of education the authors propose that the concept of Hybrid Education may serve both as a guideline for the utilization of digital technologies in education and as a methodology for fostering new forms of participation......, inclusion and engagement in society. Following T.H. Marshall’s conception of citizenship the authors suggest that becoming, belonging and the capabilities to do so is essential to digital citizenship in a culturally diverse and digitally mediated world. The paper presents a theory-based, value driven...... for Hybrid Education that are directly applicable in relation to the concept of digital citizenship. The process introduces a value-based and vision-driven design pattern approach to innovation in education by framing and aligning values and visions of the participants. This work resulted in approximately 85...

  4. Autonomy, Independence, Inclusion

    Directory of Open Access Journals (Sweden)

    Filippo Angelucci

    2015-04-01

    Full Text Available The living environment must not only meet the primary needs of living, but also the expectations of improvement of life and social relations and people’s work. The need for a living environment that responds to the needs of users with their different abilities, outside of standardizations, is increasingly felt as autonomy, independence and well-being are the result of real usability and adaptability of the spaces. The project to improve the inclusivity of living space and to promote the rehabilitation of fragile users need to be characterized as an interdisciplinary process in which the integration of specialized contributions leads to adaptive customization of space solutions and technological that evolve with the changing needs, functional capacities and abilities of individuals.

  5. Approaching Inclusion as Social Practice: Processes of Inclusion and Exclusion

    DEFF Research Database (Denmark)

    Molbæk, Mette; Hansen, Janne Hedegaard; Lassen, Mikkel

    2018-01-01

    The article presents the results of a review of international research investigating mechanisms and processes of inclusion and exclusion as an ongoing part of social practice in a school context. The review forms part of a research project investigating the social practices of inclusive education...... in primary and lower-secondary education (age 6–16) in public schools as constituted by processes of inclusion and exclusion. The project aims to shift the scientific focus of research in inclusive education from the development of pedagogical and didactic practice to the importance of community construction...... through inclusion and exclusion processes. The project arises in context of Danish education policy, while the review looked for international research findings on the limits between inclusion and exclusion: how they are drawn, by whom, for what reasons, and for whose benefit? On the background...

  6. Inclusive Business - What It Is All About? Managing Inclusive Companies

    Directory of Open Access Journals (Sweden)

    Tea Golja

    2012-01-01

    Full Text Available Following the challenges we face today, the inclusive business models are future business models through which the Millennium Development Goals can be fostered and strengthen. These are the models which, through their strategic orientation on inclusivity, include low income communities in their value chain. This can be done through combining variety of strategies which all have two common points – recognition of stakeholders and adjustment of the product to the target market. The paper presents the analysis of inclusive markets. Hence, the research results show the dispersion of inclusive businesses worldwide, type of the organization, sector coverage, and contribution to MDGs as well as the particular way of inclusion of low income communities in their value chain. The aim is to present how inclusive business benefits not only the low income societies, but the companies that operate in this way as well.

  7. Ultrafast Hydrogen-Bonding Dynamics in Amyloid Fibrils.

    Science.gov (United States)

    Pazos, Ileana M; Ma, Jianqiang; Mukherjee, Debopreeti; Gai, Feng

    2018-06-08

    While there are many studies on the subject of hydrogen bonding dynamics in biological systems, few, if any, have investigated this fundamental process in amyloid fibrils. Herein, we seek to add insight into this topic by assessing the dynamics of a hydrogen bond buried in the dry interface of amyloid fibrils. To prepare a suitable model peptide system for this purpose, we introduce two mutations into the amyloid-forming Aβ(16-22) peptide. The first one is a lysine analog at position 19, which is used to help form structurally homogeneous fibrils, and the second one is an aspartic acid derivative (DM) at position 17, which is intended (1) to be used as a site-specific infrared probe and (2) to serve as a hydrogen-bond acceptor to lysine so that an inter-β-sheet hydrogen bond can be formed in the fibrils. Using both infrared spectroscopy and atomic force microscopy, we show that (1) this mutant peptide indeed forms well defined fibrils, (2) when bulk solvent is removed, there is no detectable water present in the fibrils, (3) infrared results obtained with the DM probe are consistent with a protofibril structure that is composed of two antiparallel β-sheets stacked in a parallel fashion, leading to formation of the expected hydrogen bond. Using two-dimensional infrared spectroscopy, we further show that the dynamics of this hydrogen bond occur on a timescale of ~2.3 ps, which is attributed to the rapid rotation of the -NH3+ group of lysine around its Cε-Nζ bond. Taken together, these results suggest that (1) DM is a useful infrared marker in facilitating structure determination of amyloid fibrils and (2) even in the tightly packed core of amyloid fibrils certain amino acid sidechains can undergo ultrafast motions, hence contributing to the thermodynamic stability of the system.

  8. Surface Mediated Self-Assembly of Amyloid Peptides

    Science.gov (United States)

    Fakhraai, Zahra

    2015-03-01

    Amyloid fibrils have been considered as causative agents in many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes and amyloidosis. Amyloid fibrils form when proteins or peptides misfold into one dimensional crystals of stacked beta-sheets. In solution, amyloid fibrils form through a nucleation and growth mechanism. The rate limiting nucleation step requires a critical concentration much larger than those measured in physiological conditions. As such the exact origins of the seeds or oligomers that result in the formation of fully mature fibrils in the body remain topic intense studies. It has been suggested that surfaces and interfaces can enhance the fibrillization rate. However, studies of the mechanism and kinetics of the surface-mediated fibrillization are technologically challenging due to the small size of the oligomer and protofibril species. Using smart sample preparation technique to dry the samples after various incubation times we are able to study the kinetics of fibril formation both in solution and in the vicinity of various surfaces using high-resolution atomic force microscopy. These studies elucidate the role of surfaces in catalyzing amyloid peptide formation through a nucleation-free process. The nucleation free self-assembly is rapid and requires much smaller concentrations of peptides or proteins. We show that this process resembles diffusion limited aggregation and is governed by the peptide adhesion rate, two -dimensional diffusion of the peptides on the surface, and preferential interactions between the peptides. These studies suggest an alternative pathway for amyloid formation may exist, which could lead to new criteria for disease prevention and alternative therapies. Research was partially supported by a seed grant from the National Institute of Aging of the National Institutes of Health (NIH) under Award Number P30AG010124 (PI: John Trojanowski) and the University of Pennsylvania.

  9. Amyloid and tau cerebrospinal fluid biomarkers in HIV infection

    Directory of Open Access Journals (Sweden)

    Rosengren Lars

    2009-12-01

    Full Text Available Abstract Background Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF biomarkers related of amyloid and tau metabolism in HIV-infected patients. Methods In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ, amyloid beta fragment 1-42 (Aβ1-42, and total and hyperphosphorylated tau (t-tau and p-tau in CSF of 86 HIV-infected (HIV+ subjects, including 21 with AIDS dementia complex (ADC, 25 with central nervous system (CNS opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV- subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease. Results CSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections. Conclusions Parallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those

  10. Pollution monitoring of coastal and estuarine areas: 1. Bacterial indicators along the south Gujarat Coast

    Digital Repository Service at National Institute of Oceanography (India)

    Mohandass, C.; Nair, S.; Achuthankutty, C.T.; LokaBharathi, P.A.

    . Total coliforms and total vibrios were retrieved in 27 and 55 % of the samples. The validity of these bacterial groups as water quality indicators is discussed with statistical relations. It is sugested that inclusion of these groups could be made...

  11. Differential regulation of amyloid precursor protein sorting with pathological mutations results in a distinct effect on amyloid-β production.

    Science.gov (United States)

    Lin, Yen-Chen; Wang, Jia-Yi; Wang, Kai-Chen; Liao, Jhih-Ying; Cheng, Irene H

    2014-11-01

    The deposition of amyloid-β (Aβ) peptide, which is generated from amyloid precursor protein (APP), is the pathological hallmark of Alzheimer's disease (AD). Three APP familial AD mutations (D678H, D678N, and H677R) located at the sixth and seventh amino acid of Aβ have distinct effect on Aβ aggregation, but their influence on the physiological and pathological roles of APP remain unclear. We found that the D678H mutation strongly enhances amyloidogenic cleavage of APP, thus increasing the production of Aβ. This enhancement of amyloidogenic cleavage is likely because of the acceleration of APPD678H sorting into the endosomal-lysosomal pathway. In contrast, the APPD678N and APPH677R mutants do not cause the same effects. Therefore, this study indicates a regulatory role of D678H in APP sorting and processing, and provides genetic evidence for the importance of APP sorting in AD pathogenesis. The internalization of amyloid precursor protein (APP) increases its opportunity to be processed by β-secretase and to produce Amyloid-β (Aβ) that causes Alzheimer's disease (AD). We report a pathogenic APPD678H mutant that enhances APP internalization into the endosomal-lysosomal pathway and thus promotes the β-secretase cleavage and Aβ production. This study provides genetic evidence for the importance of APP sorting in AD pathogenesis. © 2014 International Society for Neurochemistry.

  12. secHsp70 as a tool to approach amyloid-β42 and other extracellular amyloids.

    Science.gov (United States)

    De Mena, Lorena; Chhangani, Deepak; Fernandez-Funez, Pedro; Rincon-Limas, Diego E

    2017-07-03

    Self-association of amyloidogenic proteins is the main pathological trigger in a wide variety of neurodegenerative disorders. These aggregates are deposited inside or outside the cell due to hereditary mutations, environmental exposures or even normal aging. Cumulative evidence indicates that the heat shock chaperone Hsp70 possesses robust neuroprotection against various intracellular amyloids in Drosophila and mouse models. However, its protective role against extracellular amyloids was largely unknown as its presence outside the cells is very limited. Our recent manuscript in PNAS revealed that an engineered form of secreted Hsp70 (secHsp70) is highly protective against toxicity induced by extracellular deposition of the amyloid-β42 (Aβ42) peptide. In this Extra View article, we extend our analysis to other members of the heat shock protein family. We created PhiC31-based transgenic lines for human Hsp27, Hsp40, Hsp60 and Hsp70 and compared their activities in parallel against extracellular Aβ42. Strikingly, only secreted Hsp70 exhibits robust protection against Aβ42-triggered toxicity in the extracellular milieu. These observations indicate that the ability of secHsp70 to suppress Aβ42 insults is quite unique and suggest that targeted secretion of Hsp70 may represent a new therapeutic approach against Aβ42 and other extracellular amyloids. The potential applications of this engineered chaperone are discussed.

  13. Mouse senile amyloid fibrils deposited in skeletal muscle exhibit amyloidosis-enhancing activity.

    Directory of Open Access Journals (Sweden)

    Jinze Qian

    2010-05-01

    Full Text Available Amyloidosis describes a group of protein folding diseases in which amyloid proteins are abnormally deposited in organs and/or tissues as fine fibrils. Mouse senile amyloidosis is a disorder in which apolipoprotein A-II (apoA-II deposits as amyloid fibrils (AApoAII and can be transmitted from one animal to another both by the feces and milk excreted by mice with amyloidosis. Thus, mouse AApoAII amyloidosis has been demonstrated to be a "transmissible disease". In this study, to further characterize the transmissibility of amyloidosis, AApoAII amyloid fibrils were injected into transgenic Apoa2(cTg(+/- and normal R1.P1-Apoa2(c mice to induce AApoAII systemic amyloidosis. Two months later, AApoAII amyloid deposits were found in the skeletal muscles of amyloid-affected mice, primarily in the blood vessels and in the interstitial tissues surrounding muscle fibers. When amyloid fibrils extracted from the skeletal muscles were subjected to Western blot analysis, apoA-II was detected. Amyloid fibril fractions isolated from the muscles not only demonstrated the structure of amyloid fibrils but could also induce amyloidosis in young mice depending on its fibril conformation. These findings present a possible pathogenesis of amyloidosis: transmission of amyloid fibril conformation through muscle, and shed new light on the etiology involved in amyloid disorders.

  14. The molecular mass of dextran used to modify magnetite nanoparticles affects insulin amyloid aggregation

    Energy Technology Data Exchange (ETDEWEB)

    Siposova, Katarina [Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Kosice (Slovakia); Pospiskova, Kristyna [Regional Centre of Advanced Technologies and Materials, Palacky University, Olomouc (Czech Republic); Bednarikova, Zuzana [Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Kosice (Slovakia); Department of Biochemistry, Faculty of Science, Safarik University, Kosice (Slovakia); Safarik, Ivo [Regional Centre of Advanced Technologies and Materials, Palacky University, Olomouc (Czech Republic); Department of Nanobiotechnology, Biology Centre, ISB, CAS, Ceske Budejovice (Czech Republic); Safarikova, Mirka [Department of Nanobiotechnology, Biology Centre, ISB, CAS, Ceske Budejovice (Czech Republic); Kubovcikova, Martina; Kopcansky, Peter [Department of Magnetism, Institute of Experimental Physics, Slovak Academy of Sciences, Kosice (Slovakia); Gazova, Zuzana, E-mail: gazova@saske.sk [Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Kosice (Slovakia)

    2017-04-01

    Protein transformation from its soluble state into amyloid aggregates is associated with amyloid-related diseases. Amyloid deposits of insulin fibrils have been found in the sites of subcutaneous insulin application in patients with prolonged diabetes. Using atomic force microscopy and ThT fluorescence assay we have investigated the interference of insulin amyloid aggregation with superparamagnetic Fe{sub 3}O{sub 4}-based nanoparticles (SPIONs) coated with dextran (DEX); molecular mass of dextran was equal to 15–20, 40 or 70 kDa. The obtained data indicate that all three types of dextran coated nanoparticles (NP-FeDEXs) are able to inhibit insulin fibrillization and to destroy amyloid fibrils. The extent of anti-amyloid activities depends on the properties of NP-FeDEXs, mainly on the size of nanoparticles which is determined by molecular mass of dextran molecules. The most effective inhibiting activity was observed for the smallest nanoparticles coated with 15–20 kDa dextran. Contrary, the highest destroying activity was observed for the largest NP-FeDEX (70 kDa dextran). - Highlights: • Interference of dextran- magnetite nanoparticles with insulin amyloid aggregation. • Nanoparticles inhibited insulin fibrillization and depolymerized insulin amyloid fibrils. • Size of nanoparticles significantly influences their anti-amyloid activities. • The most effective inhibition of insulin amyloid fibrillization was detected for the smallest nanoparticles. • Contrary, DC{sub 50} values decreased with increasing size of nanoparticles.

  15. The molecular mass of dextran used to modify magnetite nanoparticles affects insulin amyloid aggregation

    International Nuclear Information System (INIS)

    Siposova, Katarina; Pospiskova, Kristyna; Bednarikova, Zuzana; Safarik, Ivo; Safarikova, Mirka; Kubovcikova, Martina; Kopcansky, Peter; Gazova, Zuzana

    2017-01-01

    Protein transformation from its soluble state into amyloid aggregates is associated with amyloid-related diseases. Amyloid deposits of insulin fibrils have been found in the sites of subcutaneous insulin application in patients with prolonged diabetes. Using atomic force microscopy and ThT fluorescence assay we have investigated the interference of insulin amyloid aggregation with superparamagnetic Fe 3 O 4 -based nanoparticles (SPIONs) coated with dextran (DEX); molecular mass of dextran was equal to 15–20, 40 or 70 kDa. The obtained data indicate that all three types of dextran coated nanoparticles (NP-FeDEXs) are able to inhibit insulin fibrillization and to destroy amyloid fibrils. The extent of anti-amyloid activities depends on the properties of NP-FeDEXs, mainly on the size of nanoparticles which is determined by molecular mass of dextran molecules. The most effective inhibiting activity was observed for the smallest nanoparticles coated with 15–20 kDa dextran. Contrary, the highest destroying activity was observed for the largest NP-FeDEX (70 kDa dextran). - Highlights: • Interference of dextran- magnetite nanoparticles with insulin amyloid aggregation. • Nanoparticles inhibited insulin fibrillization and depolymerized insulin amyloid fibrils. • Size of nanoparticles significantly influences their anti-amyloid activities. • The most effective inhibition of insulin amyloid fibrillization was detected for the smallest nanoparticles. • Contrary, DC 50 values decreased with increasing size of nanoparticles.

  16. Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jiliang; Costantino, Isabel; Venugopalan, Nagarajan; Fischetti, Robert F.; Hyman, Bradley; Frosch, Matthew; Gomez-Isla, Teresa; Makowski, Lee

    2016-09-15

    Although aggregation of Aβ amyloid fibrils into plaques in the brain is a hallmark of Alzheimer's Disease (AD), the correlation between amyloid burden and severity of symptoms is weak. One possible reason is that amyloid fibrils are structurally polymorphic and different polymorphs may contribute differentially to disease. However, the occurrence and distribution of amyloid polymorphisms in human brain is poorly documented. Here we seek to fill this knowledge gap by using X-ray microdiffraction of histological sections of human tissue to map the abundance, orientation and structural heterogeneities of amyloid within individual plaques; among proximal plaques and in subjects with distinct clinical histories. A 5 µ x-ray beam was used to generate diffraction data with each pattern arising from a scattering volume of only ~ 450 µ3 , making possible collection of dozens to hundreds of diffraction patterns from a single amyloid plaque. X-ray scattering from these samples exhibited all the properties expected for scattering from amyloid. Amyloid distribution was mapped using the intensity of its signature 4.7 Å reflection which also provided information on the orientation of amyloid fibrils across plaques. Margins of plaques exhibited a greater degree of orientation than cores and orientation around blood vessels frequently appeared tangential. Variation in the structure of Aβ fibrils is reflected in the shape of the 4.7 Å peak which usually appears as a doublet. Variations in this peak correspond to differences between the structure of amyloid within cores of plaques and at their periphery. Examination of tissue from a mismatch case - an individual with high plaque burden but no overt signs of dementia at time of death - revealed a diversity of structure and spatial distribution of amyloid that is distinct from typical AD cases. We demonstrate the existence of structural polymorphisms among amyloid within and among plaques of a single individual and suggest

  17. Inclusion in a Polarised World

    OpenAIRE

    Freeman, Alan

    2005-01-01

    This paper on inclusion was presented to the at the 2005 summer school of DEEEP (Development Education Exchange in Europe Project), Härnösand - Sweden, 5 - 12 June 2005. It addresses the significance of the concept of world civilisation. It assesses how meaning may be attached to the concept of inclusion in an economically polarised world. It develops a critique of the conception of economic inclusion, by means of an exploration of linguistic inclusion and the notion of ‘disability’. ‘...

  18. Multiple Myeloma Presenting as Massive Amyloid Deposition in a Parathyroid Gland Associated with Amyloid Goiter: A Medullary Thyroid Carcinoma Mimic on Intra-operative Frozen Section.

    Science.gov (United States)

    Hill, Kirk; Diaz, Jason; Hagemann, Ian S; Chernock, Rebecca D

    2018-06-01

    Clinical examples of amyloid deposition in parathyroid glands are exceedingly rare and usually present as an incidental finding in a patient with amyloid goiter. Here, we present the first histologically documented case of parathyroid amyloid deposition that presented as a mass. The patient did not have hyperparathyroidism. The parathyroid gland was submitted for intra-operative frozen section and concern for medullary thyroid carcinoma was raised. An important histologic clue arguing against medullary thyroid carcinoma was the evenly dispersed nature of the amyloid. Histologic perinuclear clearing and parathyroid hormone immunohistochemistry confirmed parathyroid origin on permanent sections. The patient was also found to have associated amyloid goiter. Mass spectrometry of the amyloid showed it to be composed of kappa light chains. On further work-up, the patient was diagnosed with multiple myeloma. Awareness of parathyroid amyloid deposition is important as it is a histologic mimic of medullary thyroid carcinoma, especially on frozen section. Amyloid typing with evaluation for multiple myeloma in any patient with kappa or lambda light chain restriction is also important.

  19. Accessibility and inclusion informational

    Directory of Open Access Journals (Sweden)

    Mônica Sena de Souza

    2013-06-01

    Full Text Available Introduction: Discusses the role of information professionals in meeting the informational demands of people with disabilities in the information society. The librarian is crucial for the effectiveness and success in the informational inclusion of people with disabilities, considering also continuing education for their professional qualification.Objective: To provide reflections on the role of the librarian in serving users with disabilities, highlighting the need for improvement in information units, identified in the scientific literature with regard to accessibility.Methodology: Literature search, based on a review of literature in books and scientific papers, highlighting the main authors: Adams (2000, Mazzoni (2001 and Sassaki (1997, 2002, 2005.Results: The lack of informational access for people with disabilities hampers their social and political participation, hence, reduces its condition of citizenship.Conclusion: The librarian responsible for seeking continuing education, greater involvement in the events of the area and the constant search for job training, which will reflect on the best service the information needs of users with disabilities.

  20. Inclusion in the East: Chinese Students' Attitudes towards Inclusive Education

    Science.gov (United States)

    Malinen, Olli-Pekka; Savolainen, Hannu

    2008-01-01

    A sample of 523 Chinese university students was given a questionnaire on their attitudes towards the inclusion of children with disabilities into regular classrooms. Factor analysis, analysis of variance, t-test and correlations were used to assess the respondents' general attitude towards inclusion, the factor structure of the attitudes, the…

  1. Kinetics of inclusion body formation and its correlation with the characteristics of protein aggregates in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Arun K Upadhyay

    Full Text Available The objective of the research was to understand the structural determinants governing protein aggregation into inclusion bodies during expression of recombinant proteins in Escherichia coli. Recombinant human growth hormone (hGH and asparaginase were expressed as inclusion bodies in E.coli and the kinetics of aggregate formation was analyzed in details. Asparaginase inclusion bodies were of smaller size (200 nm and the size of the aggregates did not increase with induction time. In contrast, the seeding and growth behavior of hGH inclusion bodies were found to be sequential, kinetically stable and the aggregate size increased from 200 to 800 nm with induction time. Human growth hormone inclusion bodies showed higher resistance to denaturants and proteinase K degradation in comparison to those of asparaginase inclusion bodies. Asparaginase inclusion bodies were completely solubilized at 2-3 M urea concentration and could be refolded into active protein, whereas 7 M urea was required for complete solubilization of hGH inclusion bodies. Both hGH and asparaginase inclusion bodies showed binding with amyloid specific dyes. In spite of its low β-sheet content, binding with dyes was more prominent in case of hGH inclusion bodies than that of asparaginase. Arrangements of protein molecules present in the surface as well as in the core of inclusion bodies were similar. Hydrophobic interactions between partially folded amphiphillic and hydrophobic alpha-helices were found to be one of the main determinants of hGH inclusion body formation. Aggregation behavior of the protein molecules decides the nature and properties of inclusion bodies.

  2. Kinetics of Inclusion Body Formation and Its Correlation with the Characteristics of Protein Aggregates in Escherichia coli

    Science.gov (United States)

    Upadhyay, Arun K.; Murmu, Aruna; Singh, Anupam; Panda, Amulya K.

    2012-01-01

    The objective of the research was to understand the structural determinants governing protein aggregation into inclusion bodies during expression of recombinant proteins in Escherichia coli. Recombinant human growth hormone (hGH) and asparaginase were expressed as inclusion bodies in E.coli and the kinetics of aggregate formation was analyzed in details. Asparaginase inclusion bodies were of smaller size (200 nm) and the size of the aggregates did not increase with induction time. In contrast, the seeding and growth behavior of hGH inclusion bodies were found to be sequential, kinetically stable and the aggregate size increased from 200 to 800 nm with induction time. Human growth hormone inclusion bodies showed higher resistance to denaturants and proteinase K degradation in comparison to those of asparaginase inclusion bodies. Asparaginase inclusion bodies were completely solubilized at 2–3 M urea concentration and could be refolded into active protein, whereas 7 M urea was required for complete solubilization of hGH inclusion bodies. Both hGH and asparaginase inclusion bodies showed binding with amyloid specific dyes. In spite of its low β-sheet content, binding with dyes was more prominent in case of hGH inclusion bodies than that of asparaginase. Arrangements of protein molecules present in the surface as well as in the core of inclusion bodies were similar. Hydrophobic interactions between partially folded amphiphillic and hydrophobic alpha-helices were found to be one of the main determinants of hGH inclusion body formation. Aggregation behavior of the protein molecules decides the nature and properties of inclusion bodies. PMID:22479486

  3. Curcumin Attenuates Amyloid-β Aggregate Toxicity and Modulates Amyloid-β Aggregation Pathway.

    Science.gov (United States)

    Thapa, Arjun; Jett, Stephen D; Chi, Eva Y

    2016-01-20

    The abnormal misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet enriched insoluble deposits initiates a cascade of events leading to pathological processes and culminating in cognitive decline in Alzheimer's disease (AD). In particular, soluble oligomeric/prefibrillar Aβ have been shown to be potent neurotoxins. The naturally occurring polyphenol curcumin has been shown to exert a neuroprotective effect against age-related neurodegenerative diseases such as AD. However, its protective mechanism remains unclear. In this study, we investigated the effects of curcumin on the aggregation of Aβ40 as well as Aβ40 aggregate induced neurotoxicity. Our results show that the curcumin does not inhibit Aβ fibril formation, but rather enriches the population of "off-pathway" soluble oligomers and prefibrillar aggregates that were nontoxic. Curcumin also exerted a nonspecific neuroprotective effect, reducing toxicities induced by a range of Aβ conformers, including monomeric, oligomeric, prefibrillar, and fibrillar Aβ. The neuroprotective effect is possibly membrane-mediated, as curcumin reduced the extent of cell membrane permeabilization induced by Aβ aggregates. Taken together, our study shows that curcumin exerts its neuroprotective effect against Aβ induced toxicity through at least two concerted pathways, modifying the Aβ aggregation pathway toward the formation of nontoxic aggregates and ameliorating Aβ-induced toxicity possibly through a nonspecific pathway.

  4. Feasibility and acceptance of simultaneous amyloid PET/MRI

    International Nuclear Information System (INIS)

    Schuetz, Lisa; Tiepolt, Solveig; Werner, Peter; Jochimsen, Thies; Rullmann, Michael; Sattler, Bernhard; Patt, Marianne; Barthel, Henryk; Lobsien, Donald; Fritzsch, Dominik; Hoffmann, Karl-Titus; Schroeter, Matthias L.; Villringer, Arno; Berrouschot, Joerg; Saur, Dorothee; Classen, Joseph; Hesse, Swen; Sabri, Osama; Gertz, Hermann-Josef

    2016-01-01

    Established Alzheimer's disease (AD) biomarker concepts classify into amyloid pathology and neuronal injury biomarkers, while recent alternative concepts classify into diagnostic and progression AD biomarkers. However, combined amyloid positron emission tomography/magnetic resonance imaging (PET/MRI) offers the chance to obtain both biomarker category read-outs within one imaging session, with increased patient as well as referrer convenience. The aim of this pilot study was to investigate this matter for the first time. 100 subjects (age 70 ± 10 yrs, 46 female), n = 51 with clinically defined mild cognitive impairment (MCI), n = 44 with possible/probable AD dementia, and n = 5 with frontotemporal lobe degeneration, underwent simultaneous [ 18 F]florbetaben or [ 11 C]PIB PET/MRI (3 Tesla Siemens mMR). Brain amyloid load, mesial temporal lobe atrophy (MTLA) by means of the Scheltens scale, and other morphological brain pathologies were scored by respective experts. The patients/caregivers as well as the referrers were asked to assess on a five-point scale the convenience related to the one-stop-shop PET and MRI approach. In three subjects, MRI revealed temporal lobe abnormalities other than MTLA. According to the National Institute on Aging-Alzheimer's Association classification, the combined amyloid-beta PET/MRI evaluation resulted in 31 %, 45 %, and 24 % of the MCI subjects being categorized as ''MCI-unlikely due to AD'', ''MCI due to AD-intermediate likelihood'', and ''MCI due to AD-high likelihood'', respectively. 50 % of the probable AD dementia patients were categorized as ''High level of evidence of AD pathophysiological process'', and 56 % of the possible AD dementia patients as ''Possible AD dementia - with evidence of AD pathophysiological process''. With regard to the International Working Group 2 classification, 36 subjects had both positive

  5. Bacterial lung abscess

    International Nuclear Information System (INIS)

    Groskin, S.A.; Panicek, D.M.; Ewing, D.K.; Rivera, F.; Math, K.; Teixeira, J.; Heitzman, E.R.

    1987-01-01

    A retrospective review of patients with bacterial lung abscess was carried out. Demographic, clinical, and radiographical features of this patient group are compared with similar data from patients with empyema and/or cavitated lung carcinoma; differential diagnostic points are stressed. The entity of radiographically occult lung abscess is discussed. Complications associated with bacterial lung abscess are discussed. Current therapeutic options and treatment philosophy for patients with bacterial lung abscess are noted

  6. Designing Inclusive Systems Designing Inclusion for Real-world Applications

    CERN Document Server

    Clarkson, John; Robinson, Peter; Lazar, Jonathan; Heylighen, Ann

    2012-01-01

    The Cambridge Workshops on Universal Access and Assistive Technology (CWUAAT) are a series of workshops held at a Cambridge University College every two years. The workshop theme: “Designing inclusion for real-world applications” refers to the emerging potential and relevance of the latest generations of inclusive design thinking, tools, techniques, and data, to mainstream project applications such as healthcare and the design of working environments. Inclusive Design Research involves developing tools and guidance enabling product designers to design for the widest possible population, for a given range of capabilities. There are five main themes: •Designing for the Real-World •Measuring Demand And Capabilities •Designing Cognitive Interaction with Emerging Technologies •Design for Inclusion •Designing Inclusive Architecture In the tradition of CWUAAT, we have solicited and accepted contributions over a wide range of topics, both within individual themes and also across the workshop’s scope. ...

  7. Peritonitis - spontaneous bacterial

    Science.gov (United States)

    Spontaneous bacterial peritonitis (SBP); Ascites - peritonitis; Cirrhosis - peritonitis ... who are on peritoneal dialysis for kidney failure. Peritonitis may have other causes . These include infection from ...

  8. Unwinding fibril formation of medin, the peptide of the most common form of human amyloid

    International Nuclear Information System (INIS)

    Larsson, Annika; Soederberg, Linda; Westermark, Gunilla T.; Sletten, Knut; Engstroem, Ulla; Tjernberg, Lars O.; Naeslund, Jan; Westermark, Per

    2007-01-01

    Medin amyloid affects the medial layer of the thoracic aorta of most people above 50 years of age. The consequences of this amyloid are not completely known but the deposits may contribute to diseases such as thoracic aortic aneurysm and dissection or to the general diminished elasticity of blood vessels seen in elderly people. We show that the 50-amino acid residue peptide medin forms amyloid-like fibrils in vitro. With the use of Congo red staining, Thioflavin T fluorescence, electron microscopy, and a solid-phase binding assay on different synthetic peptides, we identified the last 18-19 amino acid residues to constitute the amyloid-promoting region of medin. We also demonstrate that the two C-terminal phenylalanines, previously suggested to be of importance for amyloid formation, are not required for medin amyloid formation

  9. Kinetic studies with iodine-123-labeled serum amyloid P component in patients with systemic AA and AL amyloidosis and assessment of clinical value

    NARCIS (Netherlands)

    Jager, PL; Hazenberg, BPC; Franssen, EJF; Limburg, PC; van Rijswijk, MH; Piers, DA

    In systemic amyloidosis, widespread amyloid deposition interferes with organ function, frequently with fatal consequences. Diagnosis rests on demonstrating amyloid deposits in the tissues, traditionally with histology although scintigraphic imaging with radiolabeled serum amyloid P component (SAP)

  10. Teacher preparedness for inclusive education

    African Journals Online (AJOL)

    lynette

    Department of Information Systems, Faculty of Economic & Management ... paredness of teachers for this new policy of inclusion. ... of inclusive classrooms, if viewed in global perspective (Dyson & .... teachers experience stress when including learners with special needs. ..... Stress areas and coping skills of South African.

  11. The Inclusive Classroom. Professional's Guide.

    Science.gov (United States)

    Grenot-Scheyer, Marquita; And Others

    Inclusive education reflects the changing culture of contemporary schools with emphasis on active learning, authentic assessment practices, applied curriculum, multi-level instructional approaches, and increased attention to diverse student needs and individualization. This guide is intended to help teachers implement inclusive educational…

  12. Measuring Attitudes toward Inclusive Education.

    Science.gov (United States)

    Wilczenski, Felicia L.

    1992-01-01

    Developed scale to measure attitudes toward inclusive education, in which disabled students are responsibility of regular teacher supported by specialists. Administered scale to 301 elementary and secondary teachers and to 144 undergraduate elementary education majors. Analysis yielded four discrete dimensions of inclusive education with…

  13. IDEA and Early Childhood Inclusion.

    Science.gov (United States)

    Smith, Barbara J.; Rapport, Mary Jane K.

    This paper discusses 1997 amendments to the Individuals with Disabilities Education Act (IDEA) that promote the inclusion of children with disabilities in general early childhood education settings. The evolution of inclusion policy is explored and changes in disability terminology are described. Amended provisions are then explained and include:…

  14. The Evolution of Secondary Inclusion.

    Science.gov (United States)

    Thousand, Jacqueline; Rosenberg, Richard L.; Bishop, Kathryn D.; Villa, Richard A.

    1997-01-01

    Offers an alternative "Circle of Courage" model of education, derived from Native American culture, for creating inclusive high schools that welcome, value, support, and facilitate the learning of adolescents with differing abilities. Best practices related to curriculum, instruction, assessment, and campus life for effective inclusion are…

  15. Inclusion in Malaysian Integrated Preschools

    Science.gov (United States)

    Sukumaran, Sailajah; Loveridge, Judith; Green, Vanessa A.

    2015-01-01

    Inclusive education has been introduced through a number of policy developments in Malaysia over the last 10 years but there is little research investigating the extent and nature of inclusive education for preschoolers with special educational needs (SEN). This study surveyed both regular and special education teachers in Malaysian integrated…

  16. Early Childhood Inclusion in Turkey

    Science.gov (United States)

    Diken, Ibrahim H.; Rakap, Salih; Diken, Ozlem; Tomris, Gozde; Celik, Secil

    2016-01-01

    Inclusion of young children with disabilities into regular preschool classrooms is a common practice that has been implemented for several decades in industrialized nations around the world, and many developing countries including Turkey have been developing and implementing laws, regulation, and services to support inclusion and teaching in…

  17. Early Childhood Inclusion in Spain

    Science.gov (United States)

    Giné, Climent; Balcells-Balcells, Anna; Cañadas, Margarita; Paniagua, Gema

    2016-01-01

    This article describes early childhood inclusion in educational settings in Spain. First, we address the legislative framework of preschool education in Spain and offer a brief analysis of some relevant issues, including the current situation of early childhood education and inclusion at this stage. Second, current policies and practices relating…

  18. Social Inclusion and Metrolingual Practices

    Science.gov (United States)

    Otsuji, Emi; Pennycook, Alastair

    2011-01-01

    In this paper, we explore the implications of metrolingual language practices for how we understand social inclusion. A vision of social inclusion that includes bi- and multilingual capacities may comprise an appreciation of a diversity of languages other than English, and the skills and capabilities of multilingual language users, yet it is all…

  19. Stiffening solids with liquid inclusions

    Science.gov (United States)

    Style, Robert W.; Boltyanskiy, Rostislav; Allen, Benjamin; Jensen, Katharine E.; Foote, Henry P.; Wettlaufer, John S.; Dufresne, Eric R.

    2015-01-01

    From bone and wood to concrete and carbon fibre, composites are ubiquitous natural and synthetic materials. Eshelby’s inclusion theory describes how macroscopic stress fields couple to isolated microscopic inclusions, allowing prediction of a composite’s bulk mechanical properties from a knowledge of its microstructure. It has been extended to describe a wide variety of phenomena from solid fracture to cell adhesion. Here, we show experimentally and theoretically that Eshelby’s theory breaks down for small liquid inclusions in a soft solid. In this limit, an isolated droplet’s deformation is strongly size-dependent, with the smallest droplets mimicking the behaviour of solid inclusions. Furthermore, in opposition to the predictions of conventional composite theory, we find that finite concentrations of small liquid inclusions enhance the stiffness of soft solids. A straightforward extension of Eshelby’s theory, accounting for the surface tension of the solid-liquid interface, explains our experimental observations. The counterintuitive stiffening of solids by fluid inclusions is expected whenever inclusion radii are smaller than an elastocapillary length, given by the ratio of the surface tension to Young’s modulus of the solid matrix. These results suggest that surface tension can be a simple and effective mechanism to cloak the far-field elastic signature of inclusions.

  20. Associations Between β-Amyloid Kinetics and the β-Amyloid Diurnal Pattern in the Central Nervous System.

    Science.gov (United States)

    Lucey, Brendan P; Mawuenyega, Kwasi G; Patterson, Bruce W; Elbert, Donald L; Ovod, Vitaliy; Kasten, Tom; Morris, John C; Bateman, Randall J

    2017-02-01

    Recent studies found that the concentration of amyloid-β (Aβ) fluctuates with the sleep-wake cycle. Although the amplitude of this day/night pattern attenuates with age and amyloid deposition, to our knowledge, the association of Aβ kinetics (ie, production, turnover, and clearance) with this oscillation has not been studied. To determine the association between Aβ kinetics, age, amyloid levels, and the Aβ day/night pattern in humans. We measured Aβ concentrations and kinetics in 77 adults aged 60 to 87 years with and without amyloid deposition by a novel precise mass spectrometry method at the Washington University School of Medicine in St Louis, Missouri. We compared findings of 2 orthogonal methods, enzyme-linked immunosorbent assay and mass spectrometry, to validate the day/night patterns and determine more precise estimates of the cosinor parameters. In vivo labeling of central nervous system proteins with stable isotopically labeled leucine was performed, and kinetics of Aβ40 and Aβ42 were measured. Serial cerebrospinal fluid collection via indwelling lumbar catheter over 36 to 48 hours before, during, and after in vivo labeling, with a 9-hour primed constant infusion of 13C6-leucine. The amplitude, linear increase, and other cosinor measures of each participant's serial cerebrospinal fluid Aβ concentrations and Aβ turnover rates. Of the 77 participants studied, 46 (59.7%) were men, and the mean (range) age was 72.6 (60.4-87.7) years. Day/night patterns in Aβ concentrations were more sharply defined by the precise mass spectrometry method than by enzyme-linked immunosorbent assay (mean difference of SD of residuals: Aβ40, -7.42 pM; P effects of age and amyloid on Aβ42 amplitude at least partially affect each other. Production and turnover rates suggest that day/night Aβ patterns are modulated by both production and clearance mechanisms active in sleep-wake cycles and that amyloid deposition may impair normal circadian patterns. These findings

  1. Human amyloid beta protein gene locus: HaeIII RFLP

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, J E; Gonzalez-DeWhitt, P A; Fuller, F; Cordell, B; Frossard, P M [California Biotechnology Inc., Mountain View (USA); Tinklenberg, J R; Davies, H D; Eng, L F; Yesavage, J A [Stanford Univ. School of Medicine, Palo Alto, CA (USA)

    1988-07-25

    A 2.2 kb EcoRI-EcoRI fragment from the 5{prime} end of the human amyloid beta protein cDNA was isolated from a human fibroblast cDNA library and subcloned into pGEM3. HaeIII (GGCC) detects 6 invariant bands at 0.5 kb, 1.0 kb, 1.1 kb, 1.3 kb, 1.4 kb and 1.6 kb and a two-allele polymorphism with bands at either 1.9 kb or 2.1 kb. Its frequency was studied in 50 North Americans. Human amyloid beta protein gene mapped to the long arm of chromosome 21 (21q11.2-21q21) by Southern blot analysis of human-rodent somatic cell hybrids. Co-dominant segregation was observed in two families (15 individuals).

  2. Semen amyloids participate in spermatozoa selection and clearance.

    Science.gov (United States)

    Roan, Nadia R; Sandi-Monroy, Nathallie; Kohgadai, Nargis; Usmani, Shariq M; Hamil, Katherine G; Neidleman, Jason; Montano, Mauricio; Ständker, Ludger; Röcker, Annika; Cavrois, Marielle; Rosen, Jared; Marson, Kara; Smith, James F; Pilcher, Christopher D; Gagsteiger, Friedrich; Sakk, Olena; O'Rand, Michael; Lishko, Polina V; Kirchhoff, Frank; Münch, Jan; Greene, Warner C

    2017-06-27

    Unlike other human biological fluids, semen contains multiple types of amyloid fibrils in the absence of disease. These fibrils enhance HIV infection by promoting viral fusion to cellular targets, but their natural function remained unknown. The similarities shared between HIV fusion to host cell and sperm fusion to oocyte led us to examine whether these fibrils promote fertilization. Surprisingly, the fibrils inhibited fertilization by immobilizing sperm. Interestingly, however, this immobilization facilitated uptake and clearance of sperm by macrophages, which are known to infiltrate the female reproductive tract (FRT) following semen exposure. In the presence of semen fibrils, damaged and apoptotic sperm were more rapidly phagocytosed than healthy ones, suggesting that deposition of semen fibrils in the lower FRT facilitates clearance of poor-quality sperm. Our findings suggest that amyloid fibrils in semen may play a role in reproduction by participating in sperm selection and facilitating the rapid removal of sperm antigens.

  3. Amyloid fibers provide structural integrity to Bacillus subtilis biofilms.

    Science.gov (United States)

    Romero, Diego; Aguilar, Claudio; Losick, Richard; Kolter, Roberto

    2010-02-02

    Bacillus subtilis forms biofilms whose constituent cells are held together by an extracellular matrix. Previous studies have shown that the protein TasA and an exopolysaccharide are the main components of the matrix. Given the importance of TasA in biofilm formation, we characterized the physicochemical properties of this protein. We report that purified TasA forms fibers of variable length and 10-15 nm in width. Biochemical analyses, in combination with the use of specific dyes and microscopic analyses, indicate that TasA forms amyloid fibers. Consistent with this hypothesis, TasA fibers required harsh treatments (e.g., formic acid) to be depolymerized. When added to a culture of a tasA mutant, purified TasA restored wild-type biofilm morphology, indicating that the purified protein retained biological activity. We propose that TasA forms amyloid fibers that bind cells together in the biofilm.

  4. Advances toward multifunctional cholinesterase and β-amyloid aggregation inhibitors.

    Science.gov (United States)

    Panek, Dawid; Wichur, Tomasz; Godyń, Justyna; Pasieka, Anna; Malawska, Barbara

    2017-10-01

    The emergence of a multitarget design approach in the development of new potential anti-Alzheimer's disease agents has resulted in the discovery of many multifunctional compounds focusing on various targets. Among them the largest group comprises inhibitors of both cholinesterases, with additional anti-β-amyloid aggregation activity. This review describes recent advances in this research area and presents the most interesting compounds reported over a 2-year span (2015-2016). The majority of hybrids possess heterodimeric structures obtained by linking structurally active fragments interacting with different targets. Multipotent cholinesterase inhibitors with β-amyloid antiaggregating activity may additionally possess antioxidative, neuroprotective or metal-chelating properties or less common features such as anti-β-secretase or τ-antiaggregation activity.

  5. New Cyclolignans from Origanumglandulosum Active Against b -amyloid Aggregation

    Directory of Open Access Journals (Sweden)

    Abdelkader Basli

    2014-05-01

    Full Text Available Origanum glandulosum Desf is an endemic flavoring herb widely distributed in North Africa that is commonly used in traditional medicine. This oregano species is rich in essential oils but little is known about its phenolic composition. In the present study, a crude extract of O. glandulosum was prepared in order to isolate and investigate its neuroprotective potential to inhibit β-amyloid peptide (Aβ aggregation. The three major compounds of the extract were isolated: rosmarinic acid and two cyclolignans in Origanum genus, globoidnan A and a new derivative named globoidnan B. Rosmarinic acid and globoidnan A showed significant anti-aggregative activity against β amyloid aggregation (IC50 7.0 and 12.0 µM, respectively. In contrast, globoidnan B was found to be less active.

  6. Solitary osteosclerotic plasmacytoma: association with demyelinating polyneuropathy and amyloid deposition

    Energy Technology Data Exchange (ETDEWEB)

    Voss, S.D.; Hall, F.M. [Dept. of Radiology, Beth Israel Deaconess Medical Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Murphey, M.D. [Dept. of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, DC (United States); Dept. of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD (United States); Department of Radiology, University of Maryland School of Medicine, Baltimore, Maryland (United States)

    2001-09-01

    A 51-year-old man presented with a 1-year history of polyneuropathy necessitating the use of a wheelchair. Initial diagnosis was idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and associated monoclonal gammopathy. Investigations for multiple myeloma, including bone marrow aspiration and biopsy, were negative. What was initially felt to be an incidental osteosclerotic focus noted on the radiographic bone survey was eventually shown to be a solitary osteosclereotic plasmacytoma with associated amyloid. This dramatically altered treatment. This case emphasizes the importance of including osteosclerotic plasmacytoma in the differential diagnosis of a focal sclerotic bone lesion in the clinical setting of polyneuropathy. These lesions are less likely to progress to multiple myeloma than lytic plasma cell neoplasms, and the presence of polyneuropathy often results in earlier diagnosis and treatment with enhanced prospect of cure. The finding of amyloid deposition within the osteosclerotic lesion may be of prognostic importance. (orig.)

  7. Gold Nanoparticles and Microwave Irradiation Inhibit Beta-Amyloid Amyloidogenesis

    Directory of Open Access Journals (Sweden)

    Bastus Neus

    2008-01-01

    Full Text Available Abstract Peptide-Gold nanoparticles selectively attached to β-amyloid protein (Aβ amyloidogenic aggregates were irradiated with microwave. This treatment produces dramatic effects on the Aβ aggregates, inhibiting both the amyloidogenesis and the restoration of the amyloidogenic potential. This novel approach offers a new strategy to inhibit, locally and remotely, the amyloidogenic process, which could have application in Alzheimer’s disease therapy. We have studied the irradiation effect on the amyloidogenic process in the presence of conjugates peptide-nanoparticle by transmission electronic microscopy observations and by Thioflavine T assays to quantify the amount of fibrils in suspension. The amyloidogenic aggregates rather than the amyloid fibrils seem to be better targets for the treatment of the disease. Our results could contribute to the development of a new therapeutic strategy to inhibit the amyloidogenic process in Alzheimer’s disease.

  8. Politics of Inclusion and Empowerment

    DEFF Research Database (Denmark)

    Andersen, John; Siim, Birte

    2004-01-01

    identities. Politics of empowerment has to do with the agency and mobilisation dimension of social and political change. The title of the book "Politics of Inclusion and Empowerment" address the leitmotiv: namely to discuss plussumgame between politics of inclusion and politics of empowerment......The objective of the book is to analyse different politics of inclusion and empowerment and the different paradigms of inclusion/exclusion in order to underline the close link between politics of scoial equality and politics of recognition of ciultural difference. Politics of inclusion is thus...... theproductive/innovative linkage of politics of redistributuin and politics og resognition, whnich over a longer time span creates sustainable paths of democratic and social development, which increases the capacity to handle both conflicts about economic resources and life-chances and conflicts about...

  9. Benzofuranone derivatives as effective small molecules related to insulin amyloid fibrillation: a structure-function study

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Ebrahim-Habibi, Azadeh; Navidpour, Latifeh

    2011-01-01

    amyloid fibrils under slightly destabilizing conditions in vitro and may form amyloid structures when subcutaneously injected into patients with diabetes. There is a great deal of interest in developing novel small molecule inhibitors of amyloidogenic processes, as potential therapeutic compounds...... of the five tested compounds was observed to enhance amyloid fibrillation, while the others inhibited the process when used at micromolar concentrations, which could make them interesting potential lead compounds for the design of therapeutic antiamyloidogenic compounds....

  10. The contrasting effect of macromolecular crowding on amyloid fibril formation.

    Directory of Open Access Journals (Sweden)

    Qian Ma

    Full Text Available Amyloid fibrils associated with neurodegenerative diseases can be considered biologically relevant failures of cellular quality control mechanisms. It is known that in vivo human Tau protein, human prion protein, and human copper, zinc superoxide dismutase (SOD1 have the tendency to form fibril deposits in a variety of tissues and they are associated with different neurodegenerative diseases, while rabbit prion protein and hen egg white lysozyme do not readily form fibrils and are unlikely to cause neurodegenerative diseases. In this study, we have investigated the contrasting effect of macromolecular crowding on fibril formation of different proteins.As revealed by assays based on thioflavin T binding and turbidity, human Tau fragments, when phosphorylated by glycogen synthase kinase-3β, do not form filaments in the absence of a crowding agent but do form fibrils in the presence of a crowding agent, and the presence of a strong crowding agent dramatically promotes amyloid fibril formation of human prion protein and its two pathogenic mutants E196K and D178N. Such an enhancing effect of macromolecular crowding on fibril formation is also observed for a pathological human SOD1 mutant A4V. On the other hand, rabbit prion protein and hen lysozyme do not form amyloid fibrils when a crowding agent at 300 g/l is used but do form fibrils in the absence of a crowding agent. Furthermore, aggregation of these two proteins is remarkably inhibited by Ficoll 70 and dextran 70 at 200 g/l.We suggest that proteins associated with neurodegenerative diseases are more likely to form amyloid fibrils under crowded conditions than in dilute solutions. By contrast, some of the proteins that are not neurodegenerative disease-associated are unlikely to misfold in crowded physiological environments. A possible explanation for the contrasting effect of macromolecular crowding on these two sets of proteins (amyloidogenic proteins and non-amyloidogenic proteins has been

  11. Docosahexaenoic Acid Reduces Amyloid β Production via Multiple Pleiotropic Mechanisms*

    Science.gov (United States)

    Grimm, Marcus O. W.; Kuchenbecker, Johanna; Grösgen, Sven; Burg, Verena K.; Hundsdörfer, Benjamin; Rothhaar, Tatjana L.; Friess, Petra; de Wilde, Martijn C.; Broersen, Laus M.; Penke, Botond; Péter, Mária; Vígh, László; Grimm, Heike S.; Hartmann, Tobias

    2011-01-01

    Alzheimer disease is characterized by accumulation of the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing β- and γ-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of α-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in γ-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aβ release. DHA has a typical pleiotropic effect; DHA-mediated Aβ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects. PMID:21324907

  12. The Nucleation of Protein Aggregates - From Crystals to Amyloid Fibrils.

    Science.gov (United States)

    Buell, Alexander K

    2017-01-01

    The condensation and aggregation of individual protein molecules into dense insoluble phases is of relevance in such diverse fields as materials science, medicine, structural biology and pharmacology. A common feature of these condensation phenomena is that they usually are nucleated processes, i.e. the first piece of the condensed phase is energetically costly to create and hence forms slowly compared to its subsequent growth. Here we give a compact overview of the differences and similarities of various protein nucleation phenomena, their theoretical description in the framework of colloid and polymer science and their experimental study. Particular emphasis is put on the nucleation of a specific type of filamentous protein aggregates, amyloid fibrils. The current experimentally derived knowledge on amyloid fibril nucleation is critically assessed, and we argue that it is less advanced than is generally believed. This is due to (I) the lack of emphasis that has been put on the distinction between homogeneous and heterogeneous nucleation in experimental studies (II) the use of oversimplifying and/or inappropriate theoretical frameworks for the analysis of kinetic data of amyloid fibril nucleation. A strategy is outlined and advocated of how our understanding of this important class of processes can be improved in the future. © 2017 Elsevier Inc. All rights reserved.

  13. AMYPdb: A database dedicated to amyloid precursor proteins

    Directory of Open Access Journals (Sweden)

    Delamarche Christian

    2008-06-01

    Full Text Available Abstract Background Misfolding and aggregation of proteins into ordered fibrillar structures is associated with a number of severe pathologies, including Alzheimer's disease, prion diseases, and type II diabetes. The rapid accumulation of knowledge about the sequences and structures of these proteins allows using of in silico methods to investigate the molecular mechanisms of their abnormal conformational changes and assembly. However, such an approach requires the collection of accurate data, which are inconveniently dispersed among several generalist databases. Results We therefore created a free online knowledge database (AMYPdb dedicated to amyloid precursor proteins and we have performed large scale sequence analysis of the included data. Currently, AMYPdb integrates data on 31 families, including 1,705 proteins from nearly 600 organisms. It displays links to more than 2,300 bibliographic references and 1,200 3D-structures. A Wiki system is available to insert data into the database, providing a sharing and collaboration environment. We generated and analyzed 3,621 amino acid sequence patterns, reporting highly specific patterns for each amyloid family, along with patterns likely to be involved in protein misfolding and aggregation. Conclusion AMYPdb is a comprehensive online database aiming at the centralization of bioinformatic data regarding all amyloid proteins and their precursors. Our sequence pattern discovery and analysis approach unveiled protein regions of significant interest. AMYPdb is freely accessible 1.

  14. Calcium signaling and amyloid toxicity in Alzheimer disease.

    Science.gov (United States)

    Demuro, Angelo; Parker, Ian; Stutzmann, Grace E

    2010-04-23

    Intracellular Ca(2+) signaling is fundamental to neuronal physiology and viability. Because of its ubiquitous roles, disruptions in Ca(2+) homeostasis are implicated in diverse disease processes and have become a major focus of study in multifactorial neurodegenerative diseases such as Alzheimer disease (AD). A hallmark of AD is the excessive production of beta-amyloid (Abeta) and its massive accumulation in amyloid plaques. In this minireview, we highlight the pathogenic interactions between altered cellular Ca(2+) signaling and Abeta in its different aggregation states and how these elements coalesce to alter the course of the neurodegenerative disease. Ca(2+) and Abeta intersect at several functional levels and temporal stages of AD, thereby altering neurotransmitter receptor properties, disrupting membrane integrity, and initiating apoptotic signaling cascades. Notably, there are reciprocal interactions between Ca(2+) pathways and amyloid pathology; altered Ca(2+) signaling accelerates Abeta formation, whereas Abeta peptides, particularly in soluble oligomeric forms, induce Ca(2+) disruptions. A degenerative feed-forward cycle of toxic Abeta generation and Ca(2+) perturbations results, which in turn can spin off to accelerate more global neuropathological cascades, ultimately leading to synaptic breakdown, cell death, and devastating memory loss. Although no cause or cure is currently known, targeting Ca(2+) dyshomeostasis as an underlying and integral component of AD pathology may result in novel and effective treatments for AD.

  15. Amyloid fibril systems reduce, stabilize and deliver bioavailable nanosized iron

    Science.gov (United States)

    Shen, Yi; Posavec, Lidija; Bolisetty, Sreenath; Hilty, Florentine M.; Nyström, Gustav; Kohlbrecher, Joachim; Hilbe, Monika; Rossi, Antonella; Baumgartner, Jeannine; Zimmermann, Michael B.; Mezzenga, Raffaele

    2017-07-01

    Iron-deficiency anaemia (IDA) is a major global public health problem. A sustainable and cost-effective strategy to reduce IDA is iron fortification of foods, but the most bioavailable fortificants cause adverse organoleptic changes in foods. Iron nanoparticles are a promising solution in food matrices, although their tendency to oxidize and rapidly aggregate in solution severely limits their use in fortification. Amyloid fibrils are protein aggregates initially known for their association with neurodegenerative disorders, but recently described in the context of biological functions in living organisms and emerging as unique biomaterial building blocks. Here, we show an original application for these protein fibrils as efficient carriers for iron fortification. We use biodegradable amyloid fibrils from β-lactoglobulin, an inexpensive milk protein with natural reducing effects, as anti-oxidizing nanocarriers and colloidal stabilizers for iron nanoparticles. The resulting hybrid material forms a stable protein-iron colloidal dispersion that undergoes rapid dissolution and releases iron ions during acidic and enzymatic in vitro digestion. Importantly, this hybrid shows high in vivo iron bioavailability, equivalent to ferrous sulfate in haemoglobin-repletion and stable-isotope studies in rats, but with reduced organoleptic changes in foods. Feeding the rats with these hybrid materials did not result in abnormal iron accumulation in any organs, or changes in whole blood glutathione concentrations, inferring their primary safety. Therefore, these iron-amyloid fibril hybrids emerge as novel, highly effective delivery systems for iron in both solid and liquid matrices.

  16. [Behavioural problems and personality change related to cerebral amyloid angiopathy].

    Science.gov (United States)

    Gahr, Maximilian; Connemann, Bernhard J; Schönfeldt-Lecuona, Carlos

    2012-11-01

    Cerebral amyloid angiopathy (CAA) belongs to the group of amyloidoses that are characterized by the deposition of insoluble and tissue-damaging amyloid proteins. Spontaneous intracerebral hemorrhage is the common clinical presentation of CAA resulting from the degenerative effect of beta amyloid on the cerebral vascular system. Though CAA is rather a neurological disease psychiatric symptoms can occur and even dominate the clinical picture. A case report is presented in order to illustrate the association between CAA and psychiatric symptoms. We report the case of a 54-year-old female patient with radiologic references to a probable CAA and mild cognitive impairment who developed behavioural difficulties and personality change that necessitated a psychiatric treatment. Psychiatric symptoms were most likely due to CAA. CAA can be associated with psychiatric symptoms and hence should be considered in the treatment of elderly patients with behavioural problems or personality changes. Diagnostic neuroimaging and examination of cerebrospinal fluid is recommended. © Georg Thieme Verlag KG Stuttgart · New York.

  17. Prevention of bacterial adhesion

    DEFF Research Database (Denmark)

    Klemm, Per; Vejborg, Rebecca Munk; Hancock, Viktoria

    2010-01-01

    . As such, adhesion represents the Achilles heel of crucial pathogenic functions. It follows that interference with adhesion can reduce bacterial virulence. Here, we illustrate this important topic with examples of techniques being developed that can inhibit bacterial adhesion. Some of these will become...

  18. Direct identification of amyloids by label-free quantitative LC-MS

    DEFF Research Database (Denmark)

    Dueholm, Morten Simonsen; Danielsen, Heidi Nolsøe; Hansen, Susan Hove

    adhesive and therefore bind to pipette tips and other consumables. Pure cultures, large sample volumes and high productivity of amyloids are therefore required for successful purification. We here present a quantitative proteomics technique that allow direct identification of functional amyloid candidates......Direct identification of amyloids by label-free quantitative LC-MS H. N. Danielsen, S. H. Hansen, F.-A. Herbst, P. H. Nielsen, M. S. Dueholm Amyloids are highly ordered fibrillar protein polymers used by organisms from all domains of life due to their exceptional properties. We have previously...... in complex samples based on their structural stability in the presence of increasing concentrations of formic acid....

  19. Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor.

    Science.gov (United States)

    Endo, Hitoshi; Nikaido, Yuri; Nakadate, Mamiko; Ise, Satomi; Konno, Hiroyuki

    2014-12-15

    Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model.

    Directory of Open Access Journals (Sweden)

    William J Netzer

    Full Text Available beta-amyloid levels are elevated in Down syndrome (DS patients throughout life and are believed to cause Alzheimer's disease (AD in adult members of this population. However, it is not known if beta-amyloid contributes to intellectual disability in younger individuals. We used a gamma-secretase inhibitor to lower beta-amyloid levels in young mice that model DS. This treatment corrected learning deficits characteristic of these mice, suggesting that beta-amyloid-lowering therapies might improve cognitive function in young DS patients.

  1. Amyloid fibril formation from sequences of a natural beta-structured fibrous protein, the adenovirus fiber.

    Science.gov (United States)

    Papanikolopoulou, Katerina; Schoehn, Guy; Forge, Vincent; Forsyth, V Trevor; Riekel, Christian; Hernandez, Jean-François; Ruigrok, Rob W H; Mitraki, Anna

    2005-01-28

    Amyloid fibrils are fibrous beta-structures that derive from abnormal folding and assembly of peptides and proteins. Despite a wealth of structural studies on amyloids, the nature of the amyloid structure remains elusive; possible connections to natural, beta-structured fibrous motifs have been suggested. In this work we focus on understanding amyloid structure and formation from sequences of a natural, beta-structured fibrous protein. We show that short peptides (25 to 6 amino acids) corresponding to repetitive sequences from the adenovirus fiber shaft have an intrinsic capacity to form amyloid fibrils as judged by electron microscopy, Congo Red binding, infrared spectroscopy, and x-ray fiber diffraction. In the presence of the globular C-terminal domain of the protein that acts as a trimerization motif, the shaft sequences adopt a triple-stranded, beta-fibrous motif. We discuss the possible structure and arrangement of these sequences within the amyloid fibril, as compared with the one adopted within the native structure. A 6-amino acid peptide, corresponding to the last beta-strand of the shaft, was found to be sufficient to form amyloid fibrils. Structural analysis of these amyloid fibrils suggests that perpendicular stacking of beta-strand repeat units is an underlying common feature of amyloid formation.

  2. Melanosomal formation of PMEL core amyloid is driven by aromatic residues.

    Science.gov (United States)

    Hee, Jia Shee; Mitchell, Susan M; Liu, Xinran; Leonhardt, Ralf M

    2017-03-08

    PMEL is a pigment cell protein that forms physiological amyloid in melanosomes. Many amyloids and/or their oligomeric precursors are toxic, causing or contributing to severe, incurable diseases including Alzheimer's and prion diseases. Striking similarities in intracellular formation pathways between PMEL and various pathological amyloids including Aβ and PrP Sc suggest PMEL is an excellent model system to study endocytic amyloid. Learning how PMEL fibrils assemble without apparent toxicity may help developing novel therapies for amyloid diseases. Here we identify the critical PMEL domain that forms the melanosomal amyloid core (CAF). An unbiased alanine-scanning screen covering the entire region combined with quantitative electron microscopy analysis of the full set of mutants uncovers numerous essential residues. Many of these rely on aromaticity for function suggesting a role for π-stacking in melanosomal amyloid assembly. Various mutants are defective in amyloid nucleation. This extensive data set informs the first structural model of the CAF and provides insights into how the melanosomal amyloid core forms.

  3. No association of cortical amyloid load and EEG connectivity in older people with subjective memory complaints

    Directory of Open Access Journals (Sweden)

    Stefan Teipel

    2018-01-01

    Full Text Available Changes in functional connectivity of cortical networks have been observed in resting-state EEG studies in healthy aging as well as preclinical and clinical stages of AD. Little information, however, exists on associations between EEG connectivity and cortical amyloid load in people with subjective memory complaints. Here, we determined the association of global cortical amyloid load, as measured by florbetapir-PET, with functional connectivity based on the phase-lag index of resting state EEG data for alpha and beta frequency bands in 318 cognitively normal individuals aged 70–85 years with subjective memory complaints from the INSIGHT-preAD cohort. Within the entire group we did not find any significant associations between global amyloid load and phase-lag index in any frequency band. Assessing exclusively the subgroup of amyloid-positive participants, we found enhancement of functional connectivity with higher global amyloid load in the alpha and a reduction in the beta frequency bands. In the amyloid-negative participants, higher amyloid load was associated with lower connectivity in the low alpha band. However, these correlations failed to reach significance after controlling for multiple comparisons. The absence of a strong amyloid effect on functional connectivity may represent a selection effect, where individuals remain in the cognitively normal group only if amyloid accumulation does not impair cortical functional connectivity.

  4. [Clinical Laboratory Test Using Proteomics: The Usefulness of Proteomic Techniques for Amyloid Typing].

    Science.gov (United States)

    Tasaki, Masayoshi; Obayashi, Konen; Ando, Yukio

    2015-08-01

    Amyloidosis is a heterogeneous group of disorders characterized by the deposition of amyloid fibrils. To diagnose amyloidosis, it is important to detect amyloid deposits and identify the amyloid precursor protein in specimens, such as tissues and serum. Mass spectrometry is a powerful tool to measure the molecular weight and identify the protein. Recently, mass spectrometries such as liquid chromatography/tandem mass spectrometry and surface-enhanced laser desorption/ionization time of flight mass spectrometry, have made a contribution to amyloid typing. In the paper, we describe the usefulness of mass spectrometric analyses for the typing of amyloidosis.

  5. The ARIC-PET amyloid imaging study: Brain amyloid differences by age, race, sex, and APOE.

    Science.gov (United States)

    Gottesman, Rebecca F; Schneider, Andrea L C; Zhou, Yun; Chen, Xueqi; Green, Edward; Gupta, Naresh; Knopman, David S; Mintz, Akiva; Rahmim, Arman; Sharrett, A Richey; Wagenknecht, Lynne E; Wong, Dean F; Mosley, Thomas H

    2016-08-02

    To evaluate differences in amyloid deposition in a community-based cohort without dementia by age, sex, race, education, and APOE ε4 allele status. Recruited from the longitudinal Atherosclerosis Risk in Communities study, 329 participants without dementia, ages 67-88 years, were imaged using florbetapir PET at 3 US community sites (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi). Standardized uptake value ratios (SUVRs) were calculated; global cortical SUVR >1.2 was evaluated as the primary outcome. Age, race, sex, education level, and number of APOE ε4 alleles were evaluated in multivariable models including vascular risk factors, brain white matter hyperintensity and total intracranial volume, and cognitive status. A total of 141 of the participants (43%) were black. In multivariable models, odds of elevated SUVR was increased in participants with increasing age (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.01-2.65 per 10 years of age) and black race (OR 2.08, 95% CI 1.23-3.51) but did not differ by educational level. Each ε4 allele was associated with increased odds of elevated SUVR (OR 2.65, 95% CI 1.61-4.39). In this community-based cohort without dementia, florbetapir uptake is associated with older age and APOE genotype. Black race was associated with higher SUVR, after adjusting for demographics, vascular risk factors, cognitive status, white matter hyperintensity volume, and APOE genotype, with effect sizes nearing those seen for APOE ε4. Replication of these findings is needed in other cohorts, and reasons for and consequences of these observed differences by race warrant further study. © 2016 American Academy of Neurology.

  6. Calcium-dependent and -independent binding of the pentraxin serum amyloid P component to glycosaminoglycans and amyloid proteins

    DEFF Research Database (Denmark)

    Danielsen, B; Sørensen, I J; Nybo, Mads

    1997-01-01

    precursor protein beta2M was observed. This binding was also enhanced at slightly acid pH, most pronounced at pH 5.0. The results of this study indicate that SAP can exhibit both Ca2(+)-dependent and -independent binding to ligands involved in amyloid fibril formation and that the binding is enhanced under...... and beta2M) by ELISA. An increase in the dose-dependent binding of SAP to heparan sulfate, AA-protein and beta2M was observed as the pH decreased from 8.0 to 5.0. Furthermore, a lower, but significant Ca2(+)-independent binding of SAP to heparan sulfate, dermatan sulfate, AA protein and the amyloid...

  7. Ca isotopes in refractory inclusions

    International Nuclear Information System (INIS)

    Niederer, F.R.; Papanastassiou, D.A.

    1984-01-01

    We report measurements of the absolute isotope abundance of Ca in Ca-Al-rich inclusions from the Allende and Leoville meteorites. Improved high precision measurements are reported also for 46 Ca. We find that nonlinear isotope effects in Ca are extremely rare in these inclusions. The absence of nonlinear effects in Ca, except for the effects in FUN inclusions, is in sharp contrast to the endemic effects in Ti. One fine-grained inclusion shows an excess of 46 Ca of (7 +- 1) per mille, which is consistent with addition of only 46 Ca or of an exotic (*) component with 46 Ca* approx. 48 Ca*. FUN inclusion EK-1-4-1 shows a small 46 Ca excess of (3.3 +- 1.0) per mille; this confirms that the exotic Ca components in EK-1-4-1 were even more deficient in 46 Ca relative to 48 Ca than is the case for normal Ca. The Ca in the Ca-Al-rich inclusions shows mass dependent isotope fractionation effects which have a range from -3.8 to +6.7 per mille per mass unit difference. This range is a factor of 20 wider than the range previously established for bulk meteorites and for terrestrial and lunar samples. Ca and Mg isotope fractionation effects in the Ca-Al-rich inclusions are common and attributed to kinetic isotope effects. (author)

  8. Inclusive education and social exclusion

    Directory of Open Access Journals (Sweden)

    Maria Luisa Bissoto

    2013-01-01

    Full Text Available The aim of this paper is critically examining assumptions underlying the Inclusive Education concept, arguing that this can only be effectively considered when understood in a broader context of social inclusion and exclusion. Methodologically, this article relies on international documents and bibliographic references about Inclusive Education, that have been chosen by systematize and characterize different social and educational inclusive practices, encouraging the elaboration of a general overview on this topic. The results of this analysis conclude that it is essential for Inclusive Education that educational institutions review their goals and reasons of social existence. In the concluding remarks it is argued that education is better understood as the act of encouraging and welcoming the efforts of individuals in their attempts to engage in social networking, which sustains life. This includes the acceptance of other reality interpretations and understanding that educational action cannot be restricted by the walls of institutions. It requires the participation of the whole community. Action perspectives likely to promote social inclusion and inclusive education are suggested.

  9. Inclusive education: Ideas vs reality

    Directory of Open Access Journals (Sweden)

    Jovanović-Popadić Ana M.

    2016-01-01

    Full Text Available This paper discusses some of the key factors significant for the process of implementation of inclusive education in Serbia. After a brief review of the legal provisions regulating inclusive education in our country, the results of the research of attitudes towards inclusive education of teachers from six primary schools and one school for students with disabilities, as well as their experience, competencies, working conditions and opinions on consequences of inclusive education and education of children with developmental disabilities in specialized educational institutions are shown. Research was conducted in Krusevac, on a random sample of 60 teachers (51 teachers from primary schools and 9 special education teachers from schools for students with disabilities. We used two forms of questionnaires with twenty questions, and the results show predominantly negative attitudes towards inclusion in the majority of teachers in the sample. A significant percentage of respondents in both sub-samples considered that education of children with developmental disorders in specialized institutions (schools may give better results, primarily due to a lack of systematic support to teachers of primary schools in the process of implementing educational inclusion. The conclusion provides a critical overview of the current situation and presents the potential solutions to the problems that were identified during the research, and refer to the unsustainability of the current practice of inclusive education in Serbia.

  10. In vivo detection of amyloid plaques by gadolinium-stained MRI can be used to demonstrate the efficacy of an anti-amyloid immunotherapy

    Directory of Open Access Journals (Sweden)

    Mathieu D. Santin

    2016-03-01

    Full Text Available Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer's disease. Here we have used in vivo gadolinium-stained high resolution (29*29*117µm3 MRI to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952 directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-month-old animals, but not in 5.5-month animals compared to mice treated with a control antibody (DM4. Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-month SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

  11. Amyloid-β production via cleavage of amyloid-β protein precursor is modulated by cell density.

    Science.gov (United States)

    Zhang, Can; Browne, Andrew; Divito, Jason R; Stevenson, Jesse A; Romano, Donna; Dong, Yuanlin; Xie, Zhongcong; Tanzi, Rudolph E

    2010-01-01

    Mounting evidence suggests that Alzheimer's disease (AD) is caused by the accumulation of the small peptide, amyloid-β (Aβ), a proteolytic cleavage product of amyloid-β protein precursor (AβPP). Aβ is generated through a serial cleavage of AβPP by β- and γ-secretase. Aβ40 and Aβ42 are the two main components of amyloid plaques in AD brains, with Aβ42 being more prone to aggregation. AβPP can also be processed by α-secretase, which cleaves AβPP within the Aβ sequence, thereby preventing the generation of Aβ. Little is currently known regarding the effects of cell density on AβPP processing and Aβ generation. Here we assessed the effects of cell density on AβPP processing in neuronal and non-neuronal cell lines, as well as mouse primary cortical neurons. We found that decreased cell density significantly increases levels of Aβ40, Aβ42, total Aβ, and the ratio of Aβ42: Aβ40. These results also indicate that cell density is a significant modulator of AβPP processing. Overall, these findings carry profound implications for both previous and forthcoming studies aiming to assess the effects of various conditions and genetic/chemical factors, e.g., novel drugs on AβPP processing and Aβ generation in cell-based systems. Moreover, it is interesting to speculate whether cell density changes in vivo may also affect AβPP processing and Aβ levels in the AD brain.

  12. Curcumin Decreases Amyloid-β Peptide Levels by Attenuating the Maturation of Amyloid-β Precursor Protein*

    Science.gov (United States)

    Zhang, Can; Browne, Andrew; Child, Daniel; Tanzi, Rudolph E.

    2010-01-01

    Alzheimer disease (AD) is a devastating neurodegenerative disease with no cure. The pathogenesis of AD is believed to be driven primarily by amyloid-β (Aβ), the principal component of senile plaques. Aβ is an ∼4-kDa peptide generated via cleavage of the amyloid-β precursor protein (APP). Curcumin is a compound in the widely used culinary spice, turmeric, which possesses potent and broad biological activities, including anti-inflammatory and antioxidant activities, chemopreventative effects, and effects on protein trafficking. Recent in vivo studies indicate that curcumin is able to reduce Aβ-related pathology in transgenic AD mouse models via unknown molecular mechanisms. Here, we investigated the effects of curcumin on Aβ levels and APP processing in various cell lines and mouse primary cortical neurons. We show for the first time that curcumin potently lowers Aβ levels by attenuating the maturation of APP in the secretory pathway. These data provide a mechanism of action for the ability of curcumin to attenuate amyloid-β pathology. PMID:20622013

  13. Curcumin decreases amyloid-beta peptide levels by attenuating the maturation of amyloid-beta precursor protein.

    Science.gov (United States)

    Zhang, Can; Browne, Andrew; Child, Daniel; Tanzi, Rudolph E

    2010-09-10

    Alzheimer disease (AD) is a devastating neurodegenerative disease with no cure. The pathogenesis of AD is believed to be driven primarily by amyloid-beta (Abeta), the principal component of senile plaques. Abeta is an approximately 4-kDa peptide generated via cleavage of the amyloid-beta precursor protein (APP). Curcumin is a compound in the widely used culinary spice, turmeric, which possesses potent and broad biological activities, including anti-inflammatory and antioxidant activities, chemopreventative effects, and effects on protein trafficking. Recent in vivo studies indicate that curcumin is able to reduce Abeta-related pathology in transgenic AD mouse models via unknown molecular mechanisms. Here, we investigated the effects of curcumin on Abeta levels and APP processing in various cell lines and mouse primary cortical neurons. We show for the first time that curcumin potently lowers Abeta levels by attenuating the maturation of APP in the secretory pathway. These data provide a mechanism of action for the ability of curcumin to attenuate amyloid-beta pathology.

  14. Does aluminium bind to histidine? An NMR investigation of amyloid β12 and amyloid β16 fragments.

    Science.gov (United States)

    Narayan, Priya; Krishnarjuna, Bankala; Vishwanathan, Vinaya; Jagadeesh Kumar, Dasappa; Babu, Sudhir; Ramanathan, Krishna Venkatachala; Easwaran, Kalpathy Ramaier Katchap; Nagendra, Holenarasipur Gundurao; Raghothama, Srinivasarao

    2013-07-01

    Aluminium and zinc are known to be the major triggering agents for aggregation of amyloid peptides leading to plaque formation in Alzheimer's disease. While zinc binding to histidine in Aβ (amyloid β) fragments has been implicated as responsible for aggregation, not much information is available on the interaction of aluminium with histidine. In the NMR study of the N-terminal Aβ fragments, DAEFRHDSGYEV (Aβ12) and DAEFRHDSGYEVHHQK (Aβ16) presented here, the interactions of the fragments with aluminium have been investigated. Significant chemical shifts were observed for few residues near the C-terminus when aluminium chloride was titrated with Aβ12 and Aβ16 peptides. Surprisingly, it is nonhistidine residues which seem to be involved in aluminium binding. Based on NMR constrained structure obtained by molecular modelling, aluminium-binding pockets in Aβ12 were around charged residues such as Asp, Glu. The results are discussed in terms of native structure propagation, and the relevance of histidine residues in the sequences for metal-binding interactions. We expect that the study of such short amyloid peptide fragments will not only provide clues for plaque formation in aggregated conditions but also facilitate design of potential drugs for these targets. © 2013 John Wiley & Sons A/S.

  15. Characterization of amyloid beta peptides from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein.

    Science.gov (United States)

    Pype, Stefan; Moechars, Dieder; Dillen, Lieve; Mercken, Marc

    2003-02-01

    Alzheimer's disease (AD) is marked by the presence of neurofibrillary tangles and amyloid plaques in the brain of patients. To study plaque formation, we report on further quantitative and qualitative analysis of human and mouse amyloid beta peptides (Abeta) from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP). Using enzyme-linked immunosorbant assays (ELISAs) specific for either human or rodent Abeta, we found that the peptides from both species aggregated to form plaques. The ratios of deposited Abeta1-42/1-40 were in the order of 2-3 for human and 8-9 for mouse peptides, indicating preferential deposition of Abeta42. We also determined the identity and relative levels of other Abeta variants present in protein extracts from soluble and insoluble brain fractions. This was done by combined immunoprecipitation and mass spectrometry (IP/MS). The most prominent peptides truncated either at the carboxyl- or the amino-terminus were Abeta1-38 and Abeta11-42, respectively, and the latter was strongly enriched in the extracts of deposited peptides. Taken together, our data indicate that plaques of APP-London transgenic mice consist of aggregates of multiple human and mouse Abeta variants, and the human variants that we identified were previously detected in brain extracts of AD patients.

  16. How Bureaucracy Promotes Inclusive Organizing

    DEFF Research Database (Denmark)

    Holck, Lotte

    Diversity literature in general and Feminist in particular have long promoted alternatives to bureaucracy on the premise that this form of governance is far from gender- and race-neutral, and that inclusive organizing necessitate a flatter, decentralized and more ‘organic’ set-up (Ferguson 1984...... and opportunities conducive to their inclusion. Guided by Ashcraft (2001) concept of organized dissonance, this paper explores how the combination of apparent incongruent elements of stability/flexibility and formality/informality might offer a passage for inclusive organizing....

  17. The influence of pathological mutations and proline substitutions in TDP-43 glycine-rich peptides on its amyloid properties and cellular toxicity.

    Directory of Open Access Journals (Sweden)

    Chia-Sui Sun

    Full Text Available TAR DNA-binding protein (TDP-43 was identified as the major ubiquitinated component deposited in the inclusion bodies in amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U in 2006. Later on, numerous ALS-related mutations were found in either the glycine or glutamine/asparagine-rich region on the TDP-43 C-terminus, which hinted on the importance of mutations on the disease pathogenesis. However, how the structural conversion was influenced by the mutations and the biological significance of these peptides remains unclear. In this work, various peptides bearing pathogenic or de novo designed mutations were synthesized and displayed their ability to form twisted amyloid fibers, cause liposome leakage, and mediate cellular toxicity as confirmed by transmission electron microscopy (TEM, circular dichroism (CD, Thioflavin T (ThT assay, Raman spectroscopy, calcein leakage assay, and cell viability assay. We have also shown that replacing glycines with prolines, known to obstruct β-sheet formation, at the different positions in these peptides may influence the amyloidogenesis process and neurotoxicity. In these cases, GGG308PPP mutant was not able to form beta-amyloid, cause liposome leakage, nor jeopardized cell survival, which hinted on the importance of the glycines (308-310 during amyloidogenesis.

  18. Clinical and imaging correlates of amyloid deposition in dementia with Lewy bodies.

    Science.gov (United States)

    Donaghy, Paul C; Firbank, Michael J; Thomas, Alan J; Lloyd, Jim; Petrides, George; Barnett, Nicola; Olsen, Kirsty; O'Brien, John T

    2018-04-19

    Amyloid deposition is common in dementia with Lewy bodies, but its pathophysiological significance is unclear. The objective of this study was to investigate the relationship between amyloid deposition and clinical profile, gray matter volume, and brain perfusion in dementia with Lewy bodies. Dementia with Lewy bodies (n = 37), Alzheimer's disease (n = 20), and controls (n = 20) underwent a thorough clinical assessment, 3T MRI, and early- and late-phase 18 F-Florbetapir PET-CT to assess cortical perfusion and amyloid deposition, respectively. Amyloid scans were visually categorized as positive or negative. Image analysis was carried out using statistical parametric mapping (SPM) 8. There were no significant differences between amyloid-positive and amyloid-negative dementia with Lewy bodies cases in age (P = .78), overall cognitive impairment (P = .83), level of functional impairment (P = .80), or any other clinical or cognitive scale. There were also no significant differences in hippocampal or gray matter volumes. However, amyloid-positive dementia with Lewy bodies cases had lower medial temporal lobe perfusion (P = .03) than amyloid-negative cases, although a combination of medial temporal lobe perfusion, hippocampal volume, and cognitive measures was unable to accurately predict amyloid status in dementia with Lewy bodies. Amyloid deposition was not associated with differences in clinical or neuropsychological profiles in dementia with Lewy bodies, but was associated with imaging evidence of medial temporal lobe dysfunction. The presence of amyloid in dementia with Lewy bodies cannot be identified on the basis of clinical and other imaging features and will require direct assessment via PET imaging or CSF. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf

  19. Inclusions and inhomogeneities under stress

    CSIR Research Space (South Africa)

    Nabarro, FRN

    1996-02-01

    Full Text Available Some general theorems, new and old, concerning the behaviour of elastic inclusions and inhomogeneities in bodies without or with external stress, are assembled. The principal new result is that arbitrary external tractions cannot influence the shape...

  20. Postviral Complications: Bacterial Pneumonia.

    Science.gov (United States)

    Prasso, Jason E; Deng, Jane C

    2017-03-01

    Secondary bacterial pneumonia after viral respiratory infection remains a significant source of morbidity and mortality. Susceptibility is mediated by a variety of viral and bacterial factors, and complex interactions with the host immune system. Prevention and treatment strategies are limited to influenza vaccination and antibiotics/antivirals respectively. Novel approaches to identifying the individuals with influenza who are at increased risk for secondary bacterial pneumonias are urgently needed. Given the threat of further pandemics and the heightened prevalence of these viruses, more research into the immunologic mechanisms of this disease is warranted with the hope of discovering new potential therapies. Published by Elsevier Inc.

  1. Inclusive approach to particle production

    International Nuclear Information System (INIS)

    Bialas, A.

    1977-01-01

    The problems are reviewed of inclusive spectra. The data show strong disagreement with short-range order picture which is fundamental for most of the existing descriptions of inclusive spectra. There are two physical effects which should be taken into account and which give hopes to restore the agreement with data: compositeness of hadrons and unitarity correlations. The data on diffraction dissociation and cross section rise seem to indicate that hadrons are made of well-separated objects of rather small dimensions

  2. Forum, Dedicated to Inclusive Education

    Directory of Open Access Journals (Sweden)

    Vachkov I.V.

    2015-06-01

    Full Text Available 26 – 27 of February 2015 in Kazan, in the University of Management “TISBI” been held National (All-Russian forum of promotion of ideas and principles of inclusive education (with international participants “Study and live together: open space of inclusion”. During the work of Forum the most topical questions of inclusive education implement in Russian Federation been discussed.

  3. Small heat shock protein HspB8: its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity.

    NARCIS (Netherlands)

    Wilhelmus, M.M.M.; Boelens, W.C.; Otte-Holler, I.; Kamps, B.; Kusters, B.; Maat-Schieman, M.L.; Waal, R.M.W. de; Verbeek, M.M.

    2006-01-01

    Alzheimer's disease (AD) is characterized by pathological lesions, such as senile plaques (SPs) and cerebral amyloid angiopathy (CAA), both predominantly consisting of a proteolytic cleavage product of the amyloid-beta precursor protein (APP), the amyloid-beta peptide (Abeta). CAA is also the major

  4. Bacterial vaginosis - aftercare

    Science.gov (United States)

    Bacterial vaginosis (BV) is a type of vaginal infection. The vagina normally contains both healthy bacteria and unhealthy bacteria. BV occurs when more unhealthy bacteria grow than healthy bacteria. No one knows ...

  5. Bacterial surface adaptation

    Science.gov (United States)

    Utada, Andrew

    2014-03-01

    Biofilms are structured multi-cellular communities that are fundamental to the biology and ecology of bacteria. Parasitic bacterial biofilms can cause lethal infections and biofouling, but commensal bacterial biofilms, such as those found in the gut, can break down otherwise indigestible plant polysaccharides and allow us to enjoy vegetables. The first step in biofilm formation, adaptation to life on a surface, requires a working knowledge of low Reynolds number fluid physics, and the coordination of biochemical signaling, polysaccharide production, and molecular motility motors. These crucial early stages of biofilm formation are at present poorly understood. By adapting methods from soft matter physics, we dissect bacterial social behavior at the single cell level for several prototypical bacterial species, including Pseudomonas aeruginosa and Vibrio cholerae.

  6. Bacterial intermediate filaments

    DEFF Research Database (Denmark)

    Charbon, Godefroid; Cabeen, M.; Jacobs-Wagner, C.

    2009-01-01

    Crescentin, which is the founding member of a rapidly growing family of bacterial cytoskeletal proteins, was previously proposed to resemble eukaryotic intermediate filament (IF) proteins based on structural prediction and in vitro polymerization properties. Here, we demonstrate that crescentin...

  7. Diagnosis of bacterial infection

    African Journals Online (AJOL)

    direct or indirect evidence of a compatible bacterial pathogen. Inflammation may be .... cardinal features (fever, confusion, headache and neck stiffness). .... specificity, inappropriate indications or poor sampling technique may diminish this ...

  8. Spatial patterns of brain amyloid-beta burden and atrophy rate associations in mild cognitive impairment

    NARCIS (Netherlands)

    Tosun, Duygu; Schuff, Norbert; Mathis, Chester A.; Jagust, William; Weiner, Michael W.; Saradha, A.; Abdi, Herve; Abdulkadir, Ahmed; Abeliovich, Asa; Abellan van Kan, Gabor; Abner, Erin; Acharya, Deepa; Agrusti, Antonella; Agyemang, Alex; Ahdidan, Jamila; Ahmed, Shiek; Ahn, Jae Eun; Aisen, Paul; Aksu, Yaman; Al-Akhras, Mousa; Alarcon, Marcelo; Alberca, Roman; Alexander, Gene; Alexander, Daniel; Alin, Aylin; Almeida, Fabio; Amlien, Inge; Anand, Shyam; Anderson, Dallas; Andrew, Marilee; Angersbach, Steve; Anjum, Ayesha; Aoyama, Eiji; Arfanakis, Konstantinos; Armor, Tom; Arnold, Steven; Arunagiri, Vidhya; Asatryan, Albert; Ashe-McNalley, Cody; Ashiga, Hirokazu; Assareh, Arezoo; Le Page, Aurelie; Avants, Brian; Avinash, Gopal; Aviv, Richard; Awasthi, Sukrati; Ayan-Oshodi, Mosun; Babic, Tomislav; Baek, Young; Bagci, Ulas; Bai, Shuyang; Baird, Geoffrey; Baker, John; Banks, Sarah; Bard, Jonathan; Barnes, Josephine; Bartlett, Jonathan; Bartzokis, George; Barua, Neil; Bauer, Corinna; Bayley, Peter; Beck, Irene; Becker, James; Becker, J. Alex; Beckett, Laurel; Bednar, Martin; Beg, Mirza Faisal; Bek, Stephan; Belaroussi, Boubakeur; Belmokhtar, Nabil; Bernard, Charlotte; Bertram, Lars; Bhaskar, Uday; Biffi, Alessandro; Bigler, Erin; Bilgic, Basar; Bishop, Courtney; Bittner, Daniel; Black, Ronald; Bogorodzki, Piotr; Bokde, Arun; Bonner-Jackson, Aaron; Boppana, Madhu; Bourgeat, Pierrick; Bowes, Mike; Bowman, DuBois; Bowman, Gene; Braskie, Meredith; Braunewell, Karl; Breitner, Joihn; Bresell, Anders; Brewer, James; Brickman, Adam; Britschgi, Markus; Broadbent, Steve; Brogren, Jacob; Brooks, David; Browndyke, Jeffrey; Brunton, Simon; Buchert, Ralph; Buchsbaum, Monte; Buckley, Chris; Buerger, Katharina; Burger, Cyrill; Burnham, Samantha; Burns, Jeffrey; Burton, David; Butman, John; Cabeza, Rafael; Cairns, Nigel; Callhoff, Johanna; Calvini, Piero; Cantillon, Marc; Capella, Heraldo; Carbotti, Angela; Cardona-Sanclemente, Luis Eduardo; Carle, Adam; Carmasin, Jeremy; Carranza-Ath, Fredy; Casabianca, Jodi; Casanova, Ramon; Cash, David; Cedarbaum, Jesse; Cella, Massimo; Celsis, Pierre; Chanu, Pascal; Chao, Linda; Charil, Arnaud; Chemali, Zeina; Chen, Rong; Chen, Jake; Chen, Gennan; Chen, Wei; Chen, Kewei; Chen, Shuzhong; Chen, Minhua; Cheng, Wei-Chen; Cherkas, Yauheniya; Chertkow, Howard; Cheung, Charlton; Cheung, Vinci; Chiang, Gloria; Chiba, Koji; Chin, Simon; Chisholm, Jane; Cho, Youngsang; Choe, John; Choubey, Suresh; Chowbina, Sudhir; Christensen, Anette Luther; Clark, David; Clark, Chris; Clarkson, Matt; Clayton, David; Clunie, David; Coen, Michael; Coimbra, Alexandre; Compton, David; Coppola, Giovanni; Coulin, Samuel; Cover, Keith S.; Crane, Paul; Crans, Gerald; Croop, Robert; Crowther, Daniel; Crum, William; Cui, Yue; Curry, Charles; Curtis, Steven; Cutter, Gary; Daiello, Lori; Dake, Michael; Dale, Anders; Daliri, Mohammad Reza; Damato, Vito Domenico; Darby, Eveleen; Darkner, Sune; Davatzikos, Christos; Dave, Jay; David, Renaud; DavidPrakash, Bhaskaran; Davidson, Julie; de Bruijne, Marleen; de Meyer, Geert; de Nunzio, Giorgio; Decarli, Charles; Dechairo, Bryan; DeDuck, Kristina; Dehghan, Hossein; Dejkam, Arsalan; Delfino, Manuel; Della Rosa, Pasquale Anthony; Dellavedova, Luca; Delpassand, Ebrahim; Delrieu, Julien; DeOrchis, Vincent; Depy Carron, Delphine; deToledo-Morrell, Leyla; Devanand, Davangere; Devanarayan, Viswanath; DeVous, Michael; Diaz-Arrastia, Ramon; Bradford, Dickerson; Ding, Xiaobo; Dinov, Ivo; Dobson, Howard; Dodge, Hiroko; Donohue, Michael; Dore, Vincent; Dorflinger, Ernest; Dowling, Maritza; Duan, Xujun; Dubal, Dena; Duchesne, Simon; Duff, Kevin; Dukart, Jrgen; Durazzo, Timothy; Dykstra, Kevin; Earl, Nancy; Edula, Goutham; Ekin, Ahmet; Elcoroaristizabal, Xabier; Emahazion, Tesfai; Engelman, Corinne; Epstein, Noam; Erten-Lyons, Deniz; Eskildsen, Simon; Falcone, Guido; Fan, Lingzhong; Fan, Yong; Farahibozorg, Seyedehrezvan; Farb, Norman; Farnum, Michael; Farrer, Lindsay; Farzan, Ali; Faux, Noel; Feldman, Betsy; Feldman, Howard; Feldman, Susan; Fennema-Notestine, Christine; Fernandes, Michel; Fernandez, Elsa; Ferrarini, Luca; Ferreira, Manuel Joao; Ferrer, Eugene; Figurski, Michal; Filipovych, Roman; Fillit, Howard; Finch, Stephen; Finlay, Daniel; Fiot, Jean-Baptiste; Flenniken, Derek; Fletcher, P. Thomas; Fletcher, Evan; Flynn Longmire, Crystal; Focke, Niels; Forman, Mark; Forsythe, Alan; Fox, Steven; Fox-Bosetti, Sabrina; Francis, Alexander L.; Franco-Villalobos, Conrado; Franko, Edit; Freeman, Stefanie; Friedrich, Christoph M.; Friesenhahn, Michel; Frings, Lars; Frisoni, Giovanni; Fritzsche, Klaus; Fujimoto, Yoko; Fujiwara, Ken; Fullerton, Terence; Furney, Simon; Gallins, Paul; Galvin, Ben; Gamst, Anthony; Gan, Ke; Garcia, Maria Teresa; Garg, Gaurav; Gaser, Christian; Gastineau, Edward; Gauthier, Serge; Gavett, Brandon; Gavidia, Giovana; Gazdzinski, Stefan; Ge, Qi; Ge, Tian; Gemme, Gianluca; Geraci, Joseph; Ghassabi, Zeinab; Gieschke, Ronald; Gil, Juan E.; Gill, Ryan; Gitelman, Darren; Gleason, Carey; Glymour, M. Maria; Godbey, Michael; Goghari, Vina; Gold, Michael; Goldberg, Terry; Goldman, Jennifer; Gomeni, Roberto; Gong, Shangwenyan; Gonzales, Celedon; Goodro, Robert; Gordon, Brian; Gore, Chris; Gorriz, Juan Manuel; Grachev, Igor; Grandey, Emily; Grasela, Thaddeus; Gratt, Jeremy; Gray, Katherine; Greenberg, Barry; Gregg, Keith; Gregory, Erik; Greicius, Michael; Greve, Douglas; Grill, Joshua; Gross, Alden; Gross, Alan; Guignot, Isabelle; Guo, Jeffrey; Guo, Qimiao; Guo, Hongbin; Guo, Lianghao; Habeck, Christian; Hai, Yizhen; Haight, Thaddeus; Hammarstrom, Per; Hampel, Harald; Han, Duke; Han, Jian; Han, Tony; Hanif, Muhammad; Hanna, Yousef; Hardy, Peter; Harvey, Danielle; Hasan, Md Kamrul; Hayashi, Toshihiro; Hazart, Aurelien; He, Huiguang; He, Yong; Head, Denise; Heckemann, Rolf; Heidebrink, Judith; Henderson, David; Henrard, Sebastien; Herholz, Karl; Hernandez, Monica; Herskovits, A. Zara; Hess, Christopher; Hildenbrand, Maike; Hobart, Jeremy; Hoffman, John; Holder, Daniel; Hollingworth, Paul; Holmes, Robin; Honigberg, Lee; Hoppin, Jack; Hou, Yangyang; Hsu, Ailing; Hsu, Wei-Wen; Hu, Xiaolan; Hu, Zhiwei; Hu, William; Huang, Juebin; Huang, Chien-Chih; Huang, Chingwen; Huang, Shuai; Huang, Yifan; Huang, Fude; Huang, Chun-Jung; Huang, Shu-Pang; Hubbard, Rebecca; Huentelman, Matthew; Hui, Shen; Huppertz, Hans-Jürgen; Hurko, Orest; Hurt, Stephen; Huyck, Susan; Hwang, Scott; Hyun, JungMoon; Ifeachor, Emmanuel; Iglesias, Martina; Ikari, Yasuhiko; Ikonomidou, Vasiliki; Imani, Farzin; Immermann, Fred; Inlow, Mark; Inoue, Lurdes; Insel, Philip; Irizarry, Michael; Irungu, Benson mwangi; Ishibashi, Taro; Ishii, Kenji; Ismail, Sara; Ismail, Shahina; Ito, Kaori; Iturria-Medina, Yasser; Iwatsubo, Takeshi; Jacobson, Mark; Jacqmin, Philippe; Jafari, Aria; Jafari-Khouzani, Kourosh; Jaffe, Carl; Jara, Hernan; Jasperse, Bas; Jedynak, Bruno; Jefferson, Angela; Jennings, J. Richard; Jessen, Walter; Jia, Fucang; Jiang, Tianzi; Jing, Huang; Johnson, Julene; Johnson, Sterling; Johnson, David K.; Jones, Richard; Juengling, Freimut; Juh, Rahyeong; Julin, Per; Kadish, Bill; Kahle-Wrobleski, Kristin; Kallam, Hanimi Reddy; Kamboh, M. Ilyas; Kaneko, Tomoki; Kaneta, Tomohiro; Kang, Ju Hee; Karageorgiou, Elissaios; Karantzoulis, Stella; Karlawish, Jason; Katz, Elyse; Kaushik, Sandeep S.; Kauwe, John; Kawakami, Hirofumi; Kazimipoor, Borhan; Kelleher, Thomas; Kennedy, Richard; Kerchner, Geoffrey; Kerrouche, Nacer; Khalil, Iya; Khalil, Andre; Killeen, Neil; Killiany, Ron; Kim, Jong Hun; Kim, Heeyoung; Kim, Ana; Kim, Yeonhee; Kim, Hyoungkyu; Kim, Seongkyun; Kim, Hyewon; Kimberg, Daniel; Kimura, Tokunori; King, Richard; Kirby, Justin; Kirsch, Wolff; Klimas, Michael; Kline, Richard; Kling, Mitchel; Klopfenstein, Erin; Koikkalainen, Juha; Kokomoor, Anders; Kolasny, Anthony; Koppel, Jeremy; Korolev, Igor; Kotran, Nickolas; Kouassi, Alex; Kowalczyk, Adam; Kozma, Lynn; Krams, Michael; Kratzer, Martina; Kuceyeski, Amy; Kuhn, Felix Pierre; Kumar, Sreedhar; Kuo, Hsun Ting; Kuo, Julie; Kurosawa, Ken; Kwon, Oh Hun; Labrish, Catherine; Laforet, Genevieve; Lai, Song; Lakatos, Anita; Lam, On Ki; Lampron, Antoine; Landau, Susan; Landen, Jaren; Lane, Richard; Langbaum, Jessica; Langford, Dianne; Lanius, Vivian; Laxamana, Joel; Le, Trung; Leahy, Richard; Lee, Jong-Min; Lee, Vita; Lee, Joseph H.; Lee, Grace; Lee, Dongsoo; Lee, Noah; Lefkimmiatis, Stamatis; Lemaitre, Herve; Lenfant, Pierre; Lenz, Robert; Leoutsakos, Jeannie-Marie; Lester, Gayle; Levey, Allan; Li, Shi-jiang; Li, Shanshan; Li, Wenjun; Li, Chin-Shang; Li, Xiaodong; Li, Rui; Li, Ming; Li, Lexin; Li, Jinhe; Li, Yi; Li, Quanzheng; Li, Gang; Liang, Kuchang; Liang, Peipeng; Liang, Lichen; Liao, Yuan-Lin; Lin, Ling-chih; Lin, Lan; Lin, Mingkuan; Lin, Ai-Ling; Liu, Songling; Liu, Yuan; Liu, Tianming; Liu, Meijie; Liu, Xiuwen; Liu, Li; Liu, Honggang; Liu, Pu; Liu, Tao; Liu, Sophia; Liu, Dazhong; Lo, Raymond; Lobanov, Victor; Loewenstein, David; Logovinsky, Veronika; Long, Xiaojing; Long, Ziyi; Looi, Jeffrey; Lu, Po-Haong; Lukic, Ana; Lull, Juan J.; Luo, Xiongjian; Lynch, John; Ma, Lei; Mackin, Scott; Mada, Marius; Magda, Sebastian; Maglio, Silvio; Maikusa, Norihide; Mak, Henry Ka-Fung; Malave, Vicente; Maldjian, Joseph; Mandal, Pravat; Mangin, Jean-Francois; Manjon, Jose; Mantri, Ninad; Manzour, Amir; Marambaud, Philippe; Marchewka, Artur; Marek, Kenneth; Markind, Samuel; Marshall, Gad; Martinez Torteya, Antonio; Mather, Mara; Mathis, Chester; Matoug, Sofia; Matsuo, Yoshiyuki; Mattei, Peter; Matthews, Dawn; McArdle, John; McCarroll, Steven; McEvoy, Linda; McGeown, William; McGonigle, John; McIntyre, John; McLaren, Donald; McQuail, Joseph; Meadowcroft, Mark; Meda, Shashwath; Mehta, Nirav; Melie-Garcia, Lester; Melrose, Rebecca; Mendonca, Brian; Menendez, Manuel; Meredith, Jere; Merrill, David; Mesulam, Marek-Marsel; Metti, Andrea; Meyer, Carsten; Mez, Jesse; Mickael, Guedj; Miftahof, Roustem; Mikhno, Arthur; Miller, David; Millikin, Colleen; Min, Ye; Mirza, Mubeena; Mistridis, Panagiota; Mitchell, Meghan; Mitsis, Effie; Mohan, Ananth; Moore, Dana; Moradi Birgani, Parmida; Moratal, David; Morimoto, Bruce; Mormino, Elizabeth; Mortamet, Benedicte; Moscato, Pablo; Mueller, Kathyrne; Mueller, Susanne; Mueller, Notger; Mukherjee, Shubhabrata; Mulder, Emma; Murayama, Shigeo; Murphy, Michael; Murray, Brian; Musiek, Erik; Myers, Amanda; Najafi, Shahla; Nazarparvar, Babak; Nazeri, Arash; Nettiksimmons, Jasmine; Neu, Scott; Ng, Yen-Bee; Nguyen, Nghi; Nguyen Xuan, Tuong; Nichols, Thomas; Nicodemus, Kristin; Niecko, Timothy; Nielsen, Casper; Notomi, Keiji; Nutakki, Gopi Chand; O'Bryant, Sid; O'Neil, Alison; Obisesan, Thomas; Oh, Dong Hoon; Oh, Joonmi; Okonkwo, Ozioma; Olde Rikkert, Marcel; Olmos, Salvador; Ortner, Marion; Ostrowitzki, Susanne; Oswald, Annahita; Ott, Brian; Ourselin, Sebastien; Ouyang, Gaoxiang; Paiva, Renata; Pan, Zhifang; Pande, Yogesh; Pardo, Jose; Pardoe, Heath; Park, Hyunjin; Park, Lovingly; Park, Moon Ho; Park, Sang hyun; Park, Kee Hyung; Park, Sujin; Parsey, Ramin; Parveen, Riswana; Paskavitz, James; Patel, Yogen; Patil, Manasi; Pawlak, Mikolaj; Payoux, Pierre; Pearson, Jim; Peavy, Guerry; Pell, Gaby; Peng, Yahong; Pennec, Xavier; Pepin, Jean louis; Perea, Rodrigo; Perneczky, Robert; Petitti, Diana; Petrella, Jeffrey; Peyrat, Jean-Marc; Pezoa, Jorge; Pham, Chi-Tuan; Phillips, Justin; Phillips, Nicole; Pierson, Ronald; Piovezan, Mauro; Podhorski, Adam; Pollari, Mika; Pontecorvo, Michael; Poppenk, Jordan; Posner, Holly; Potkin, Steven; Potter, Guy; Potter, Elizabeth; Poulin, Stephane; Prasad, Gautam; Prenger, Kurt; Prince, Jerry; Priya, Anandh; Puchakayala, Shashidhar Reddy; Qiu, Ruolun; Qiu, Anqi; Qiu, Wendy; Qualls, Constance Dean; Rabie, Huwaida; Rajeesh, Rajeesh; Rallabandi, V. P. Subramanyam; Ramage, Amy; Randolph, Christopher; Rao, Anil; Rao, Divya; Raubertas, Richard; Ray, Debashis; Razak, Hana; Redolfi, Alberto; Reed, Bruce; Reid, Andrew; Reilhac, Anthonin; Reinsberger, Claus; Restrepo, Lucas; Retico, Alessandra; Richards, John; Riddle, William; Ries, Michele; Rincon, Mariano; Rischall, Matt; Rizk-Jackson, Angela; Robieson, Weining; Rocha-Rego, Vanessa; Rogalski, Emily; Rogers, Elizabeth; Rojas, Ignacio; Rojas Balderrama, Javier; Romero, Klaus; Rorden, Chris; Rosand, Jonathan; Rosen, Allyson; Rosen, Ori; Rosenberg, Paul; Ross, David; Roubini, Eli; Rousseau, François; Rowe, Christopher; Rubin, Daniel; Rubright, Jonathan; Ruiz, Agustin; Rusinek, Henry; Ryan, Laurie; Saad, Ahmed; Sabbagh, Marway; Sabuncu, Mert; Sachs, Michael; Sadeghi, Ali; Said, Yasmine; Saint-Aubert, Laure; Sakata, Muneyuki; Salat, David; Salmon, David; Salter, Hugh; Samwald, Matthias; Sanchez, Luciano; Sanders, Elizabeth; Sanjo, Nobuo; Sarnel, Haldun; Sato, Hajime; Sato, Shinji; Saumier, Daniel; Savio, Alexandre; Sawada, Ikuhisa; Saykin, Andrew; Schaffer, J. David; Scharre, Douglas; Schegerin, Marc; Schlosser, Gretchen; Schmand, Ben; Schmansky, Nick; Schmidt, Mark; Schmidt-Wilcke, Tobias; Schneider, Lon; Schramm, Hauke; Schuerch, Markus; Schwartz, Eben; Schwartz, Craig; Schwarz, Adam; Seethamraju, Ravi; Seixas, Flavio; Selnes, Per; Senjem, Matthew; Senlin, Wang; Seo, Sang Won; Sethuraman, Gopalan; Sevigny, Jeffrey; Sfikas, Giorgos; Sghedoni, Roberto; Shah, Said Khalid; Shahbaba, Babak; Shams, Soheil; Shattuck, David; Shaw, Leslie; Sheela, Jaba; Shen, Weijia; Shen, Qian; Shera, David; Sherman, John; Sherva, Richard; Shi, Feng; Shukla, Vinay; Shuler, Catherine; Shulman, Joshua; Siegel, Rene; Siemers, Eric; Silveira, Margarida; Silver, Michael; Silverman, Daniel; Sim, Ida; Simmons, Andy; Simoes, Rita; Simon, Melvin; Simpson, Ivor; Singh, Simer Preet; Singh, Nikhil; Siuciak, Judy; Sjogren, Niclas; Skinner, Jeannine; Skup, Martha; Small, Gary; Smith, Michael; Smith, Benjamin; Smith, Charles; Smyth, Timothy; Snow, Sarah; Soares, Holly; Soldea, Octavian; Solomon, Paul; Solomon, Alan; Som, Subhojit; Song, Changhong; Song, Mingli; Sosova, Iveta; Soudah, Eduardo; Soydemir, Melih; Spampinato, Maria Vittoria; Spenger, Christian; Sperling, Reisa; Spiegel, Rene; Spies, Lothar; Squarcia, Sandro; Squire, Larry; Staff, Roger; Stern, Yaakov; Straw, Jack; Stricker, Nikki; Strittmatter, Stephen; Stühler, Elisabeth; Styren, Scot; Subramanian, Vijayalakshmi; Sugishita, Morihiro; Sukkar, Rafid; Sun, Jia; Sun, Ying; Sun, Yu; Sundell, Karen; Suri, Muhammad; Suzuki, Akiyuki; Svetnik, Vladimir; Swan, Melanie; Takahasi, Tetsuhiko; Takeuchi, Tomoko; Tanaka, Shoji; Tanchi, Chaturaphat; Tancredi, Daniel; Tao, Wenwen; Tao, Dacheng; Taylor-Reinwald, Lisa; Teng, Edmond; Terlizzi, Rita; Thames, April; Thiele, Frank; Thomas, Benjamin; Thomas, Ronald; Thompson, Paul; Thompson, Wesley; Thornton-Wells, Tricia; Thorvaldsson, Valgeir; Thurfjell, Lennart; Titeux, Laurence; Tokuda, Takahiko; Toledo, Juan B.; Tolli, Tuomas; Toma, Ahmed; Tomita, Naoki; Toro, Roberto; Torrealdea, Patxi; Tousian, Mona; Toussaint, Paule; Toyoshiba, Hiroyoshi; Tractenberg, Rochelle E.; Trittschuh, Emily; Trojanowski, John; Truran, Diana; Tsechpenakis, Gavriil; Tucker-Drob, Elliot; Tufail, Ahsan; Tung, Joyce; Turken, And; Ueda, Yoji; Ullrich, Lauren; Umadevi Venkataraju, Kannan; Umar, Nisser; Uzunbas, Gokhan; van de Nes, Joseph; van der Brug, Marcel; van Horn, John; van Leemput, Koen; van Train, Kenneth; van Zeeland, Ashley; Vasanawala, Minal; Vemuri, Prashanthi; Verwaerde, Philippe; Videbaek, Charlotte; Vidoni, Eric; Villanueva-Meyer, Javier; Visser, Pieter Jelle; Vitolo, Ottavio; Vounou, Maria; Wade, Sara; Walhovd, Kristine B.; Wan, Hong; Wang, Huanli; Wang, Yongmei Michelle; Wang, Yalin; Wang, Angela; Wang, Lei; Wang, Yue; Wang, Xu; Wang, Ze; Wang, Yaping; Wang, Tiger; Wang, Alex; Wang, Huali; Wang, Li-San; Wang, Wei; Wang, Li; Ward, Michael; Warfield, Simon; Waring, Stephen; Watanabe, Toshiyuki; Webb, David; Wei, Lili; Weiner, Michael; Wen, Shu-Hui; Wenjing, Li; Wenzel, Fabian; Westlye, Lars T.; Whitcher, Brandon; Whitlow, Christopher; Whitwell, Jennifer; Wilhelmsen, Kirk; Williams, David; Wilmot, Beth; Wimsatt, Matt; Wingo, Thomas; Wiste, Heather; Wolfson, Tanya; Wolke, Ira; Wolz, Robin; Woo, Jongwook; Woo, Ellen; Woods, Lynn; Worth, Andrew; Worth, Eric; Wouters, Hans; Wu, Teresa; Wu, Yi-Gen; Wu, Liang; Wu, Xiaoling; Wyman, Bradley; Wyss-Coray, Tony; Xiao, Guanghua; Xiao, Liu; Xie, Sharon; Xu, Shunbin; Xu, Ye; Xu, Yi-Zheng; Xu, Guofan; Xu, Jun; Yamane, Tomohiko; Yamashita, Fumio; Yan, Yunyi; Yan, Pingkun; Yang, Eric; Yang, Jinzhong; Yang, Qing X.; Yang, Zijiang; Yang, Guang; Yang, Zhitong; Yang, Wenlu; Ye, Liang; Ye, Byoung Seok; Ye, Jieping; Ye, Jong; Yee, Laura; Yesavage, Jerome; Ying, Song; Yoo, Bongin; Young, Jonathan; Yu, Shiwei; Yu, Dongchuan; Yuan, Guihong; Yuan, Kai; Yushkevich, Paul; Zaborszky, Laszlo; Zagorodnov, Vitali; Zagorski, Michael; Zawadzki, Rezi; Zeitzer, Jamie; Zelinski, Elizabeth; Zhang, Kurt; Zhang, Huixiong; Zhang, Tianhao; Zhang, Xin; Zhang, Ping; Zhang, Bin; Zhang, Jing; Zhang, Linda; Zhang, Lijun; Zhang, Zhiguo; Zhao, Qinying; Zhao, Jim; Zhao, Peng; Zhen, Xiantong; Zheng, Yuanjie; Zhijun, Yao; Zhou, Bin; Zhou, Sheng; Zhu, Wen; Zhu, Hongtu; Zhu, Wanlin; Zilka, Samantha; Zito, Giancarlo; Zou, Heng

    2011-01-01

    Amyloid-β accumulation in the brain is thought to be one of the earliest events in Alzheimer's disease, possibly leading to synaptic dysfunction, neurodegeneration and cognitive/functional decline. The earliest detectable changes seen with neuroimaging appear to be amyloid-β accumulation detected by

  9. A comparative analysis of the aggregation behavior of amyloid-β peptide variants

    NARCIS (Netherlands)

    Vandersteen, Annelies; Hubin, Ellen; Sarroukh, Rabia; De Baets, Greet; Schymkowitz, Joost; Rousseau, Frederic; Subramaniam, Vinod; Raussens, Vincent; Wenschuh, Holger; Wildemann, Dirk; Broersen, Kerensa

    2012-01-01

    Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Alzheimer disease (AD). The in vivo amyloid-β peptide pool consists of both C- and N-terminally truncated or mutated peptides, and the composition thereof significantly determines AD risk. Other

  10. Amyloid Load in Fat Tissue Reflects Disease Severity and Predicts Survival in Amyloidosis

    NARCIS (Netherlands)

    Van Gameren, Ingrid I.; Hazenberg, Bouke P. C.; Bijzet, Johan; Haagsma, Elizabeth B.; Vellenga, Edo; Posthumus, Marcel D.; Jager, Pieter L.; Van Rijswijk, Martin H.

    Objective. The severity of systemic amyloidosis is thought to be related to the extent of amyloid deposition. We studied whether amyloid load in fat tissue reflects disease severity and predicts survival. Methods. We studied all consecutive patients with systemic amyloidosis seen between January

  11. Interaction of the amyloid β peptide with sodium dodecyl sulfate as a membrane-mimicking detergent.

    NARCIS (Netherlands)

    Hashemi, Shabestari M.; Meeuwenoord, N.J.; Filippov, D.V.; Huber, M.I.

    2016-01-01

    The amyloid β (A β) peptide is important in the context of Alzheimer's disease, since it is one of the major components of the fibrils that constitute amyloid plaques. Agents that can influence fibril formation are important, and of those, membrane mimics are particularly relevant, because the

  12. Microglia kill amyloid-beta1-42 damaged neurons by a CD14-dependent process

    NARCIS (Netherlands)

    Bate, Clive; Veerhuis, Robert; Eikelenboom, Piet; Williams, Alun

    2004-01-01

    Activated microglia are closely associated with neuronal damage in Alzheimer's disease. In the present study, neurons exposed to low concentrations of amyloid-beta1-42, a toxic fragment of the amyloid-beta protein, were killed by microglia in a process that required cell-cell contact. Pre-treating

  13. Influence of hydrophobic Teflon particles on the structure of amyloid beta-peptide

    NARCIS (Netherlands)

    Giacomelli, C.E.; Norde, W.

    2003-01-01

    The amyloid beta-protein (Abeta) constitutes the major peptide component of the amyloid plaque deposits of Alzheimer's disease in humans. The Abeta changes from a nonpathogenic to a pathogenic conformation resulting in self-aggregation and deposition of the peptide. It has been established that

  14. Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia A Meta-analysis

    NARCIS (Netherlands)

    Jansen, W.J.; Ossenkoppele, R.; Knol, D.L.; Tijms, B.M.; Scheltens, P.; Verhey, F.R.J.; Visser, P.J.

    2015-01-01

    IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.

  15. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis

    NARCIS (Netherlands)

    Jansen, W.J.; Ossenkoppele, R.; Knol, D.L.; Tijms, B.M.; Scheltens, P.J.; Verhey, F.R.J.; Visser, P.J.; Aalten, P.; Aarsland, D.; Alcolea, D.; Alexander, M.; Almdahl, I.S.; Arnold, S.E.; Baldeiras, I.; Barthel, H.; Berckel, B.N. van; Bibeau, K.; Blennow, K.; Brooks, D.J.; Buchem, M.A. van; Camus, V.; Cavedo, E.; Chen, K.; Chetelat, G.; Cohen, A.D.; Drzezga, A.; Engelborghs, S.; Fagan, A.M.; Fladby, T.; Fleisher, A.S.; Flier, W.M. van der; Ford, L.; Forster, S.; Fortea, J.; Foskett, N.; Frederiksen, K.S.; Freund-Levi, Y.; Frisoni, G.B.; Froelich, L.; Gabryelewicz, T.; Gill, K.D.; Gkatzima, O.; Gomez-Tortosa, E.; Gordon, M.F.; Grimmer, T.; Hampel, H.; Hausner, L.; Hellwig, S.; Herukka, S.K.; Hildebrandt, H.; Ishihara, L.; Ivanoiu, A.; Jagust, W.J.; Johannsen, P.; Kandimalla, R.; Kapaki, E.; Klimkowicz-Mrowiec, A.; Klunk, W.E.; Kohler, S.; Koglin, N.; Kornhuber, J.; Kramberger, M.G.; Laere, K. Van; Landau, S.M.; Lee, D.Y.; Leon, M.; Lisetti, V.; Lleo, A.; Madsen, K.; Maier, W.; Marcusson, J.; Mattsson, N.; Mendonca, A. de; Meulenbroek, O.V.; Meyer, P.T.; Mintun, M.A.; Mok, V.; Molinuevo, J.L.; Mollergard, H.M.; Morris, J.C.; Mroczko, B.; Mussele, S. Van der; Na, D.L.; Newberg, A.; Nordberg, A.; Nordlund, A.; Novak, G.P.; Paraskevas, G.P.; Parnetti, L.; Perera, G.; Peters, O.; Popp, J.; Prabhakar, S.; Rabinovici, G.D.; Ramakers, I.H.; Rami, L.; Oliveira, C.R.; Rinne, J.O.; Rodrigue, K.M.; Rodriguez-Rodriguez, E.; Verbeek, M.M.; et al.,

    2015-01-01

    IMPORTANCE: Cerebral amyloid-beta aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention

  16. Protein Folding and Aggregation into Amyloid: The Interference by Natural Phenolic Compounds

    Directory of Open Access Journals (Sweden)

    Massimo Stefani

    2013-06-01

    Full Text Available Amyloid aggregation is a hallmark of several degenerative diseases affecting the brain or peripheral tissues, whose intermediates (oligomers, protofibrils and final mature fibrils display different toxicity. Consequently, compounds counteracting amyloid aggregation have been investigated for their ability (i to stabilize toxic amyloid precursors; (ii to prevent the growth of toxic oligomers or speed that of fibrils; (iii to inhibit fibril growth and deposition; (iv to disassemble preformed fibrils; and (v to favor amyloid clearance. Natural phenols, a wide panel of plant molecules, are one of the most actively investigated categories of potential amyloid inhibitors. They are considered responsible for the beneficial effects of several traditional diets being present in green tea, extra virgin olive oil, red wine, spices, berries and aromatic herbs. Accordingly, it has been proposed that some natural phenols could be exploited to prevent and to treat amyloid diseases, and recent studies have provided significant information on their ability to inhibit peptide/protein aggregation in various ways and to stimulate cell defenses, leading to identify shared or specific mechanisms. In the first part of this review, we will overview the significance and mechanisms of amyloid aggregation and aggregate toxicity; then, we will summarize the recent achievements on protection against amyloid diseases by many natural phenols.

  17. Cellular and substrate adhesion molecules (integrins) and their ligands in cerebral amyloid plaques in Alzheimer's disease

    NARCIS (Netherlands)

    Eikelenboom, P.; Zhan, S. S.; Kamphorst, W.; van der Valk, P.; Rozemuller, J. M.

    1994-01-01

    Integrins belonging to different subfamilies can be identified immunohistochemically in cerebral amyloid plaques. Monoclonal antibodies against the VLA family beta 1-integrins show staining of the corona of classical amyloid plaques for beta 1, alpha 3 and alpha 6. Immunostaining reveal also the

  18. Minocycline does not affect amyloid beta phagocytosis by human microglial cells

    NARCIS (Netherlands)

    Familian, Atoosa; Eikelenboom, Piet; Veerhuis, Robert

    2007-01-01

    Activated microglia accumulate in amyloid beta (Abeta) plaques containing amyloid associated factors SAP and C1q in Alzheimer's disease (AD) brain. Microglia are involved in AD pathogenesis by promoting Abeta plaque formation and production of pro-inflammatory cytokines. On the other hand,

  19. The Role of Functional Amyloids in Multicellular Growth and Development of Gram-Positive Bacteria

    NARCIS (Netherlands)

    Dragoš, A.; Kovács, Á.T.; Claessen, D.

    2017-01-01

    Amyloid fibrils play pivotal roles in all domains of life. In bacteria, these fibrillar structures are often part of an extracellular matrix that surrounds the producing organism and thereby provides protection to harsh environmental conditions. Here, we discuss the role of amyloid fibrils in the

  20. Amyloid-β secretion, generation, and lysosomal sequestration in response to proteasome inhibition

    DEFF Research Database (Denmark)

    Agholme, Lotta; Hallbeck, Martin; Benedikz, Eirikur

    2012-01-01

    , as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPP(Swe) transfected SH-SY5Y neuroblastoma cells. We show...

  1. Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

    DEFF Research Database (Denmark)

    Jansen, Willemijn J; Ossenkoppele, Rik; Tijms, Betty M

    2018-01-01

    Importance: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention tr...

  2. Conformational changes of the amyloid beta-peptide (1-40) adsorbed on solid surfaces

    NARCIS (Netherlands)

    Giacomelli, CE; Norde, W

    2005-01-01

    The conformational change of the 39-43 residues of the amyloid beta-peptide (A beta) toward a beta-sheet enriched state promotes self-aggregation of the peptide molecules and constitutes the major peptide component of the amyloid plaques in Alzheimer patients. The crucial question behind the

  3. Conformational changes of the amyloid beta-peptide (1-40) adsorbed on solid surfaces

    NARCIS (Netherlands)

    Giacomelli, C.E.; Norde, W.

    2005-01-01

    The conformational change of the 39-43 residues of the amyloid beta -peptide (A beta) toward a beta -sheet enriched state promotes self-aggregation of the peptide molecules and constitutes the major peptide component of the amyloid plaques in Alzheimer patients. The crucial question behind the

  4. Diagnostic performance and prognostic value of extravascular retention of I-123-labeled serum amyloid P component in systemic amyloidosis

    NARCIS (Netherlands)

    Hazenberg, Bouke P. C.; van Rijswijk, Martin H.; Lub-de Hooge, Marjolijn N.; Vellenga, Edo; Haagsma, Elizabeth B.; Posthumus, Marcel D.; Jager, Pieter L.

    Serum amyloid P component (SAP) binds to amyloid.I-123-SAP scintigraphy is used to evaluate the extent and distribution of amyloid in systemic amyloidosis and has great clinical value in the detection of systemic amyloidosis. The aim of the study was to assess during scintigraphy the diagnostic

  5. Spectroscopic study of Alzheimer's amyloid fibrils using terahertz time domain spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Euna; Kim, Jeonghoi; Han, Younho; Moon, Kiwon; Lim, Meehyun; Han, Haewook; Park, Joonhyuck; Kim, Sungjee [POSTECH, Pohang (Korea, Republic of)

    2008-11-15

    Alzheimer's disease, one of the most common neurodegenerative diseases, is characterized by extensive amyloid deposition. Amyloid deposits contain the abundant fibrils formed by amyloid β protein (Aβ). Because amyloid fibrils are associated with amyloid diseases, including Alzheimer's disease, type 2 diabetes, prion disease, Parkinson's disease, senile systemic amyloidosis and Huntington's disease, there has been considerable interest within the biomedical and biochemical research communities. In transmission electron microscopic (TEM)images, amyloid firils are 0.1∼10μm long and approximately 10nm wide. Amyloid fibrils commonly exhibit self assembled filaments, often described as twisted or parallel assemblies of finer protofilaments. They are formed by the spontaneous aggregation of a wide variety of peptides and proteins. Structural studies of amyloid fibrils have revealed that the common structural motif of virtually all amyloid fibrils consists of cross β sheets in which the peptide strands are arranged perpendicular to the long axis of the fiber. But little was known until recently about the molecular level structures of amyloid fibils. Therefore, spectroscopic investigation of both amyloid fibrils and Aβ at the molecular level can provide the significant evidence for the molecular understanding of amyloidogenesis and for the development of innovative therapeutic and diagnostic approaches. We used terahertz time domain spectroscopy (THz TDS)to investigate both Aβ and amyloid fibril. THz TDS, developed over the last two decades, is a powerful tool to extract the properties of biomaterials and provides unique spectral signatures of biomolecules within 0.1∼10THz, which exists between microwave and infrared frequency range. Current interest in THz radiation arises from its capability of probing the delocalized collective vibrational modes in proteins. Studying the collective modes of proteins in THz frequency range can play an

  6. Spectroscopic study of Alzheimer's amyloid fibrils using terahertz time domain spectroscopy

    International Nuclear Information System (INIS)

    Jung, Euna; Kim, Jeonghoi; Han, Younho; Moon, Kiwon; Lim, Meehyun; Han, Haewook; Park, Joonhyuck; Kim, Sungjee

    2008-01-01

    Alzheimer's disease, one of the most common neurodegenerative diseases, is characterized by extensive amyloid deposition. Amyloid deposits contain the abundant fibrils formed by amyloid β protein (Aβ). Because amyloid fibrils are associated with amyloid diseases, including Alzheimer's disease, type 2 diabetes, prion disease, Parkinson's disease, senile systemic amyloidosis and Huntington's disease, there has been considerable interest within the biomedical and biochemical research communities. In transmission electron microscopic (TEM)images, amyloid firils are 0.1∼10μm long and approximately 10nm wide. Amyloid fibrils commonly exhibit self assembled filaments, often described as twisted or parallel assemblies of finer protofilaments. They are formed by the spontaneous aggregation of a wide variety of peptides and proteins. Structural studies of amyloid fibrils have revealed that the common structural motif of virtually all amyloid fibrils consists of cross β sheets in which the peptide strands are arranged perpendicular to the long axis of the fiber. But little was known until recently about the molecular level structures of amyloid fibils. Therefore, spectroscopic investigation of both amyloid fibrils and Aβ at the molecular level can provide the significant evidence for the molecular understanding of amyloidogenesis and for the development of innovative therapeutic and diagnostic approaches. We used terahertz time domain spectroscopy (THz TDS)to investigate both Aβ and amyloid fibril. THz TDS, developed over the last two decades, is a powerful tool to extract the properties of biomaterials and provides unique spectral signatures of biomolecules within 0.1∼10THz, which exists between microwave and infrared frequency range. Current interest in THz radiation arises from its capability of probing the delocalized collective vibrational modes in proteins. Studying the collective modes of proteins in THz frequency range can play an important role in

  7. Feasibility and acceptance of simultaneous amyloid PET/MRI

    Energy Technology Data Exchange (ETDEWEB)

    Schuetz, Lisa; Tiepolt, Solveig; Werner, Peter; Jochimsen, Thies; Rullmann, Michael; Sattler, Bernhard; Patt, Marianne; Barthel, Henryk [Leipzig University Hospital, Department of Nuclear Medicine, Leipzig (Germany); Lobsien, Donald; Fritzsch, Dominik; Hoffmann, Karl-Titus [Leipzig University Hospital, Department of Neuroradiology, Leipzig (Germany); Schroeter, Matthias L.; Villringer, Arno [Leipzig University Hospital and Max Planck Institute for Human Cognitive and Brain Sciences, Day Clinic for Cognitive Neurology, Leipzig (Germany); Leipzig University Hospital, IFB Adiposity Diseases, Leipzig (Germany); Berrouschot, Joerg [Clinical Centre Altenburger Land, Altenburg (Germany); Saur, Dorothee; Classen, Joseph [Leipzig University Hospital, Department of Neurology, Leipzig (Germany); Hesse, Swen; Sabri, Osama [Leipzig University Hospital, Department of Nuclear Medicine, Leipzig (Germany); Leipzig University Hospital, IFB Adiposity Diseases, Leipzig (Germany); Gertz, Hermann-Josef [Leipzig University Hospital, Department of Psychiatry, Leipzig (Germany)

    2016-11-15

    Established Alzheimer's disease (AD) biomarker concepts classify into amyloid pathology and neuronal injury biomarkers, while recent alternative concepts classify into diagnostic and progression AD biomarkers. However, combined amyloid positron emission tomography/magnetic resonance imaging (PET/MRI) offers the chance to obtain both biomarker category read-outs within one imaging session, with increased patient as well as referrer convenience. The aim of this pilot study was to investigate this matter for the first time. 100 subjects (age 70 ± 10 yrs, 46 female), n = 51 with clinically defined mild cognitive impairment (MCI), n = 44 with possible/probable AD dementia, and n = 5 with frontotemporal lobe degeneration, underwent simultaneous [{sup 18}F]florbetaben or [{sup 11}C]PIB PET/MRI (3 Tesla Siemens mMR). Brain amyloid load, mesial temporal lobe atrophy (MTLA) by means of the Scheltens scale, and other morphological brain pathologies were scored by respective experts. The patients/caregivers as well as the referrers were asked to assess on a five-point scale the convenience related to the one-stop-shop PET and MRI approach. In three subjects, MRI revealed temporal lobe abnormalities other than MTLA. According to the National Institute on Aging-Alzheimer's Association classification, the combined amyloid-beta PET/MRI evaluation resulted in 31 %, 45 %, and 24 % of the MCI subjects being categorized as ''MCI-unlikely due to AD'', ''MCI due to AD-intermediate likelihood'', and ''MCI due to AD-high likelihood'', respectively. 50 % of the probable AD dementia patients were categorized as ''High level of evidence of AD pathophysiological process'', and 56 % of the possible AD dementia patients as ''Possible AD dementia - with evidence of AD pathophysiological process''. With regard to the International Working Group 2 classification, 36 subjects had both

  8. Serum amyloid A and haptoglobin concentrations and liver fat percentage in lactating dairy cows with abomasal displacement.

    Science.gov (United States)

    Guzelbektes, H; Sen, I; Ok, M; Constable, P D; Boydak, M; Coskun, A

    2010-01-01

    There has been increased interest in measuring the serum concentration of acute phase reactants such as serum amyloid A [SAA] and haptoglobin [haptoglobin] in periparturient cattle in order to provide a method for detecting the presence of inflammation or bacterial infection. To determine whether [SAA] and [haptoglobin] are increased in cows with displaced abomasum as compared with healthy dairy cows. Fifty-four adult dairy cows in early lactation that had left displaced abomasum (LDA, n = 34), right displaced abomasum or abomasal volvulus (RDA/AV, n = 11), or were healthy on physical examination (control, n = 9). Inflammatory diseases or bacterial infections such as mastitis, metritis, or pneumonia were not clinically apparent in any animal. Jugular venous blood was obtained from all cows and analyzed. Liver samples were obtained by biopsy in cattle with abomasal displacement. [SAA] and [haptoglobin] concentrations were increased in cows with LDA or RDA/AV as compared with healthy controls. Cows with displaced abomasum had mild to moderate hepatic lipidosis, based on liver fat percentages of 9.3 +/- 5.3% (mean +/- SD, LDA) and 10.8 +/- 7.7% (RDA/AV). [SAA] and [haptoglobin] were most strongly associated with liver fat percentage, r(s) = +0.55 (P hepatic lipidosis in cattle with abomasal displacement.

  9. Becoming Inclusive: A Code of Conduct for Inclusion and Diversity.

    Science.gov (United States)

    Schmidt, Bonnie J; MacWilliams, Brent R; Neal-Boylan, Leslie

    There are increasing concerns about exclusionary behaviors and lack of diversity in the nursing profession. Exclusionary behaviors, which may include incivility, bullying, and workplace violence, discriminate and isolate individuals and groups who are different, whereas inclusive behaviors encourage diversity. To address inclusion and diversity in nursing, this article offers a code of conduct. This code of conduct builds on existing nursing codes of ethics and applies to nursing students and nurses in both educational and practice settings. Inclusive behaviors that are demonstrated in nurses' relationships with patients, colleagues, the profession, and society are described. This code of conduct provides a basis for measureable change, empowerment, and unification of the profession. Recommendations, implications, and a pledge to action are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen

    Science.gov (United States)

    Usmani, Shariq M.; Zirafi, Onofrio; Müller, Janis; Sandi-Monroy, Nathallie; Yadav, Jay K.; Meier, Christoph; Weil, Tanja; Roan, Nadia R.; Greene, Warner C.; Walther, Paul; Nilsson, K. Peter R.; Hammarström, Per; Wetzel, Ronald; Pilcher, Christopher D.; Gagsteiger, Friedrich; Fändrich, Marcus; Kirchhoff, Frank; Münch, Jan

    2014-01-01

    Naturally occurring fragments of the abundant semen proteins prostatic acid phosphatase (PAP) and semenogelins form amyloid fibrils in vitro. These fibrils boost HIV infection and may play a key role in the spread of the AIDS pandemic. However, the presence of amyloid fibrils in semen remained to be demonstrated. Here, we use state of the art confocal and electron microscopy techniques for direct imaging of amyloid fibrils in human ejaculates. We detect amyloid aggregates in all semen samples and find that they partially consist of PAP fragments, interact with HIV particles and increase viral infectivity. Our results establish semen as a body fluid that naturally contains amyloid fibrils that are exploited by HIV to promote its sexual transmission. PMID:24691351

  11. Technical considerations on scanning and image analysis for amyloid PET in dementia

    International Nuclear Information System (INIS)

    Akamatsu, Go; Ohnishi, Akihito; Aita, Kazuki; Ikari, Yasuhiko; Senda, Michio; Yamamoto, Yasuji

    2017-01-01

    Brain imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), can provide essential and objective information for the early and differential diagnosis of dementia. Amyloid PET is especially useful to evaluate the amyloid-β pathological process as a biomarker of Alzheimer's disease. This article reviews critical points about technical considerations on the scanning and image analysis methods for amyloid PET. Each amyloid PET agent has its own proper administration instructions and recommended uptake time, scan duration, and the method of image display and interpretation. In addition, we have introduced general scanning information, including subject positioning, reconstruction parameters, and quantitative and statistical image analysis. We believe that this article could make amyloid PET a more reliable tool in clinical study and practice. (author)

  12. Technical Considerations on Scanning and Image Analysis for Amyloid PET in Dementia.

    Science.gov (United States)

    Akamatsu, Go; Ohnishi, Akihito; Aita, Kazuki; Ikari, Yasuhiko; Yamamoto, Yasuji; Senda, Michio

    2017-01-01

    Brain imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), can provide essential and objective information for the early and differential diagnosis of dementia. Amyloid PET is especially useful to evaluate the amyloid-β pathological process as a biomarker of Alzheimer's disease. This article reviews critical points about technical considerations on the scanning and image analysis methods for amyloid PET. Each amyloid PET agent has its own proper administration instructions and recommended uptake time, scan duration, and the method of image display and interpretation. In addition, we have introduced general scanning information, including subject positioning, reconstruction parameters, and quantitative and statistical image analysis. We believe that this article could make amyloid PET a more reliable tool in clinical study and practice.

  13. Extracellular DNA facilitates the formation of functional amyloids in Staphylococcus aureus biofilms.

    Science.gov (United States)

    Schwartz, Kelly; Ganesan, Mahesh; Payne, David E; Solomon, Michael J; Boles, Blaise R

    2016-01-01

    Persistent staphylococcal infections often involve surface-associated communities called biofilms. Staphylococcus aureus biofilm development is mediated by the co-ordinated production of the biofilm matrix, which can be composed of polysaccharides, extracellular DNA (eDNA) and proteins including amyloid fibers. The nature of the interactions between matrix components, and how these interactions contribute to the formation of matrix, remain unclear. Here we show that the presence of eDNA in S. aureus biofilms promotes the formation of amyloid fibers. Conditions or mutants that do not generate eDNA result in lack of amyloids during biofilm growth despite the amyloidogeneic subunits, phenol soluble modulin peptides, being produced. In vitro studies revealed that the presence of DNA promotes amyloid formation by PSM peptides. Thus, this work exposes a previously unacknowledged interaction between biofilm matrix components that furthers our understanding of functional amyloid formation and S. aureus biofilm biology. © 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.

  14. Co-deposition of basement membrane components during the induction of murine splenic AA amyloid

    DEFF Research Database (Denmark)

    Lyon, A W; Narindrasorasak, S; Young, I D

    1991-01-01

    Past studies have demonstrated that during murine AA amyloid induction there is co-deposition of the AA amyloid peptide and the basement membrane form of heparan sulfate proteoglycan. The synthesis and accumulation of heparan sulfate proteoglycan does not usually occur in the absence of other...... basement membrane components, such as type IV collagen, laminin, and fibronectin. Using immunohistochemical techniques, the present experiments have demonstrated that in addition to the heparan sulfate proteoglycan, there are other basement membrane components present in splenic AA amyloid deposits...... and these are present as soon as AA amyloid deposits are detectable. The results indicate that within the time constraints imposed by the experiments, the basement membrane components, fibronectin, laminin, type IV collagen, and heparan sulfate proteoglycan are co-deposited 36 to 48 hours after the AgNO3 and amyloid...

  15. Amyloid Fibrils as Building Blocks for Natural and Artificial Functional Materials.

    Science.gov (United States)

    Knowles, Tuomas P J; Mezzenga, Raffaele

    2016-08-01

    Proteinaceous materials based on the amyloid core structure have recently been discovered at the origin of biological functionality in a remarkably diverse set of roles, and attention is increasingly turning towards such structures as the basis of artificial self-assembling materials. These roles contrast markedly with the original picture of amyloid fibrils as inherently pathological structures. Here we outline the salient features of this class of functional materials, both in the context of the functional roles that have been revealed for amyloid fibrils in nature, as well as in relation to their potential as artificial materials. We discuss how amyloid materials exemplify the emergence of function from protein self-assembly at multiple length scales. We focus on the connections between mesoscale structure and material function, and demonstrate how the natural examples of functional amyloids illuminate the potential applications for future artificial protein based materials. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. The proteome response to amyloid protein expression in vivo.

    Directory of Open Access Journals (Sweden)

    Ricardo A Gomes

    Full Text Available Protein misfolding disorders such as Alzheimer, Parkinson and transthyretin amyloidosis are characterized by the formation of protein amyloid deposits. Although the nature and location of the aggregated proteins varies between different diseases, they all share similar molecular pathways of protein unfolding, aggregation and amyloid deposition. Most effects of these proteins are likely to occur at the proteome level, a virtually unexplored reality. To investigate the effects of an amyloid protein expression on the cellular proteome, we created a yeast expression system using human transthyretin (TTR as a model amyloidogenic protein. We used Saccharomyces cerevisiae, a living test tube, to express native TTR (non-amyloidogenic and the amyloidogenic TTR variant L55P, the later forming aggregates when expressed in yeast. Differential proteome changes were quantitatively analyzed by 2D-differential in gel electrophoresis (2D-DIGE. We show that the expression of the amyloidogenic TTR-L55P causes a metabolic shift towards energy production, increased superoxide dismutase expression as well as of several molecular chaperones involved in protein refolding. Among these chaperones, members of the HSP70 family and the peptidyl-prolyl-cis-trans isomerase (PPIase were identified. The latter is highly relevant considering that it was previously found to be a TTR interacting partner in the plasma of ATTR patients but not in healthy or asymptomatic subjects. The small ubiquitin-like modifier (SUMO expression is also increased. Our findings suggest that refolding and degradation pathways are activated, causing an increased demand of energetic resources, thus the metabolic shift. Additionally, oxidative stress appears to be a consequence of the amyloidogenic process, posing an enhanced threat to cell survival.

  17. Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Matias-Guiu, Jordi A.; Pytel, Vanesa; Galan, Lucia; Valles-Salgado, Maria; Guerrero, Antonio; Moreno-Ramos, Teresa; Matias-Guiu, Jorge; Cabrera-Martin, Maria Nieves; Carreras, Jose Luis

    2016-01-01

    We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS). This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with 18 F-fluorodeoxyglucose (FDG), and amyloid-PET with 18 F-florbetaben. Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased 18 F-florbetaben uptake compared to controls. We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint. (orig.)

  18. In vivo amyloid imaging with PET in frontotemporal dementia

    International Nuclear Information System (INIS)

    Engler, Henry; Santillo, Alexander F.; Lindau, Maria; Lannfelt, Lars; Kilander, Lena; Wang, Shu Xia; Savitcheva, Irina; Nordberg, Agneta; Laangstroem, Bengt

    2008-01-01

    N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. The aim of this study is to investigate PIB retention in FTD. Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD. (orig.)

  19. Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Matias-Guiu, Jordi A.; Pytel, Vanesa; Galan, Lucia; Valles-Salgado, Maria; Guerrero, Antonio; Moreno-Ramos, Teresa; Matias-Guiu, Jorge [Hospital Clinico San Carlos, San Carlos Institute for Health Research (IdISSC), Universidad Complutense de Madrid, Department of Neurology, Madrid (Spain); Cabrera-Martin, Maria Nieves; Carreras, Jose Luis [Hospital Clinico San Carlos, San Carlos Institute for Health Research (IdISSC), Universidad Complutense de Madrid, Department of Nuclear Medicine, Madrid (Spain)

    2016-10-15

    We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS). This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with {sup 18}F-fluorodeoxyglucose (FDG), and amyloid-PET with {sup 18}F-florbetaben. Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased {sup 18}F-florbetaben uptake compared to controls. We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint. (orig.)

  20. In vivo amyloid imaging with PET in frontotemporal dementia

    Energy Technology Data Exchange (ETDEWEB)

    Engler, Henry [Uruguay University Hospital of Clinics and Faculty of Science, Department of Nuclear Medicine, Montevideo (Uruguay); Uppsala University Hospital, Department of Nuclear Medicine, Uppsala (Sweden); Uppsala University, Department of Medical Sciences, Uppsala (Sweden); GE Healthcare, Uppsala Imanet, Uppsala (Sweden); Santillo, Alexander F.; Lindau, Maria; Lannfelt, Lars; Kilander, Lena [Uppsala University, Department of Public Health and Caring Sciences/Geriatrics, Uppsala (Sweden); Wang, Shu Xia [Guangdong Provincial People' s Hospital, Weilun PET Centre, Guangzhou (China); Savitcheva, Irina [Uppsala University Hospital, Department of Nuclear Medicine, Uppsala (Sweden); Nordberg, Agneta [Karolinska Institute, Division of Molecular Neuropharmacology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden); Laangstroem, Bengt [GE Healthcare, Uppsala Imanet, Uppsala (Sweden); Uppsala University, Departments of Biochemistry and Organic Chemistry, Uppsala (Sweden)

    2008-01-15

    N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. The aim of this study is to investigate PIB retention in FTD. Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD. (orig.)

  1. Multiple isoforms of the human pentraxin serum amyloid P component

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH

    1995-01-01

    Human serum amyloid P component (SAP) isolated from 20 healthy individuals was analyzed by anion exchange chromatography and isoelectric focusing (IEF) in order to investigate the existence of multiple forms of SAP and interindividual structural differences. Anion exchange chromatography showed one...... major and several minor subpopulations of SAP. IEF of all SAP isolates showed a previously unreported degree of heterogeneity with six isoelectric forms (pKi range 5.5-6.1) and with minor interindividual differences in respect of isoelectric points. Total enzymatic deglycosylation of SAP reduced...... the number of bands in IEF to two indicating the existence of two types of polypeptide chains....

  2. Mass Determination of Entire Amyloid Fibrils by Using Mass Spectrometry.

    Science.gov (United States)

    Doussineau, Tristan; Mathevon, Carole; Altamura, Lucie; Vendrely, Charlotte; Dugourd, Philippe; Forge, Vincent; Antoine, Rodolphe

    2016-02-12

    Amyloid fibrils are self-assembled protein structures with important roles in biology (either pathogenic or physiological), and are attracting increasing interest in nanotechnology. However, because of their high aspect ratio and the presence of some polymorphism, that is, the possibility to adopt various structures, their characterization is challenging and basic information such as their mass is unknown. Here we show that charge-detection mass spectrometry, recently developed for large self-assembled systems such as viruses, provides such information in a straightforward manner. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease.

    Science.gov (United States)

    Parbo, Peter; Ismail, Rola; Hansen, Kim V; Amidi, Ali; Mårup, Frederik H; Gottrup, Hanne; Brændgaard, Hans; Eriksson, Bengt O; Eskildsen, Simon F; Lund, Torben E; Tietze, Anna; Edison, Paul; Pavese, Nicola; Stokholm, Morten G; Borghammer, Per; Hinz, Rainer; Aanerud, Joel; Brooks, David J

    2017-07-01

    See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-β have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition. © 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.

  4. Demands from the school inclusion

    Directory of Open Access Journals (Sweden)

    Selma Norberto Matos

    2014-04-01

    Full Text Available From the implementation of public policies on school inclusion, mainly those directed to the target audience of special education, the number of students with special educational needs in common classes has increased. This fact has helped to compose the picture in schools where the limitations and contradictions of the Brazilian educational system have appeared. Educational actors and authors are challenged to build knowledge able of responding to demands of daily school, concerning living and learning in diversity. Whereas this inclusive process is new in the schools, the study aimed to analyze the demands of teachers from the school inclusion. The research was qualitative and exploratory, and six teachers, their students with special educational needs and three professionals in the Nucleus of Inclusive Education from the Municipal Department of Education took in it. Technique of participant observation, field diary, semi-structured interview and questionnaire were used for data collection, while analysis of content was used for discussion of the data. The results indicate that there are achievements and contradictions in the reality of schools that themselves propose inclusive; advances and limitations resulting from the municipal politics; that the model of performance of the group of special education, in the context analyzed, may be revised or expanded; and that the teachers has demands with regard to public policy, training, and the psychologist.

  5. Social inclusion and mental health.

    Science.gov (United States)

    Cobigo, Virginie; Stuart, Heather

    2010-09-01

    Recent research on approaches to improving social inclusion for people with mental disabilities is reviewed. We describe four approaches (or tools) that can be used to improve social inclusion for people with mental disabilities: legislation, community-based supports and services, antistigma/antidiscrimination initiatives, and system monitoring and evaluation. While legislative solutions are the most prevalent, and provide an important framework to support social inclusion, research shows that their full implementation remains problematic. Community-based supports and services that are person-centered and recovery-oriented hold considerable promise, but they are not widely available nor have they been widely evaluated. Antistigma and antidiscrimination strategies are gaining in popularity and offer important avenues for eliminating social barriers and promoting adequate and equitable access to care. Finally, in the context of the current human rights and evidence-based health paradigms, systematic evidence will be needed to support efforts to promote social inclusion for people with mental disabilities, highlight social inequities, and develop best practice approaches. Tools that promote social inclusion of persons with mental disabilities are available, though not yet implemented in a way to fully realize the goals of current disability discourse.

  6. Inclusive production at LHC energies

    International Nuclear Information System (INIS)

    Merino, C.; Pajares, C.; Shabelski, Yu.M.

    2011-01-01

    We consider the first LHC data for pp collisions in the framework of Regge theory. The integral cross sections and inclusive densities of secondaries are determined by the Pomeron exchange, and we present the corresponding predictions for them. The first measurements of inclusive densities in the midrapidity region are in agreement with these predictions. The contribution of the baryon-number transfer due to String Junction diffusion in the rapidity space is at the origin of the differences in the inclusive spectra of particle and antiparticle in the central region, and this effect could be significant at LHC energies. We discuss the first data of ALICE and LHCb collaborations on the baryon/antibaryon asymmetry at LHC. (orig.)

  7. Evaluation of Sialic Acid and Acute Phase Proteins (Haptoglobin and Serum Amyloid A in Clinical and Subclinical Bovine Mastitis

    Directory of Open Access Journals (Sweden)

    S. Nazifi*, M. Haghkhah1, Z. Asadi, M. Ansari-Lari2, M. R. Tabandeh3, Z. Esmailnezhad and M. Aghamiri

    2011-01-01

    Full Text Available The present study was conducted to evaluate the concentrations of sialic acids (total, lipid bound and protein bound and their correlation with acute phase proteins (haptoglobin and serum amyloid A in clinical and subclinical mastitis of cattle. Thirty subclinical mastitic cows with positive California mastitis test (CMT test and no clinical signs of mastitis, 10 clinical mastitic cows and 10 healthy cows with negative CMT test and normal somatic cell count were selected. Milk and blood samples were collected after confirmation of clinical and subclinical mastitis by somatic cell count and bacterial identification. Serum haptoglobin (Hp, serum amyloid A (SAA, total sialic acid (TSA, lipid bound sialic acid (LBSA and protein bound sialic acid (PBSA were measured by validated standard methods. Haptoglobin and SAA increased significantly in both types of mastitis compared with control group (P<0.001. However, the ratio of HP/SAA was significantly different from the control group only in clinical mastitis. The results showed that TSA and LBSA were significantly different in control group compared with clinical and subclinical mastitis (P<0.001. Protein bound sialic acid did not change in subclinical mastitis in comparison with control group (P=0.86. There was positive correlation between LBSA and PBSA in clinical mastitis (r=0.72, P=0.02 whereas significant negative correlation was observed between LBSA and PBSA in subclinical mastitis (r=-0.62, P<0.001. Results also showed no correlation between Hp and SAA with each other or with any other parameters in study groups.

  8. Amyloid arthropathy of the hip joint: MR demonstration of presumed amyloid lesions in 152 patients with long-term hemodialysis

    International Nuclear Information System (INIS)

    Otake, S.; Yamana, D.; Tsuruta, Y.; Mizutani, H.; Ohba, S.

    1998-01-01

    The aim of this study was to determine the spectrum of MR findings of presumed amyloid arthropathy of the hip joints in patients on long-term hemodialysis. We prospectively performed T1- and T2-weighted spin-echo imaging on 152 consecutive patients on hemodialysis. The duration of hemodialysis ranged from 5 months to 24 years, 2 months (mean: 8 years, 8 months). The frequency, location, and signal intensity of bone lesions were assessed. In 12 cases with contrast-enhanced MR examination, enhancement pattern of bone lesions, synovial lesions, and intra-articular lesions were characterized. Bone lesions presumed to be amyloid deposits were identified in 60 patients (39 %). Magnetic resonance imaging revealed that amyloid lesions were more extensive than anticipated by plain radiographs. All bone lesions showed decreased signal intensity on T1-weighted images. On T2-weighted images, bone lesions showed increased signal intensity in 32 patients (54 %), decreased signal intensity in 11 patients (18 %), and both increased and decreased signal intensity in 17 patients (28 %). Following intravenous injection of gadolinium-based contrast, all bone lesions showed moderate enhancement. Synovial thickening could not be identified on T1- and T2-weighted images. However, contrast-enhanced images showed thickened synovial membrane, which could be differentiated from joint fluid. Intra-articular nodules showed decreased or intermediate signal intensity on T1-weighted images and decreased signal intensity on T2-weighted images; the intra-articular nodules were contiguous with subchondral bone lesions. Magnetic resonance imaging is useful for evaluating the distribution and extent of amyloidosis of the hip joints in patients undergoing long-term hemodialysis. (orig.) (orig.)

  9. The late endocytic Rab39a GTPase regulates the interaction between multivesicular bodies and chlamydial inclusions.

    Science.gov (United States)

    Gambarte Tudela, Julian; Capmany, Anahi; Romao, Maryse; Quintero, Cristian; Miserey-Lenkei, Stephanie; Raposo, Graca; Goud, Bruno; Damiani, Maria Teresa

    2015-08-15

    Given their obligate intracellular lifestyle, Chlamydia trachomatis ensure that they have access to multiple host sources of essential lipids by interfering with vesicular transport. These bacteria hijack Rab6-, Rab11- and Rab14-controlled trafficking pathways to acquire sphingomyelin from the Golgi complex. Another important source of sphingolipids, phospholipids and cholesterol are multivesicular bodies (MVBs). Despite their participation in chlamydial inclusion development and bacterial replication, the molecular mechanisms mediating the interaction between MVBs and chlamydial inclusions remain unknown. In the present study, we demonstrate that Rab39a labels a subset of late endocytic vesicles - mainly MVBs - that move along microtubules. Moreover, Rab39a is actively recruited to chlamydial inclusions throughout the pathogen life cycle by a bacterial-driven process that depends on the Rab39a GTP- or GDP-binding state. Interestingly, Rab39a participates in the delivery of MVBs and host sphingolipids to maturing chlamydial inclusions, thereby promoting inclusion growth and bacterial development. Taken together, our findings indicate that Rab39a favours chlamydial replication and infectivity. This is the first report showing that a late endocytic Rab GTPase is involved in chlamydial infection development. © 2015. Published by The Company of Biologists Ltd.

  10. Doing Research Inclusively: Bridges to Multiple Possibilities in Inclusive Research

    Science.gov (United States)

    Nind, Melanie; Vinha, Hilra

    2014-01-01

    This article reports on a study of how people do research that matters to people with learning disabilities and that involves them and their views and experiences. The study was an attempt to bring together people doing inclusive research so that, collectively, we could take stock of our practices. This would add to the individual reports and…

  11. The Inclusion of Music/the Music of Inclusion

    Science.gov (United States)

    Lubet, Alex

    2009-01-01

    The intention of this paper is to situate music within inclusive education. Intersections of music--widely regarded as a "talent" or hyperability--and disability provide unique perspectives on social organisation in general and human valuation in particular. Music is a ubiquitous and an essential component of learning beginning in infancy.…

  12. Inhibitory Activities of Antioxidant Flavonoids from Tamarix gallica on Amyloid Aggregation Related to Alzheimer's and Type 2 Diabetes Diseases.

    Science.gov (United States)

    Ben Hmidene, Asma; Hanaki, Mizuho; Murakami, Kazuma; Irie, Kazuhiro; Isoda, Hiroko; Shigemori, Hideyuki

    2017-01-01

    The prevention of amyloid aggregation is promising for the treatment of age-related diseases such as Alzheimer's (AD) and type 2 diabetes (T2D). Ten antioxidant flavonoids isolated from the medicinal halophyte Tamarix gallica were tested for their amyloid aggregation inhibition potential. Glucuronosylated flavonoids show relatively strong inhibitory activity of Amyloid β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregation compared to their aglycone analogs. Structure-activity relationship of the flavonoids suggests that the catechol moiety is important for amyloid aggregation inhibition, while the methylation of the carboxyl group in the glucuronide moiety and of the hydroxyl group in the aglycone flavonoids decreased it.

  13. Characterization of interactions between inclusion membrane proteins from Chlamydia trachomatis

    Directory of Open Access Journals (Sweden)

    Emilie eGauliard

    2015-02-01

    Full Text Available Chlamydiae are obligate intracellular pathogens of eukaryotes. The bacteria grow in an intracellular vesicle called an inclusion, the membrane of which is heavily modified by chlamydial proteins called Incs (Inclusion membrane proteins. Incs represent 7-10% of the genomes of Chlamydia and, given their localization at the interface between the host and the pathogen, likely play a key role in the development and pathogenesis of the bacterium. However, their functions remain largely unknown. Here, we characterized the interaction properties between various Inc proteins of C. trachomatis, using a bacterial two-hybrid (BACTH method suitable for detecting interactions between integral membrane proteins. To validate this approach, we first examined the oligomerization properties of the well-characterized IncA protein and showed that both the cytoplasmic domain and the transmembrane region independently contribute to IncA oligomerization. We then analyzed a set of Inc proteins and identified novel interactions between these components. Two small Incs, IncF and Ct222, were found here to interact with many other Inc proteins and may thus represent interaction nodes within the inclusion membrane. Our data suggest that the Inc proteins may assemble in the membrane of the inclusion to form specific multi-molecular complexes in an hierarchical and temporal manner. These studies will help to better define the putative functions of the Inc proteins in the infectious process of Chlamydia.

  14. Inclusiveness program - a SWOT analysis

    Science.gov (United States)

    Dósa, M.; Szegő, K.

    2017-09-01

    The Inclusiveness Program was created with the aim to integrate currently under-represented countries into the mainstream of European planetary research. Main stages of the working plan include setting up a database containing all the research institutes and universities where astronomical or geophysical research is carried out. It is necessary to identify their problems and needs. Challenging part of the project is to find exact means that help their work in a sustainable way. Strengths, weaknesses, opportunities and threats of the program were identified based on feedback from the inclusiveness community. Our conclusions, further suggestions are presented.

  15. A new integrated dual time-point amyloid PET/MRI data analysis method

    Energy Technology Data Exchange (ETDEWEB)

    Cecchin, Diego; Zucchetta, Pietro; Turco, Paolo; Bui, Franco [University Hospital of Padua, Nuclear Medicine Unit, Department of Medicine - DIMED, Padua (Italy); Barthel, Henryk; Tiepolt, Solveig; Sabri, Osama [Leipzig University, Department of Nuclear Medicine, Leipzig (Germany); Poggiali, Davide; Cagnin, Annachiara; Gallo, Paolo [University Hospital of Padua, Neurology, Department of Neurosciences (DNS), Padua (Italy); Frigo, Anna Chiara [University Hospital of Padua, Biostatistics, Epidemiology and Public Health Unit, Department of Cardiac, Thoracic and Vascular Sciences, Padua (Italy)

    2017-11-15

    In the initial evaluation of patients with suspected dementia and Alzheimer's disease, there is no consensus on how to perform semiquantification of amyloid in such a way that it: (1) facilitates visual qualitative interpretation, (2) takes the kinetic behaviour of the tracer into consideration particularly with regard to at least partially correcting for blood flow dependence, (3) analyses the amyloid load based on accurate parcellation of cortical and subcortical areas, (4) includes partial volume effect correction (PVEC), (5) includes MRI-derived topographical indexes, (6) enables application to PET/MRI images and PET/CT images with separately acquired MR images, and (7) allows automation. A method with all of these characteristics was retrospectively tested in 86 subjects who underwent amyloid ({sup 18}F-florbetaben) PET/MRI in a clinical setting (using images acquired 90-110 min after injection, 53 were classified visually as amyloid-negative and 33 as amyloid-positive). Early images after tracer administration were acquired between 0 and 10 min after injection, and later images were acquired between 90 and 110 min after injection. PVEC of the PET data was carried out using the geometric transfer matrix method. Parametric images and some regional output parameters, including two innovative ''dual time-point'' indexes, were obtained. Subjects classified visually as amyloid-positive showed a sparse tracer uptake in the primary sensory, motor and visual areas in accordance with the isocortical stage of the topographic distribution of the amyloid plaque (Braak stages V/VI). In patients classified visually as amyloid-negative, the method revealed detectable levels of tracer uptake in the basal portions of the frontal and temporal lobes, areas that are known to be sites of early deposition of amyloid plaques that probably represented early accumulation (Braak stage A) that is typical of normal ageing. There was a strong correlation between

  16. A new integrated dual time-point amyloid PET/MRI data analysis method

    International Nuclear Information System (INIS)

    Cecchin, Diego; Zucchetta, Pietro; Turco, Paolo; Bui, Franco; Barthel, Henryk; Tiepolt, Solveig; Sabri, Osama; Poggiali, Davide; Cagnin, Annachiara; Gallo, Paolo; Frigo, Anna Chiara

    2017-01-01

    In the initial evaluation of patients with suspected dementia and Alzheimer's disease, there is no consensus on how to perform semiquantification of amyloid in such a way that it: (1) facilitates visual qualitative interpretation, (2) takes the kinetic behaviour of the tracer into consideration particularly with regard to at least partially correcting for blood flow dependence, (3) analyses the amyloid load based on accurate parcellation of cortical and subcortical areas, (4) includes partial volume effect correction (PVEC), (5) includes MRI-derived topographical indexes, (6) enables application to PET/MRI images and PET/CT images with separately acquired MR images, and (7) allows automation. A method with all of these characteristics was retrospectively tested in 86 subjects who underwent amyloid ( 18 F-florbetaben) PET/MRI in a clinical setting (using images acquired 90-110 min after injection, 53 were classified visually as amyloid-negative and 33 as amyloid-positive). Early images after tracer administration were acquired between 0 and 10 min after injection, and later images were acquired between 90 and 110 min after injection. PVEC of the PET data was carried out using the geometric transfer matrix method. Parametric images and some regional output parameters, including two innovative ''dual time-point'' indexes, were obtained. Subjects classified visually as amyloid-positive showed a sparse tracer uptake in the primary sensory, motor and visual areas in accordance with the isocortical stage of the topographic distribution of the amyloid plaque (Braak stages V/VI). In patients classified visually as amyloid-negative, the method revealed detectable levels of tracer uptake in the basal portions of the frontal and temporal lobes, areas that are known to be sites of early deposition of amyloid plaques that probably represented early accumulation (Braak stage A) that is typical of normal ageing. There was a strong correlation between age

  17. Bacterial Cell Mechanics.

    Science.gov (United States)

    Auer, George K; Weibel, Douglas B

    2017-07-25

    Cellular mechanical properties play an integral role in bacterial survival and adaptation. Historically, the bacterial cell wall and, in particular, the layer of polymeric material called the peptidoglycan were the elements to which cell mechanics could be primarily attributed. Disrupting the biochemical machinery that assembles the peptidoglycan (e.g., using the β-lactam family of antibiotics) alters the structure of this material, leads to mechanical defects, and results in cell lysis. Decades after the discovery of peptidoglycan-synthesizing enzymes, the mechanisms that underlie their positioning and regulation are still not entirely understood. In addition, recent evidence suggests a diverse group of other biochemical elements influence bacterial cell mechanics, may be regulated by new cellular mechanisms, and may be triggered in different environmental contexts to enable cell adaptation and survival. This review summarizes the contributions that different biomolecular components of the cell wall (e.g., lipopolysaccharides, wall and lipoteichoic acids, lipid bilayers, peptidoglycan, and proteins) make to Gram-negative and Gram-positive bacterial cell mechanics. We discuss the contribution of individual proteins and macromolecular complexes in cell mechanics and the tools that make it possible to quantitatively decipher the biochemical machinery that contributes to bacterial cell mechanics. Advances in this area may provide insight into new biology and influence the development of antibacterial chemotherapies.

  18. Biodegradability of bacterial surfactants.

    Science.gov (United States)

    Lima, Tânia M S; Procópio, Lorena C; Brandão, Felipe D; Carvalho, André M X; Tótola, Marcos R; Borges, Arnaldo C

    2011-06-01

    This work aimed at evaluating the biodegradability of different bacterial surfactants in liquid medium and in soil microcosms. The biodegradability of biosurfactants by pure and mixed bacterial cultures was evaluated through CO(2) evolution. Three bacterial strains, Acinetobacter baumanni LBBMA ES11, Acinetobacter haemolyticus LBBMA 53 and Pseudomonas sp. LBBMA 101B, used the biosurfactants produced by Bacillus sp. LBBMA 111A (mixed lipopeptide), Bacillus subtilis LBBMA 155 (lipopeptide), Flavobacterium sp. LBBMA 168 (mixture of flavolipids), Dietzia Maris LBBMA 191(glycolipid) and Arthrobacter oxydans LBBMA 201(lipopeptide) as carbon sources in minimal medium. The synthetic surfactant sodium dodecyl sulfate (SDS) was also mineralized by these microorganisms, but at a lower rate. CO(2) emitted by a mixed bacterial culture in soil microcosms with biosurfactants was higher than in the microcosm containing SDS. Biosurfactant mineralization in soil was confirmed by the increase in surface tension of the soil aqueous extracts after incubation with the mixed bacterial culture. It can be concluded that, in terms of biodegradability and environmental security, these compounds are more suitable for applications in remediation technologies in comparison to synthetic surfactants. However, more information is needed on structure of biosurfactants, their interaction with soil and contaminants and scale up and cost for biosurfactant production.

  19. Neuroprotective effects of statins against amyloid β-induced neurotoxicity

    Directory of Open Access Journals (Sweden)

    Hsin-Hua Li

    2018-01-01

    Full Text Available A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer's disease (AD. In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β (Aβ levels by affecting amyloid precursor protein (APP cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuroprotective effects against AD. Statins may play a beneficial role in reducing Aβ-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing Aβ-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase (AMPK in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.

  20. Comparing the Folds of Prions and Other Pathogenic Amyloids

    Directory of Open Access Journals (Sweden)

    José Miguel Flores-Fernández

    2018-05-01

    Full Text Available Pathogenic amyloids are the main feature of several neurodegenerative disorders, such as Creutzfeldt–Jakob disease, Alzheimer’s disease, and Parkinson’s disease. High resolution structures of tau paired helical filaments (PHFs, amyloid-β(1-42 (Aβ(1-42 fibrils, and α-synuclein fibrils were recently reported using cryo-electron microscopy. A high-resolution structure for the infectious prion protein, PrPSc, is not yet available due to its insolubility and its propensity to aggregate, but cryo-electron microscopy, X-ray fiber diffraction, and other approaches have defined the overall architecture of PrPSc as a 4-rung β-solenoid. Thus, the structure of PrPSc must have a high similarity to that of the fungal prion HET-s, which is part of the fungal heterokaryon incompatibility system and contains a 2-rung β-solenoid. This review compares the structures of tau PHFs, Aβ(1-42, and α-synuclein fibrils, where the β-strands of each molecule stack on top of each other in a parallel in-register arrangement, with the β-solenoid folds of HET-s and PrPSc.

  1. Redundancy and divergence in the amyloid precursor protein family.

    Science.gov (United States)

    Shariati, S Ali M; De Strooper, Bart

    2013-06-27

    Gene duplication provides genetic material required for functional diversification. An interesting example is the amyloid precursor protein (APP) protein family. The APP gene family has experienced both expansion and contraction during evolution. The three mammalian members have been studied quite extensively in combined knock out models. The underlying assumption is that APP, amyloid precursor like protein 1 and 2 (APLP1, APLP2) are functionally redundant. This assumption is primarily supported by the similarities in biochemical processing of APP and APLPs and on the fact that the different APP genes appear to genetically interact at the level of the phenotype in combined knockout mice. However, unique features in each member of the APP family possibly contribute to specification of their function. In the current review, we discuss the evolution and the biology of the APP protein family with special attention to the distinct properties of each homologue. We propose that the functions of APP, APLP1 and APLP2 have diverged after duplication to contribute distinctly to different neuronal events. Our analysis reveals that APLP2 is significantly diverged from APP and APLP1. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  2. Iodine-123-labelled serum amyloid P component scintigraphy in amyloidosis

    International Nuclear Information System (INIS)

    Saile, R.; Deveaux, M.; Marchandise, X.; Duquesnoy, B.

    1993-01-01

    This study describes the results of scintigraphy with iodine-123-labelled serum amyloid P component (SAP) as a means of establishing the distribution of organ involvement in amyloidosis. The significance of 123 I-SAP scans obtained in 15 patients with biopsy-proven AA or AL amyloidosis is discussed. Biopsy-proven amyloidosis was typically confirmed by scintigraphy, though such confirmation was not obtained in the kidneys in six patients with histological proof of extensive renal amyloid deposition. This lack of uptake may have been due to the accumulation of a major part of the 123 I-SAP in the spleen and/or liver. Twenty-four hour whole-body retention of 123 I-SAP was higher in patients with amyloidosis than in controls. Twenty-four hour tracer accumulation of the radioactivity in the extravascular compartment was notably greater in patients than in controls and appeared to be a good diagnostic criterion. We conclude that 123 I-SAP scintigraphy may be helpful for the evaluation of organ involvement not only in patients with biopsy-proven amyloidosis but also when a biopsy cannot be performed or when a strong suspicion of amyloidosis exists in spite of repeated negative biopsises. (orig.)

  3. Aspects of structural landscape of human islet amyloid polypeptide

    Energy Technology Data Exchange (ETDEWEB)

    He, Jianfeng, E-mail: hjf@bit.edu.cn; Dai, Jin, E-mail: daijing491@gmail.com [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Li, Jing, E-mail: jinglichina@139.com [Institute of Biopharmaceutical Research, Yangtze River Pharmaceutical Group Beijing Haiyan Pharmaceutical Co., Ltd, Beijing 102206 (China); Peng, Xubiao, E-mail: xubiaopeng@gmail.com [Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Niemi, Antti J., E-mail: Antti.Niemi@physics.uu.se [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Laboratoire de Mathematiques et Physique Theorique CNRS UMR 6083, Fédération Denis Poisson, Université de Tours, Parc de Grandmont, F37200 Tours (France)

    2015-01-28

    The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation.

  4. Serum amyloid A protein in amyloidosis, rheumatic, and neoplastic diseases

    International Nuclear Information System (INIS)

    Benson, M.D.; Cohen, A.S.

    1979-01-01

    Serum levels of amyloid protein A (SAA) have been shown to be elevated in different types of amyloidosis and in rheumatic diseases by radioimmunoassay using 125 iodine labeled AA and anti-AA. SAA levels were elevated in both primary and secondary amyloidosis, but there were highly significant differences between these levels. In heredofamilial amyloid, SAA levels were within normal limits. While the mean SAA level was elevated in persons over 70 years, the fact that some persons in this age group had normal levels suggested that marked elevation after age 70 may be due to occult inflammatory or neoplastic disease. High SAA levels in patients with rheumatoid arthritis correlated, in most cases, with physician evaluation of disease activity and Westergren ESR. SAA levels in patients with systemic lupus erythematosus were lower than those in patients with rheumatoid arthritis, and most patients with degenerative joint disease had normal levels. Very high levels of SAA were found in patients with neoplastic diseases. Patients with carcinoma of the lung and bowel had much higher levels than patients with carcinoma of the breast. Determination of SAA levels may be of value in evaluating different forms of systemic amyloidosis, assessing the activity of rheumatic disease, and screening for occult inflammatory or neoplastic disease

  5. Photoacoustic assay for probing amyloid formation: feasibility study

    Science.gov (United States)

    Petrova, Elena; Yoon, Soon Joon; Pelivanov, Ivan; O'Donnell, Matthew

    2018-02-01

    The formation of amyloid - aggregate of misfolded proteins - is associated with more than 50 human pathologies, including Alzheimer's disease, Parkinson's disease, and Type 2 diabetes mellitus. Investigating protein aggregation is a critical step in drug discovery and development of therapeutics targeted to these pathologies. However, screens to identify protein aggregates are challenging due to the stochastic character of aggregate nucleation. Here we employ photoacoustics (PA) to screen thermodynamic conditions and solution components leading to formation of protein aggregates. Particularly, we study the temperature dependence of the Gruneisen parameter in optically-contrasted, undersaturated and supersaturated solutions of glycoside hydrolase (lysozyme). As nucleation of protein aggregates proceeds in two steps, where the first is liquid-liquid separation (rearrangement of solute's density), the PA response from complex solutions and its temperature-dependence monitor nucleation and differentiate undersaturated and supersaturated protein solutions. We demonstrate that in the temperature range from 22 to 0° C the PA response of contrasted undersaturated protein solution behaves similar to water and exhibits zero thermal expansion at 4°C or below, while the response of contrasted supersaturated protein solution is nearly temperature independent, similar to the behavior of oils. These results can be used to develop a PA assay for high-throughput screening of multi-parametric conditions (pH, ionic strength, chaperone, etc.) for protein aggregation that can become a key tool in drug discovery, targeting aggregate formation for a variety of amyloids.

  6. Regulation of amyloid precursor protein processing by its KFERQ motif.

    Science.gov (United States)

    Park, Ji-Seon; Kim, Dong-Hou; Yoon, Seung-Yong

    2016-06-01

    Understanding of trafficking, processing, and degradation mechanisms of amyloid precursor protein (APP) is important because APP can be processed to produce β-amyloid (Aβ), a key pathogenic molecule in Alzheimer's disease (AD). Here, we found that APP contains KFERQ motif at its C-terminus, a consensus sequence for chaperone-mediated autophagy (CMA) or microautophagy which are another types of autophagy for degradation of pathogenic molecules in neurodegenerative diseases. Deletion of KFERQ in APP increased C-terminal fragments (CTFs) and secreted N-terminal fragments of APP and kept it away from lysosomes. KFERQ deletion did not abolish the interaction of APP or its cleaved products with heat shock cognate protein 70 (Hsc70), a protein necessary for CMA or microautophagy. These findings suggest that KFERQ motif is important for normal processing and degradation of APP to preclude the accumulation of APP-CTFs although it may not be important for CMA or microautophagy. [BMB Reports 2016; 49(6): 337-342].

  7. Polymorphism complexity and handedness inversion in serum albumin amyloid fibrils.

    Science.gov (United States)

    Usov, Ivan; Adamcik, Jozef; Mezzenga, Raffaele

    2013-12-23

    Protein-based amyloid fibrils can show a great variety of polymorphic structures within the same protein precursor, although the origins of these structural homologues remain poorly understood. In this work we investigate the fibrillation of bovine serum albumin--a model globular protein--and we follow the polymorphic evolution by a statistical analysis of high-resolution atomic force microscopy images, complemented, at larger length scales, by concepts based on polymer physics formalism. We identify six distinct classes of coexisting amyloid fibrils, including flexible left-handed twisted ribbons, rigid right-handed helical ribbons and nanotubes. We show that the rigid fibrils originate from flexible fibrils through two diverse polymorphic transitions, first, via a single-fibril transformation when the flexible left-handed twisted ribbons turn into the helical left-handed ribbons, to finally evolve into nanotube-like structures, and second, via a double-fibril transformation when two flexible left-handed twisted ribbons wind together resulting in a right-handed twisted ribbon, followed by a rigid right-handed helical ribbon polymorphic conformation. Hence, the change in handedness occurs with an increase in the level of the fibril's structural organization.

  8. Morphology and mechanical properties of multi-stranded amyloid fibrils probed by atomistic and coarse-grained simulations

    International Nuclear Information System (INIS)

    Yoon, Gwonchan; Lee, Myeongsang; Kim, Kyungwoo; In Kim, Jae; Joon Chang, Hyun; Baek, Inchul; Na, Sungsoo; Eom, Kilho

    2015-01-01

    Amyloid fibrils are responsible for pathogenesis of various diseases and exhibit the structural feature of an ordered, hierarchical structure such as multi-stranded helical structure. As the multi-strandedness of amyloid fibrils has recently been found to be highly correlated with their toxicity and infectivity, it is necessary to study how the hierarchical (i.e. multi-stranded) structure of amyloid fibril is formed. Moreover, although it has recently been reported that the nanomechanics of amyloid proteins plays a key role on the amyloid-induced pathogenesis, a critical role that the multi-stranded helical structure of the fibrils plays in their nanomechanical properties has not fully characterized. In this work, we characterize the morphology and mechanical properties of multi-stranded amyloid fibrils by using equilibrium molecular dynamics simulation and elastic network model. It is shown that the helical pitch of multi-stranded amyloid fibril is linearly proportional to the number of filaments comprising the amyloid fibril, and that multi-strandedness gives rise to improving the bending rigidity of the fibril. Moreover, we have also studied the morphology and mechanical properties of a single protofilament (filament) in order to understand the effect of cross-β structure and mutation on the structures and mechanical properties of amyloid fibrils. Our study sheds light on the underlying design principles showing how the multi-stranded amyloid fibril is formed and how the structure of amyloid fibrils governs their nanomechanical properties. (paper)

  9. Bacterial meningitis in children

    International Nuclear Information System (INIS)

    Marji, S.

    2007-01-01

    To demonstrate the epidemiology, clinical manifestations and bacteriological profile of bacterial meningitis in children beyond the neonatal period in our hospital. This was a retrospective descriptive study conducted at Prince Rashid Hospital in Irbid, Jordan. The medical records of 50 children with the diagnosis of bacterial meningitis during 4 years period, were reviewed. The main cause of infection was streptococcus pneumoniae, followed by Haemophilus influenza and Niesseria meningitides. Mortality was higher in infants and meningococcal infection, while complications were more encountered in cases of streptococcus pneumoniae. Cerebrospinal fluid culture was positive in 11 cases and Latex agglutination test in 39. There is a significant reduction of the numbers of bacterial meningitis caused by Haemophilus influenza type B species. (author)

  10. Diverse Perspectives on Inclusive School Communities

    Science.gov (United States)

    Tsokova, Diana; Tarr, Jane

    2012-01-01

    What is an inclusive school community? How do stakeholders perceive their roles and responsibilities towards inclusive school communities? How can school communities become more inclusive through engagement with individual perspectives? "Diverse Perspectives on Inclusive School Communities" captures and presents the voices of a wide…

  11. Inclusion in the Workplace - Text Version | NREL

    Science.gov (United States)

    Careers » Inclusion in the Workplace - Text Version Inclusion in the Workplace - Text Version This is the text version for the Inclusion: Leading by Example video. I'm Martin Keller. I'm the NREL of the laboratory. Another very important element in inclusion is diversity. Because if we have a

  12. Difference, inclusion, and mathematics education

    DEFF Research Database (Denmark)

    Figueiras, Lourdes; Healy, Lulu; Skovsmose, Ole

    2016-01-01

    The round-table discussion on Difference, Inclusion and Mathematics Education was in included in the scientific programme of VI SIPEM in recognition and celebration of the emerging body of research into the challenges of building a culture of mathematics education which values and respects the di...

  13. Early Childhood Inclusion in Croatia

    Science.gov (United States)

    Ljubešic, Marta; Šimleša, Sanja

    2016-01-01

    This article explains early childhood inclusion in Croatia from its beginnings up to challenges in current policy and practice. The first preschool education for children with disabilities dates back to the 1980s and was provided in special institutions. In the last 10 years, mainstream kindergartens have been enrolling children with disabilities…

  14. Inclusion body myositis. Clinical aspects

    NARCIS (Netherlands)

    Cox, Fieke Maria Elisabeth

    2014-01-01

    Sporadische inclusion body myositis (IBM) is een van de meest voor voorkomende verworven spierziekte die ontstaat na het 50e levensjaar. In dit proefschrift worden de klinische aspecten van sporadische IBM beschreven. Uit de studie met betrekking tot het natuurlijk beloop blijkt dat de ziekte niet

  15. Inclusive Education and the Arts

    Science.gov (United States)

    Allan, Julie

    2014-01-01

    This paper addresses the troubled, problematic and contested field of inclusive education, characterised by antagonisms between so-called inclusionists and special educationists; frustration, particularly among disability activists caused by the abstraction of the social model of disability and the expansion of the special educational needs…

  16. Inclusive Education: Lessons from History

    Science.gov (United States)

    Boroson, Barbara

    2017-01-01

    How has education evolved from exclusion to inclusion, from judgment to acceptance, and from disability to difference? This is the question that frames Barbara Boroson's article in the theme issue, "Differences, Not Disabilities." Boroson begins by taking a historical view of how schools have treated those who were perceived to be…

  17. Nonlocal quasilinear damped differential inclusions

    Directory of Open Access Journals (Sweden)

    Mouffak Benchohra

    2002-01-01

    Full Text Available In this paper we investigate the existence of mild solutions to second order initial value problems for a class of damped differential inclusions with nonlocal conditions. By using suitable fixed point theorems, we study the case when the multivalued map has convex and nonconvex values.

  18. Evolution: From Isolation to Inclusion.

    Science.gov (United States)

    Kehoe, Sharon M.

    1998-01-01

    Today, school district leaders must comply with multiple federal statutes (Individuals with Disabilities Act, Section 504 of the Rehabilitation Act, and Americans with Disabilities Act). The trend is toward full inclusion, despite judicial overrulings, clarifications of "least restrictive environment," and emergence of opposing groups.…

  19. Tracing Inclusion: Determining Teacher Attitudes

    Science.gov (United States)

    Logan, Brenda E.; Wimer, Gregory

    2013-01-01

    Though there appears to be an onslaught of No Child Left Behind, there is still more emphasis on testing than ever before. With the new implementation of national common-core standards, many school districts have moved towards full inclusive classrooms. However, it is rare that teachers have any input on whether such major decisions are apropos…

  20. Early Childhood Inclusion in Israel

    Science.gov (United States)

    Al-Yagon, Michal; Aram, Dorit; Margalit, Malka

    2016-01-01

    This article describes conceptual aspects, current policies and practices, and research representing the Israeli perspective regarding early childhood inclusion (ECI) at preschool ages (3-6 years). We review legislative, historical, attitudinal, philosophical, practical, empirical, and cultural issues regarding ECI in Israel. Finally, we focus on…

  1. Early Childhood Inclusion in Australia

    Science.gov (United States)

    Kemp, Coral R.

    2016-01-01

    From the introduction of early intervention services in Australian in the mid-1970s, the families of children with intellectual and multiple disabilities have been encouraged to enroll their children in local preschools and childcare centers. Children with disabilities have also accessed a range of alternatives to full inclusion, such as reverse…

  2. Inclusive fitness theory and eusociality

    DEFF Research Database (Denmark)

    Abbot, P.; Wrangham, R.; Abe, J.

    2011-01-01

    Arising from M. A. Nowak, C. E. Tarnita & E. O. Wilson 466, 1057-1062 (2010); Nowak et al. reply. Nowak et al. argue that inclusive fitness theory has been of little value in explaining the natural world, and that it has led to negligible progress in explaining the evolution of eusociality. However...

  3. Detection of AA-type amyloid protein in labial salivary glands.

    Science.gov (United States)

    Sacsaquispe, Sonia-Julia; Antúnez-de Mayolo, Eleazar-Antonio; Vicetti, Rodolfo; Delgado, Wilson-Alejandro

    2011-03-01

    Among the diverse forms of amyloidosis, secondary type is the most frequent one. Diagnosis of amyloid deposition is based on the identification of the fibrillary protein amyloid by means of Congo Red (CR) or crystal violet (CV) stains, but these techniques do not differentiate between the different types of amyloid fibrils. The aim of this study was to identify by immunofluorescence (IF) AA amyloid a pathological fibrillar low-molecular-weight protein formed by cleavage of serum amyloid A (SAA) protein in labial salivary gland (LSG) biopsies from patients with secondary amyloidosis. 98 LSG were studied, 65 were from patients with secondary amyloidosis and 33 from subjects with chronic inflammatory diseases without evidence of this anomaly. All sections were stained with hematoxylin and eosin (H &E), CV, CR and IF using anti-AA antibodies. Positive and negative controls were used for all techniques. CV and CR demonstrated that the amyloid substance was found mainly distributed periductally (93.8%), followed by periacinar and perivascular locations (p <0.001); however, the IF demonstrated that amyloid AA substance predominates in the periacinar area (73.8%), followed by periductal and perivascular locations (p <0.001). IF has a sensitivity of 83%, 100% of specificity, 100% of predictive positive value and 75% of predictive negative value. The results of this study confirm the efficacy of the LSG biopsy as a highly reliable method for diagnosis of secondary amyloidosis.

  4. Proteomic analysis of highly prevalent amyloid A amyloidosis endemic to endangered island foxes.

    Directory of Open Access Journals (Sweden)

    Patricia M Gaffney

    Full Text Available Amyloid A (AA amyloidosis is a debilitating, often fatal, systemic amyloid disease associated with chronic inflammation and persistently elevated serum amyloid A (SAA. Elevated SAA is necessary but not sufficient to cause disease and the risk factors for AA amyloidosis remain poorly understood. Here we identify an extraordinarily high prevalence of AA amyloidosis (34% in a genetically isolated population of island foxes (Urocyon littoralis with concurrent chronic inflammatory diseases. Amyloid deposits were most common in kidney (76%, spleen (58%, oral cavity (45%, and vasculature (44% and were composed of unbranching, 10 nm in diameter fibrils. Peptide sequencing by mass spectrometry revealed that SAA peptides were dominant in amyloid-laden kidney, together with high levels of apolipoprotein E, apolipoprotein A-IV, fibrinogen-α chain, and complement C3 and C4 (false discovery rate ≤ 0.05. Reassembled peptide sequences showed island fox SAA as an 111 amino acid protein, most similar to dog and artic fox, with 5 unique amino acid variants among carnivores. SAA peptides extended to the last two C-terminal amino acids in 5 of 9 samples, indicating that near full length SAA was often present in amyloid aggregates. These studies define a remarkably prevalent AA amyloidosis in island foxes with widespread systemic amyloid deposition, a unique SAA sequence, and the co-occurrence of AA with apolipoproteins.

  5. Insights into the variability of nucleated amyloid polymerization by a minimalistic model of stochastic protein assembly

    Energy Technology Data Exchange (ETDEWEB)

    Eugène, Sarah, E-mail: Sarah.Eugene@inria.fr; Doumic, Marie, E-mail: Philippe.Robert@inria.fr, E-mail: Marie.Doumic@inria.fr [INRIA de Paris, 2 Rue Simone Iff, CS 42112, 75589 Paris Cedex 12 (France); Sorbonne Universités, UPMC Université Pierre et Marie Curie, UMR 7598, Laboratoire Jacques-Louis Lions, F-75005 Paris (France); Xue, Wei-Feng, E-mail: W.F.Xue@kent.ac.uk [School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ (United Kingdom); Robert, Philippe, E-mail: Philippe.Robert@inria.fr [INRIA de Paris, 2 Rue Simone Iff, CS 42112, 75589 Paris Cedex 12 (France)

    2016-05-07

    Self-assembly of proteins into amyloid aggregates is an important biological phenomenon associated with human diseases such as Alzheimer’s disease. Amyloid fibrils also have potential applications in nano-engineering of biomaterials. The kinetics of amyloid assembly show an exponential growth phase preceded by a lag phase, variable in duration as seen in bulk experiments and experiments that mimic the small volumes of cells. Here, to investigate the origins and the properties of the observed variability in the lag phase of amyloid assembly currently not accounted for by deterministic nucleation dependent mechanisms, we formulate a new stochastic minimal model that is capable of describing the characteristics of amyloid growth curves despite its simplicity. We then solve the stochastic differential equations of our model and give mathematical proof of a central limit theorem for the sample growth trajectories of the nucleated aggregation process. These results give an asymptotic description for our simple model, from which closed form analytical results capable of describing and predicting the variability of nucleated amyloid assembly were derived. We also demonstrate the application of our results to inform experiments in a conceptually friendly and clear fashion. Our model offers a new perspective and paves the way for a new and efficient approach on extracting vital information regarding the key initial events of amyloid formation.

  6. Adult bacterial meningitis

    DEFF Research Database (Denmark)

    Meyer, C N; Samuelsson, I S; Galle, M

    2004-01-01

    Episodes of adult bacterial meningitis (ABM) at a Danish hospital in 1991-2000 were identified from the databases of the Department of Clinical Microbiology, and compared with data from the Danish National Patient Register and the Danish National Notification System. Reduced penicillin susceptibi......Episodes of adult bacterial meningitis (ABM) at a Danish hospital in 1991-2000 were identified from the databases of the Department of Clinical Microbiology, and compared with data from the Danish National Patient Register and the Danish National Notification System. Reduced penicillin...

  7. Inclusion

    DEFF Research Database (Denmark)

    Jørgensen, Stine Kaplan

    2017-01-01

    Paperet sætter fokus på inklusion i en dans sammenhæng, med særligt fokus på mobning. Der tages udgangspunkt i et fællesskabsorienteret mobbesyn, der udpeger særlige opmærksomhedspunkter til såvel forebyggelse som intervention....

  8. INCLUSIVE CULTURE IN PRE-SCHOOL INSTITUTIONS

    Directory of Open Access Journals (Sweden)

    Irena NOVACHEVSKA

    2011-04-01

    Full Text Available Inclusive education is a rational concept that refers to the overall and long-term transformation of institutional systems in society, especially in education. Along with the transformation, a number of important and unresolved issues still appear in both theory and practice, as the duty of pre-school institutions and schools is to educate every student in the mainstream education system. One of the most important aspects of inclusion is the inclusive culture. Regardless of the good inclusive policy and practice, one cannot talk about successful inclusion without a properly developed inclusive institutional culture.This paper is a contribution to the research considering the development of inclusive culture in three preschool institutions. It is based on the thinking and attitudes of the pre­school staff toward the necessity of developing and nurturing an inclusive culture. Successful inclusion of pupils with special needs in the mainstream school system cannot be conceived without an inclusive culture.

  9. Peptide p5 binds both heparinase-sensitive glycosaminoglycans and fibrils in patient-derived AL amyloid extracts

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Emily B.; Williams, Angela [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Heidel, Eric [Department of Surgery, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Macy, Sallie [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Kennel, Stephen J. [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Department of Radiology, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Wall, Jonathan S., E-mail: jwall@utmck.edu [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Department of Radiology, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States)

    2013-06-21

    Highlights: •Polybasic peptide p5 binds human light chain amyloid extracts. •The binding of p5 with amyloid involves both glycosaminoglycans and fibrils. •Heparinase treatment led to a correlation between p5 binding and fibril content. •p5 binding to AL amyloid requires electrostatic interactions. -- Abstract: In previously published work, we have described heparin-binding synthetic peptides that preferentially recognize amyloid deposits in a mouse model of reactive systemic (AA) amyloidosis and can be imaged by using positron and single photon emission tomographic imaging. We wanted to extend these findings to the most common form of visceral amyloidosis, namely light chain (AL); however, there are no robust experimental animal models of AL amyloidosis. To further define the binding of the lead peptide, p5, to AL amyloid, we characterized the reactivity in vitro of p5 with in situ and patient-derived AL amyloid extracts which contain both hypersulfated heparan sulfate proteoglycans as well as amyloid fibrils. Histochemical staining demonstrated that the peptide specifically localized with tissue-associated AL amyloid deposits. Although we anticipated that p5 would undergo electrostatic interactions with the amyloid-associated glycosaminoglycans expressing heparin-like side chains, no significant correlation between peptide binding and glycosaminoglycan content within amyloid extracts was observed. In contrast, following heparinase I treatment, although overall binding was reduced, a positive correlation between peptide binding and amyloid fibril content became evident. This interaction was further confirmed using synthetic light chain fibrils that contain no carbohydrates. These data suggest that p5 can bind to both the sulfated glycosaminoglycans and protein fibril components of AL amyloid. Understanding these complex electrostatic interactions will aid in the optimization of synthetic peptides for use as amyloid imaging agents and potentially as

  10. A high-glycemic diet is associated with cerebral amyloid burden in cognitively normal older adults.

    Science.gov (United States)

    Taylor, Matthew K; Sullivan, Debra K; Swerdlow, Russell H; Vidoni, Eric D; Morris, Jill K; Mahnken, Jonathan D; Burns, Jeffrey M

    2017-12-01

    Background: Little is known about the relation between dietary intake and cerebral amyloid accumulation in aging. Objective: We assessed the association of dietary glycemic measures with cerebral amyloid burden and cognitive performance in cognitively normal older adults. Design: We performed cross-sectional analyses relating dietary glycemic measures [adherence to a high-glycemic-load diet (HGLDiet) pattern, intakes of sugar and carbohydrates, and glycemic load] with cerebral amyloid burden (measured by florbetapir F-18 positron emission tomography) and cognitive performance in 128 cognitively normal older adults who provided eligibility screening data for the University of Kansas's Alzheimer's Prevention through Exercise (APEX) Study. The study began in November 2013 and is currently ongoing. Results: Amyloid was elevated in 26% ( n = 33) of participants. HGLDiet pattern adherence ( P = 0.01), sugar intake ( P = 0.03), and carbohydrate intake ( P = 0.05) were significantly higher in participants with elevated amyloid burden. The HGLDiet pattern was positively associated with amyloid burden both globally and in all regions of interest independently of age, sex, and education (all P ≤ 0.001). Individual dietary glycemic measures (sugar intake, carbohydrate intake, and glycemic load) were also positively associated with global amyloid load and nearly all regions of interest independently of age, sex, and educational level ( P ≤ 0.05). Cognitive performance was associated only with daily sugar intake, with higher sugar consumption associated with poorer global cognitive performance (global composite measure and Mini-Mental State Examination) and performance on subtests of Digit Symbol, Trail Making Test B, and Block Design, controlling for age, sex, and education. Conclusion: A high-glycemic diet was associated with greater cerebral amyloid burden, which suggests diet as a potential modifiable behavior for cerebral amyloid accumulation and subsequent Alzheimer

  11. Depressive symptoms accelerate cognitive decline in amyloid-positive MCI patients

    Energy Technology Data Exchange (ETDEWEB)

    Brendel, Matthias; Xiong, Guoming; Delker, Andreas [University of Munich, Department of Nuclear Medicine, Munich (Germany); Pogarell, Oliver [University of Munich, Department of Psychiatry, Munich (Germany); Bartenstein, Peter; Rominger, Axel [University of Munich, Department of Nuclear Medicine, Munich (Germany); Munich Cluster for Systems Neurology (SyNergy), Munich (Germany); Collaboration: for the Alzheimer' s Disease Neuroimaging Initiative

    2015-04-01

    Late-life depression even in subsyndromal stages is strongly associated with Alzheimer's disease (AD). Furthermore, brain amyloidosis is an early biomarker in subjects who subsequently suffer from AD and can be sensitively detected by amyloid PET. Therefore, we aimed to compare amyloid load and glucose metabolism in subsyndromally depressed subjects with mild cognitive impairment (MCI). [{sup 18}F]AV45 PET, [{sup 18}F]FDG PET and MRI were performed in 371 MCI subjects from the Alzheimer's Disease Neuroimaging Initiative Subjects were judged β-amyloid-positive (Aβ+; 206 patients) or β-amyloid-negative (Aβ-; 165 patients) according to [{sup 18}F]AV45 PET. Depressive symptoms were assessed by the Neuropsychiatric Inventory Questionnaire depression item 4. Subjects with depressive symptoms (65 Aβ+, 41 Aβ-) were compared with their nondepressed counterparts. Conversion rates to AD were analysed (mean follow-up time 21.5 ± 9.1 months) with regard to coexisting depressive symptoms and brain amyloid load. Aβ+ depressed subjects showed large clusters with a higher amyloid load in the frontotemporal and insular cortices (p < 0.001) with coincident hypermetabolism (p < 0.001) in the frontal cortices than nondepressed subjects. Faster progression to AD was observed in subjects with depressive symptoms (p < 0.005) and in Aβ+ subjects (p < 0.001). Coincident depressive symptoms additionally shortened the conversion time in all Aβ+ subjects (p < 0.005) and to a greater extent in those with a high amyloid load (p < 0.001). Our results clearly indicate that Aβ+ MCI subjects with depressive symptoms have an elevated amyloid load together with relative hypermetabolism of connected brain areas compared with cognitively matched nondepressed individuals. MCI subjects with high amyloid load and coexistent depressive symptoms are at high risk of faster conversion to AD. (orig.)

  12. Depressive symptoms accelerate cognitive decline in amyloid-positive MCI patients

    International Nuclear Information System (INIS)

    Brendel, Matthias; Xiong, Guoming; Delker, Andreas; Pogarell, Oliver; Bartenstein, Peter; Rominger, Axel

    2015-01-01

    Late-life depression even in subsyndromal stages is strongly associated with Alzheimer's disease (AD). Furthermore, brain amyloidosis is an early biomarker in subjects who subsequently suffer from AD and can be sensitively detected by amyloid PET. Therefore, we aimed to compare amyloid load and glucose metabolism in subsyndromally depressed subjects with mild cognitive impairment (MCI). [ 18 F]AV45 PET, [ 18 F]FDG PET and MRI were performed in 371 MCI subjects from the Alzheimer's Disease Neuroimaging Initiative Subjects were judged β-amyloid-positive (Aβ+; 206 patients) or β-amyloid-negative (Aβ-; 165 patients) according to [ 18 F]AV45 PET. Depressive symptoms were assessed by the Neuropsychiatric Inventory Questionnaire depression item 4. Subjects with depressive symptoms (65 Aβ+, 41 Aβ-) were compared with their nondepressed counterparts. Conversion rates to AD were analysed (mean follow-up time 21.5 ± 9.1 months) with regard to coexisting depressive symptoms and brain amyloid load. Aβ+ depressed subjects showed large clusters with a higher amyloid load in the frontotemporal and insular cortices (p < 0.001) with coincident hypermetabolism (p < 0.001) in the frontal cortices than nondepressed subjects. Faster progression to AD was observed in subjects with depressive symptoms (p < 0.005) and in Aβ+ subjects (p < 0.001). Coincident depressive symptoms additionally shortened the conversion time in all Aβ+ subjects (p < 0.005) and to a greater extent in those with a high amyloid load (p < 0.001). Our results clearly indicate that Aβ+ MCI subjects with depressive symptoms have an elevated amyloid load together with relative hypermetabolism of connected brain areas compared with cognitively matched nondepressed individuals. MCI subjects with high amyloid load and coexistent depressive symptoms are at high risk of faster conversion to AD. (orig.)

  13. Key points concerning amyloid infectivity and prion-like neuronal invasion

    Directory of Open Access Journals (Sweden)

    Alba eEspargaró

    2016-04-01

    Full Text Available Amyloid aggregation has been related to an increasing number of human illnesses, from Alzheimer and Parkinson’s diseases to Creutzfeldt-Jakob disease. Traditionally only prions have been considered as infectious agents with a high capacity of propagation. Although recent publications have showed that many amyloid proteins, including amyloid β-peptide, α-synuclein and tau protein, also propagate in a prion-like manner, the link between propagation of pathological proteins and neurotoxicity has not been evidenced. The extremely low infectivity in natural conditions of the most of non-prion amyloids is far from the spreading capacity displayed by the prions. However, it is important to elucidate the key factors that cause non-prion amyloids become infectious agents. In recent years, important advances in the understanding of the amyloid processes of amyloid-like proteins and unrelated prions (i.e., yeast and fungal prions have yielded essential information that can be applied to shed light on the prion phenomenon in mammals and humans. As shown in this review, recent evidences suggest that there are key factors that could dramatically modulate the prion capacity of proteins in the amyloid conformation. The concentration of nuclei, the presence of oligomers, and the toxicity, resistance and localization of these aggregates could be key factors affecting their spreading. In short, those factors that favor the high concentration of extracellular nuclei or oligomers, characterized by a small size, with a low toxicity could dramatically increase prion propensity; whereas low concentrations of highly toxic intracellular amyloids, with a large size, would prevent infectivity.

  14. Disease Transmission by Misfolded Prion-Protein Isoforms, Prion-Like Amyloids, Functional Amyloids and the Central Dogma.

    Science.gov (United States)

    Daus, Martin L

    2016-01-04

    In 1982, the term "prions" (proteinaceous infectious particles) was coined to specify a new principle of infection. A misfolded isoform of a cellular protein has been described as the causative agent of a fatal neurodegenerative disease. At the beginning of prion research scientists assumed that the infectious agent causing transmissible spongiform encephalopathy (TSE) was a virus, but some unconventional properties of these pathogens were difficult to bring in line with the prevailing viral model. The discovery that prions (obviously devoid of any coding nucleic acid) can store and transmit information similarly to DNA was initially even denoted as being "heretical" but is nowadays mainly accepted by the scientific community. This review describes, from a historical point of view, how the "protein-only hypothesis" expands the Central Dogma. Definition of both, the prion principle and the Central Dogma, have been essential steps to understand information storage and transfer within and among cells and organisms. Furthermore, the current understanding of the infectivity of prion-proteins after misfolding is summarized succinctly. Finally, prion-like amyloids and functional amyloids, as found in yeast and bacteria, will be discussed.

  15. Disease Transmission by Misfolded Prion-Protein Isoforms, Prion-Like Amyloids, Functional Amyloids and the Central Dogma

    Directory of Open Access Journals (Sweden)

    Martin L. Daus

    2016-01-01

    Full Text Available In 1982, the term “prions” (proteinaceous infectious particles was coined to specify a new principle of infection. A misfolded isoform of a cellular protein has been described as the causative agent of a fatal neurodegenerative disease. At the beginning of prion research scientists assumed that the infectious agent causing transmissible spongiform encephalopathy (TSE was a virus, but some unconventional properties of these pathogens were difficult to bring in line with the prevailing viral model. The discovery that prions (obviously devoid of any coding nucleic acid can store and transmit information similarly to DNA was initially even denoted as being “heretical” but is nowadays mainly accepted by the scientific community. This review describes, from a historical point of view, how the “protein-only hypothesis” expands the Central Dogma. Definition of both, the prion principle and the Central Dogma, have been essential steps to understand information storage and transfer within and among cells and organisms. Furthermore, the current understanding of the infectivity of prion-proteins after misfolding is summarized succinctly. Finally, prion-like amyloids and functional amyloids, as found in yeast and bacteria, will be discussed.

  16. Amyloid β Is Not the Major Factor Accounting for Impaired Adult Hippocampal Neurogenesis in Mice Overexpressing Amyloid Precursor Protein

    Directory of Open Access Journals (Sweden)

    Hongyu Pan

    2016-10-01

    Full Text Available Adult hippocampal neurogenesis was impaired in several Alzheimer's disease models overexpressing mutant human amyloid precursor protein (hAPP. However, the effects of wild-type hAPP on adult neurogenesis and whether the impaired adult hippocampal neurogenesis was caused by amyloid β (Aβ or APP remained unclear. Here, we found that neurogenesis was impaired in the dentate gyrus (DG of adult mice overexpressing wild-type hAPP (hAPP-I5 compared with controls. However, the adult hippocampal neurogenesis was more severely impaired in hAPP-I5 than that in hAPP-J20 mice, which express similar levels of hAPP mRNA but much higher levels of Aβ. Furthermore, reducing Aβ levels did not affect the number of doublecortin-positive cells in the DG of hAPP-J20 mice. Our results suggested that hAPP was more likely an important factor inhibiting adult neurogenesis, and Aβ was not the major factor affecting neurogenesis in the adult hippocampus of hAPP mice.

  17. Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes.

    Science.gov (United States)

    Tang, Weihao; Tam, Joshua H K; Seah, Claudia; Chiu, Justin; Tyrer, Andrea; Cregan, Sean P; Meakin, Susan O; Pasternak, Stephen H

    2015-07-14

    Alzheimer's disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β - and γ - secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer's disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production.

  18. Inclusion control in high-performance steels

    International Nuclear Information System (INIS)

    Holappa, L.E.K.; Helle, A.S.

    1995-01-01

    Progress of clean steel production, fundamentals of oxide and sulphide inclusions as well as inclusion morphology in normal and calcium treated steels are described. Effects of cleanliness and inclusion control on steel properties are discussed. In many damaging constructional and engineering applications the nonmetallic inclusions have a quite decisive role in steel performance. An example of combination of good mechanical properties and superior machinability by applying inclusion control is presented. (author)

  19. Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants.

    Directory of Open Access Journals (Sweden)

    Mira ePolajnar

    2012-08-01

    Full Text Available Epilepsies are characterised by abnormal electrophysiological activity of the brain. Among various types of inherited epilepsies different epilepsy syndromes, among them progressive myoclonus epilepsies with features of ataxia and neurodegeneration, are counted. The progressive myoclonus epilepsy of type 1 (EPM1, also known as Unverricht-Lundborg disease presents with features of cerebellar atrophy and increased oxidative stress. It has been found that EPM1 is caused by mutations in human cystatin B gene (human stefin B. We first describe the role of protein aggregation in other neurodegenerative conditions. Protein aggregates appear intraneurally but are also excreted, such as is the case with senile plaques of amyloid- β (Aβ that accumulate in the brain parenchyma and vessel walls. A common characteristic of such diseases is the change of the protein conformation towards β secondary structure that accounts for the strong tendency of such proteins to aggregate and form amyloid fibrils. Second, we describe the patho-physiology of EPM1 and the normal and aberrant roles of stefin B in a mouse model of the disease. Furthermore, we discuss how the increased protein aggregation observed with some of the mutants of human stefin B may relate to the neurodegeneration that occurs in rare EPM1 patients. Our hypothesis (Ceru et al., 2005 states that some of the EPM1 mutants of human stefin B may undergo aggregation in neural cells, thus gaining additional toxic function (apart from loss of normal function. Our in vitro experiments thus far have confirmed that 4 mutants undergo increased aggregation relative to the wild-type protein. It has been shown that the R68X mutant forms amyloid-fibrils very rapidly, even at neutral pH and forms perinuclear inclusions, whereas the G4R mutant exhibits a prolonged lag phase, during which the toxic prefibrillar aggregates accumulate and are scattered more diffusely over the cytoplasm. Initial experiments on the G50E

  20. Investigation of Amyloid Structures at Nanoscale via AFM based Dynamic Nanomechncial Microscopy

    DEFF Research Database (Denmark)

    Zhang, Shuai

    2014-01-01

    Amyloid structures are one important kind of protein aggregations. They are a group of stable misfolded species, other than native states, which have been found to accumulate as plaques on neuron cells. This behavior is considered to associate with tens of human neurodegenerative diseases...... summarized the main methodologies of DNM. I also utilized DNM to explore the path way of amyloid self-assembly, and the substrate effect to the conformation of amyloid structures. Furthermore, 2D peptide based material has also been characterized by DNM....

  1. Influence of retinoic acid on mesenchymal stem cell differentiation in amyloid hydrogels

    Directory of Open Access Journals (Sweden)

    Reeba Susan Jacob

    2015-12-01

    Full Text Available This paper presents data related to the research article “Self healing hydrogels composed of amyloid nano fibrils for cell culture and stem cell differentiation” [1]. Here we probed the collective influence of all-trans retinoic acid (RA and substrate properties (amyloid hydrogel on human mesenchymal stem cell (hMSC differentiation. Stem cells were cultured on soft amyloid hydrogels [1,2] in the presence and absence of matrix encapsulated RA. The cell morphology was imaged and assessed via quantification of circularity. Further immunostaining and quantitative real time PCR was used to quantify various markers of differentiation in the neuronal lineage.

  2. The Role of Functional Amyloids in Multicellular Growth and Development of Gram-Positive Bacteria

    DEFF Research Database (Denmark)

    Dragoš, Anna; Kovács, Ákos T.; Claessen, Dennis

    2017-01-01

    Amyloid fibrils play pivotal roles in all domains of life. In bacteria, these fibrillar structures are often part of an extracellular matrix that surrounds the producing organism and thereby provides protection to harsh environmental conditions. Here, we discuss the role of amyloid fibrils...... in the two distant Gram-positive bacteria, Streptomyces coelicolor and Bacillus subtilis. We describe how amyloid fibrils contribute to a multitude of developmental processes in each of these systems, including multicellular growth and community development. Despite this variety of tasks, we know...... surprisingly little about how their assembly is organized to fulfill all these roles....

  3. [Bacterial biofilms and infection].

    Science.gov (United States)

    Lasa, I; Del Pozo, J L; Penadés, J R; Leiva, J

    2005-01-01

    In developed countries we tend to think of heart disease and the numerous forms of cancer as the main causes of mortality, but on a global scale infectious diseases come close, or may even be ahead: 14.9 million deaths in 2002 compared to cardiovascular diseases (16.9 million deaths) and cancer (7.1 million deaths) (WHO report 2004). The infectious agents responsible for human mortality have evolved as medical techniques and hygienic measures have changed. Modern-day acute infectious diseases caused by specialized bacterial pathogens such as diphtheria, tetanus, cholera, plague, which represented the main causes of death at the beginning of XX century, have been effectively controlled with antibiotics and vaccines. In their place, more than half of the infectious diseases that affect mildly immunocompromised patients involve bacterial species that are commensal with the human body; these can produce chronic infections, are resistant to antimicrobial agents and there is no effective vaccine against them. Examples of these infections are the otitis media, native valve endocarditis, chronic urinary infections, bacterial prostatitis, osteomyelitis and all the infections related to medical devices. Direct analysis of the surface of medical devices or of tissues that have been foci of chronic infections shows the presence of large numbers of bacteria surrounded by an exopolysaccharide matrix, which has been named the "biofilm". Inside the biofilm, bacteria grow protected from the action of the antibodies, phagocytic cells and antimicrobial treatments. In this article, we describe the role of bacterial biofilms in human persistent infections.

  4. Interfering with bacterial gossip

    DEFF Research Database (Denmark)

    Bjarnsholt, Thomas; Tolker-Nielsen, Tim; Givskov, Michael

    2011-01-01

    that appropriately target bacteria in their relevant habitat with the aim of mitigating their destructive impact on patients. In this review we describe molecular mechanisms involved in “bacterial gossip” (more scientifically referred to as quorum sensing (QS) and c-di-GMP signaling), virulence, biofilm formation...

  5. Bacterial fingerprints across Europe

    NARCIS (Netherlands)

    Glasner, Corinna

    2014-01-01

    Bacterial pathogens, such as Staphylococcus aureus and carbapenemase-producing Enterobacteriaceae (CPE), impose major threats to human health worldwide. Both have a ‘Jekyll & Hyde’ character, since they can be present as human commensals, but can also become harmful invasive pathogens especially

  6. Bacterial membrane proteomics.

    Science.gov (United States)

    Poetsch, Ansgar; Wolters, Dirk

    2008-10-01

    About one quarter to one third of all bacterial genes encode proteins of the inner or outer bacterial membrane. These proteins perform essential physiological functions, such as the import or export of metabolites, the homeostasis of metal ions, the extrusion of toxic substances or antibiotics, and the generation or conversion of energy. The last years have witnessed completion of a plethora of whole-genome sequences of bacteria important for biotechnology or medicine, which is the foundation for proteome and other functional genome analyses. In this review, we discuss the challenges in membrane proteome analysis, starting from sample preparation and leading to MS-data analysis and quantification. The current state of available proteomics technologies as well as their advantages and disadvantages will be described with a focus on shotgun proteomics. Then, we will briefly introduce the most abundant proteins and protein families present in bacterial membranes before bacterial membrane proteomics studies of the last years will be presented. It will be shown how these works enlarged our knowledge about the physiological adaptations that take place in bacteria during fine chemical production, bioremediation, protein overexpression, and during infections. Furthermore, several examples from literature demonstrate the suitability of membrane proteomics for the identification of antigens and different pathogenic strains, as well as the elucidation of membrane protein structure and function.

  7. [Spontaneous bacterial peritonitis].

    Science.gov (United States)

    Velkey, Bálint; Vitális, Eszter; Vitális, Zsuzsanna

    2017-01-01

    Spontaneous bacterial peritonitis occurs most commonly in cirrhotic patients with ascites. Pathogens get into the circulation by intestinal translocation and colonize in peritoneal fluid. Diagnosis of spontaneous bacterial peritonitis is based on elevated polymorphonuclear leukocyte count in the ascites (>0,25 G/L). Ascites culture is often negative but aids to get information about antibiotic sensitivity in positive cases. Treatment in stable patient can be intravenous then orally administrated ciprofloxacin or amoxicillin/clavulanic acid, while in severe cases intravenous III. generation cephalosporin. Nosocomial spontaneous bacterial peritonitis often caused by Gram-positive bacteria and multi-resistant pathogens can also be expected thus carbapenem should be the choice of the empiric treatment. Antibiotic prophylaxis should be considered. Norfloxacin is used most commonly, but changes are expected due to increase in quinolone resistance. As a primary prophylaxis, a short-term antibiotic treatment is recommended after gastrointestinal bleeding for 5 days, while long-term prophylaxis is for patients with low ascites protein, and advanced disease (400 mg/day). Secondary prophylaxis is recommended for all patients recovered from spontaneous bacterial peritonitis. Due to increasing antibiotic use of antibiotics prophylaxis is debated to some degree. Orv. Hetil., 2017, 158(2), 50-57.

  8. Inactivation of Prions and Amyloid Seeds with Hypochlorous Acid.

    Directory of Open Access Journals (Sweden)

    Andrew G Hughson

    2016-09-01

    Full Text Available Hypochlorous acid (HOCl is produced naturally by neutrophils and other cells to kill conventional microbes in vivo. Synthetic preparations containing HOCl can also be effective as microbial disinfectants. Here we have tested whether HOCl can also inactivate prions and other self-propagating protein amyloid seeds. Prions are deadly pathogens that are notoriously difficult to inactivate, and standard microbial disinfection protocols are often inadequate. Recommended treatments for prion decontamination include strongly basic (pH ≥~12 sodium hypochlorite bleach, ≥1 N sodium hydroxide, and/or prolonged autoclaving. These treatments are damaging and/or unsuitable for many clinical, agricultural and environmental applications. We have tested the anti-prion activity of a weakly acidic aqueous formulation of HOCl (BrioHOCl that poses no apparent hazard to either users or many surfaces. For example, BrioHOCl can be applied directly to skin and mucous membranes and has been aerosolized to treat entire rooms without apparent deleterious effects. Here, we demonstrate that immersion in BrioHOCl can inactivate not only a range of target microbes, including spores of Bacillus subtilis, but also prions in tissue suspensions and on stainless steel. Real-time quaking-induced conversion (RT-QuIC assays showed that BrioHOCl treatments eliminated all detectable prion seeding activity of human Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, cervine chronic wasting disease, sheep scrapie and hamster scrapie; these findings indicated reductions of ≥103- to 106-fold. Transgenic mouse bioassays showed that all detectable hamster-adapted scrapie infectivity in brain homogenates or on steel wires was eliminated, representing reductions of ≥~105.75-fold and >104-fold, respectively. Inactivation of RT-QuIC seeding activity correlated with free chlorine concentration and higher order aggregation or destruction of proteins generally, including prion

  9. Corticosteroids for Bacterial Keratitis

    Science.gov (United States)

    Srinivasan, Muthiah; Mascarenhas, Jeena; Rajaraman, Revathi; Ravindran, Meenakshi; Lalitha, Prajna; Glidden, David V.; Ray, Kathryn J.; Hong, Kevin C.; Oldenburg, Catherine E.; Lee, Salena M.; Zegans, Michael E.; McLeod, Stephen D.; Lietman, Thomas M.; Acharya, Nisha R.

    2013-01-01

    Objective To determine whether there is a benefit in clinical outcomes with the use of topical corticosteroids as adjunctive therapy in the treatment of bacterial corneal ulcers. Methods Randomized, placebo-controlled, double-masked, multicenter clinical trial comparing prednisolone sodium phosphate, 1.0%, to placebo as adjunctive therapy for the treatment of bacterial corneal ulcers. Eligible patients had a culture-positive bacterial corneal ulcer and received topical moxifloxacin for at least 48 hours before randomization. Main Outcome Measures The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months from enrollment. Secondary outcomes included infiltrate/scar size, reepithelialization, and corneal perforation. Results Between September 1, 2006, and February 22, 2010, 1769 patients were screened for the trial and 500 patients were enrolled. No significant difference was observed in the 3-month BSCVA (−0.009 logarithm of the minimum angle of resolution [logMAR]; 95% CI, −0.085 to 0.068; P = .82), infiltrate/scar size (P = .40), time to reepithelialization (P = .44), or corneal perforation (P > .99). A significant effect of corticosteroids was observed in subgroups of baseline BSCVA (P = .03) and ulcer location (P = .04). At 3 months, patients with vision of counting fingers or worse at baseline had 0.17 logMAR better visual acuity with corticosteroids (95% CI, −0.31 to −0.02; P = .03) compared with placebo, and patients with ulcers that were completely central at baseline had 0.20 logMAR better visual acuity with corticosteroids (−0.37 to −0.04; P = .02). Conclusions We found no overall difference in 3-month BSCVA and no safety concerns with adjunctive corticosteroid therapy for bacterial corneal ulcers. Application to Clinical Practice Adjunctive topical corticosteroid use does not improve 3-month vision in patients with bacterial corneal ulcers. PMID:21987582

  10. Amyloid-PET burden and regional distribution in cerebral amyloid angiopathy: a systematic review and meta-analysis of biomarker performance.

    Science.gov (United States)

    Charidimou, Andreas; Farid, Karim; Tsai, Hsin-Hsi; Tsai, Li-Kai; Yen, Rouh-Fang; Baron, Jean-Claude

    2018-04-01

    We performed a meta-analysis to synthesise current evidence on amyloid-positron emission tomography (PET) burden and presumed preferential occipital distribution in sporadic cerebral amyloid angiopathy (CAA). In a PubMed systematic search, we identified case-control studies with extractable data on global and occipital-to-global amyloid-PET uptake in symptomatic patients with CAA (per Boston criteria) versus control groups (healthy participants or patients with non-CAA deep intracerebral haemorrhage) and patients with Alzheimer's disease. To circumvent PET studies' methodological variation, we generated and used 'fold change', that is, ratio of mean amyloid uptake (global and occipital-to-global) of CAA relative to comparison groups. Amyloid-PET uptake biomarker performance was then quantified by random-effects meta-analysis on the ratios of the means. A ratio >1 indicates that amyloid-PET uptake (global or occipital/global) is higher in CAA than comparison groups, and a ratio 90% with probable CAA) and 138 controls (96 healthy elderly, 42 deep intracerebral haemorrhage controls) and 72 patients with Alzheimer's disease, were included. Global amyloid-PET ratio between patients with CAA and controls was above 1, with an average effect size of 1.18 (95% CI 1.08 to 1.28; pPET uptake ratio did not differ between patients with CAA versus patients with deep intracerebral haemorrhage or healthy controls. By contrast, occipital-to-global amyloid-PET uptake ratio was above 1 in patients with CAA versus those with Alzheimer's disease, with an average ratio of 1.10 (95% CI 1.03 to 1.19; p=0.009) and high statistical heterogeneity. Our analysis provides exploratory actionable data on the overall effect sizes and strength of amyloid-PET burden and distribution in patients with CAA, useful for future larger studies. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless

  11. Variation of amino acid sequences of serum amyloid a (SAA) and immunohistochemical analysis of amyloid a (AA) in Japanese domestic cats.

    Science.gov (United States)

    Tei, Meina; Uchida, Kazuyuki; Chambers, James K; Watanabe, Ken-Ichi; Tamamoto, Takashi; Ohno, Koichi; Nakayama, Hiroyuki

    2018-02-02

    Amyloid A (AA) amyloidosis, a fatal systemic amyloid disease, occurs secondary to chronic inflammatory conditions in humans. Although persistently elevated serum amyloid A (SAA) levels are required for its pathogenesis, not all individuals with chronic inflammation necessarily develop AA amyloidosis. Furthermore, many diseases in cats are associated with the elevated production of SAA, whereas only a small number actually develop AA amyloidosis. We hypothesized that a genetic mutation in the SAA gene may strongly contribute to the pathogenesis of feline AA amyloidosis. In the present study, genomic DNA from four Japanese domestic cats (JDCs) with AA amyloidosis and from five without amyloidosis was analyzed using polymerase chain reaction (PCR) amplification and direct sequencing. We identified the novel variation combination of 45R-51A in the deduced amino acid sequences of four JDCs with amyloidosis and five without. However, there was no relationship between amino acid variations and the distribution of AA amyloid deposits, indicating that differences in SAA sequences do not contribute to the pathogenesis of AA amyloidosis. Immunohistochemical analysis using antisera against the three different parts of the feline SAA protein-i.e., the N-terminal, central, and C-terminal regions-revealed that feline AA contained the C-terminus, unlike human AA. These results indicate that the cleavage and degradation of the C-terminus are not essential for amyloid fibril formation in JDCs.

  12. Friendship in inclusive physical education.

    Science.gov (United States)

    Seymour, Helena; Reid, Greg; Bloom, Gordon A

    2009-07-01

    Social interaction and development of friendships between children with and without a disability are often proposed as potential outcomes of inclusive education. Physical activity specialists assert that exercise and sport environments may be conducive to social and friendship outcomes. This study investigated friendship in inclusive physical education from the perspective of students with (n = 8) and without (n = 8) physical disabilities. All participants attended a reversely integrated school and were interviewed using a semistructured, open-ended format. An adapted version of Weiss, Smith, and Theeboom's (1996) interview guide exploring perceptions of peer relationships in the sport domain was used. Four conceptual categories emerged from the analysis: development of friendship, best friend, preferred physical activities and outcomes, and dealing with disability. The results demonstrated the key characteristics of best friends and the influential role they play.

  13. Bacterial infec tions in travellers

    African Journals Online (AJOL)

    namely bacterial causes of travellers' diarrhoea and skin infections, as well as .... Vaccination: protective efficacy against typhoid may be overcome by ingesting a high bacterial load. Vaccine ..... preparation such as cream sauce. Only after ...

  14. EDPS 265: The Inclusive Classroom

    OpenAIRE

    Begeske, Jasmine

    2014-01-01

    EDPS 265: The Inclusive Classroom is a foundational, large enrollment lecture course and is taught in a lecture hall with a stadium style seating arraignment. This configuration results in a course that is not student-centered, promotes one-way communication and hinders cooperative learning. Education courses should be structured so that the course in itself is instructive. This course teaches interventions for reaching all students, using techniques that engage students in the learning proce...

  15. Student' responses to inclusive design

    DEFF Research Database (Denmark)

    Herriott, Richard; Geert Jensen, Birgitte

    2013-01-01

    interact with our environment and technology. Specifically this involved welfare technology, equipment and tools that can help with daily activities. This technology is designed help to citizens to be 'master of his or her own life' while off-setting capability changes due to declining physical ability...... was originally written for the DRTS 2012 conference "Articulating Design Thinking" and proposed for inclusion in a special edition of Design Issues....

  16. Student Engagement In Inclusive Classrooms

    DEFF Research Database (Denmark)

    Rangvid, Beatrice Schindler

    There is general agreement that to thrive and learn at their best, students must be engaged. However, schools face a particular challenge to provide a suitable and engaging learning environment for SEN (special educational needs) students who are educated in general education classes. Using data......-students as for other students. This highlights the need for better inclusion initiatives aimed at strengthening engagement of SEN-students in regular classrooms....

  17. Lipopolysaccharide induces amyloid formation of antimicrobial peptide HAL-2.

    Science.gov (United States)

    Wang, Jiarong; Li, Yan; Wang, Xiaoming; Chen, Wei; Sun, Hongbin; Wang, Junfeng

    2014-11-01

    Lipopolysaccharide (LPS), the important component of the outer membrane of Gram-negative bacteria, contributes to the integrity of the outer membrane and protects the cell against bactericidal agents, including antimicrobial peptides. However, the mechanisms of interaction between antimicrobial peptides and LPS are not clearly understood. Halictines-2 (HAL-2), one of the novel antimicrobial peptides, was isolated from the venom of the eusocial bee Halictus sexcinctus. HAL-2 has exhibited potent antimicrobial activity against Gram-positive and Gram-negative bacteria and even against cancer cells. Here, we studied the interactions between HAL-2 and LPS to elucidate the antibacterial mechanism of HAL-2 in vitro. Our results show that HAL-2 adopts a significant degree of β-strand structure in the presence of LPS. LPS is capable of inducing HAL-2 amyloid formation, which may play a vital role in its antimicrobial activity. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Natural Modulators of Amyloid-Beta Precursor Protein Processing

    Science.gov (United States)

    Zhang, Can; Tanzi, Rudolph E.

    2013-01-01

    Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia, with no cure currently available. The pathogenesis of AD is believed to be primarily driven by Aβ, the principal component of senile plaques. Aβ is an ~4 kDa peptide generated from the amyloid-β precursor protein (APP) through proteolytic secretases. Natural products, particularly those utilized in traditional Chinese medicine (TCM), have a long history alleviating common clinical disorders, including dementia. However, the cell/molecular pathways mediated by these natural products are largely unknown until recently when the underlying molecular mechanisms of the disorders begin to be elucidated. Here, the mechanisms with which natural products modulate the pathogenesis of AD are discussed, in particular, by focusing on their roles in the processing of APP. PMID:22998566

  19. How curcumin affords effective protection against amyloid fibrillation in insulin?

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Ebrahim Habibi, Azadeh; Ghasemi, Atiyeh Ghasemi

    2013-01-01

    Since the formation of amyloid structures from proteins was recognized in numerous diseases, many efforts have been devoted to the task of finding effective anti-amyloidogenic compounds. In a number of these investigations, the existence of “generic” compounds is implicitly acknowledged. Curcumin...... been shown effectively influenced by micro molar concentrations of curcumin. Under amyloidogenic conditions (pH 2.5 and 37°C), the compound was observed to inhibit fibril formation of insulin in a dose-dependent manner. Moreover, addition of curcumin to the protein incubated in such conditions...... at different time points resulted in reduced amounts of final fibrils. Disaggregation of pre-formed fibrils was also observed upon addition of curcumin, as well as reduction in final fibril amounts after seeding. Overall, this compound appears to be able to interact with native, intermediate and fibrillar...

  20. Amyloid protein unfolding and insertion kinetics on neuronal membrane mimics

    Science.gov (United States)

    Qiu, Liming; Buie, Creighton; Vaughn, Mark; Cheng, Kwan

    2010-03-01

    Atomistic details of beta-amyloid (Aβ ) protein unfolding and lipid interaction kinetics mediated by the neuronal membrane surface are important for developing new therapeutic strategies to prevent and cure Alzheimer's disease. Using all-atom MD simulations, we explored the early unfolding and insertion kinetics of 40 and 42 residue long Aβ in binary lipid mixtures with and without cholesterol that mimic the cholesterol-depleted and cholesterol-enriched lipid nanodomains of neurons. The protein conformational transition kinetics was evaluated from the secondary structure profile versus simulation time plot. The extent of membrane disruption was examined by the calculated order parameters of lipid acyl chains and cholesterol fused rings as well as the density profiles of water and lipid headgroups at defined regions across the lipid bilayer from our simulations. Our results revealed that both the cholesterol content and the length of the protein affect the protein-insertion and membrane stability in our model lipid bilayer systems.

  1. Disrupting beta-amyloid aggregation for Alzheimer disease treatment.

    Science.gov (United States)

    Estrada, L D; Soto, C

    2007-01-01

    Alzheimer's disease is a devastating degenerative disorder for which there is no cure or effective treatment. Although the etiology of Alzheimer's disease is not fully understood, compelling evidence indicates that deposition of aggregates composed by a misfolded form of the amyloid beta peptide (Abeta) is the central event in the disease pathogenesis. Therefore, an attractive therapeutic strategy is to prevent or reverse Abeta misfolding and aggregation. Diverse strategies have been described to identify inhibitors of this process, including screening of libraries of small molecules chemical compounds, rational design of synthetic peptides, assessment of natural Abeta-binding proteins and stimulation of the immune system by vaccination. In this article we describe these different approaches, their principles and their potential strengths and weaknesses. Overall the available data suggest that the development of drugs to interfere with Abeta misfolding and aggregation is a feasible target that hold great promise for the treatment of Alzheimer's disease.

  2. Ten Challenges of the Amyloid Hypothesis of Alzheimer's Disease.

    Science.gov (United States)

    Kepp, Kasper Planeta

    2017-01-01

    The inability to effectively halt or cure Alzheimer's disease (AD), exacerbated by the recent failures of high-profile clinical trials, emphasizes the urgent need to understand the complex biochemistry of this major neurodegenerative disease. In this paper, ten central, current challenges of the major paradigm in the field, the amyloid hypothesis, are sharply formulated. These challenges together show that new approaches are necessary that address data heterogeneity, increase focus on the proteome level, use available human patient data more actively, account for the aging phenotype as a background model of the disease, unify our understanding of the interplay between genetic and non-genetic risk factors, and combine into one framework both the familial and sporadic forms of the disease.

  3. Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity

    Science.gov (United States)

    Smith, Levi M.; Strittmatter, Stephen M.

    2017-01-01

    In Alzheimer’s disease (AD), insoluble and fibrillary amyloid-β (Aβ) peptide accumulates in plaques. However, soluble Aβ oligomers are most potent in creating synaptic dysfunction and loss. Therefore, receptors for Aβ oligomers are hypothesized to be the first step in a neuronal cascade leading to dementia. A number of cell-surface proteins have been described as Aβ binding proteins, and one or more are likely to mediate Aβ oligomer toxicity in AD. Cellular prion protein (PrPC) is a high-affinity Aβ oligomer binding site, and a range of data delineates a signaling pathway leading from Aβ complexation with PrPC to neuronal impairment. Further study of Aβ binding proteins will define the molecular basis of this crucial step in AD pathogenesis. PMID:27940601

  4. FAMILIAL AMYLOID POLYNEUROPATHY——CLINICAL REPORT OF A FAMILY

    Institute of Scientific and Technical Information of China (English)

    李延峰; 郭玉璞; 池田修一; 方定华

    1996-01-01

    This paper reports a familial amyloid polyneumpathy (FAP) family in China. This family being investigated had 69 members of five generations. From the third generation, there have been 16 patients. The age of onset was about 3 to 5 decades. The initial symptoms were autonomic nerve symptcans, such as impotence, dyspepaia and diarrhoea, associated with the sensory loss of lower extremities. As the disease progressed. the upper extremities and motor ability were also involved. The duration of disease course wasabout 8-10 years, most patients died of infection and cacbexia. Sural biopsy in 3 patients had showed positive Congo red staining. From the clinical view, this FAP family is similar to FAP I found in Japan. Thetrue classification, however, should be confirmed by further genetic analysis.

  5. Synaptic transmission block by presynaptic injection of oligomeric amyloid beta

    Science.gov (United States)

    Moreno, Herman; Yu, Eunah; Pigino, Gustavo; Hernandez, Alejandro I.; Kim, Natalia; Moreira, Jorge E.; Sugimori, Mutsuyuki; Llinás, Rodolfo R.

    2009-01-01

    Early Alzheimer's disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)Aβ42, but not oAβ40 or extracellular oAβ42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oAβ42-microinjected terminals, without affecting clathrin-coated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD. PMID:19304802

  6. Contribution of simple saccharides to the stabilization of amyloid structure

    International Nuclear Information System (INIS)

    Fung, Justin; Darabie, Audrey A.; McLaurin, JoAnne

    2005-01-01

    The use of osmolytes or chaperones to stabilize proteins/peptides that misfold in neurodegenerative diseases is an attractive concept for drug development. We have investigated the role of a series of small carbohydrates for protection of the natively structured Alzheimer's amyloid-β peptides (Aβ). Using circular dichroism spectroscopy to follow the β-structural transitions and electron microscopy to examine tertiary structural characteristics, we demonstrate that the hydrogen bonding capacity of the carbohydrate determines the inhibition or promotion of fibrillogenesis. Three sugar molecules that vary only in their distribution of potential H-bonding partners promote various structural changes in Aβ. Two of these sugar molecules are excluded from Aβ during aggregation and promote mature fibre growth, while the other binds Aβ promoting nucleation and the accumulation of protofibrils. Our studies suggest that utilization of a combinatorial strategy to alter H-bonding capacity across a simple carbohydrate molecule may represent a novel drug design strategy

  7. Preparation of Stable Amyloid-β Oligomers Without Perturbative Methods.

    Science.gov (United States)

    Kotler, Samuel A; Ramamoorthy, Ayyalusamy

    2018-01-01

    Soluble amyloid-β (Aβ) oligomers have become a focal point in the study of Alzheimer's disease due to their ability to elicit cytotoxicity. A number of recent studies have concentrated on the structural characterization of soluble Aβ oligomers to gain insight into their mechanism of toxicity. Consequently, providing reproducible protocols for the preparation of such oligomers is of utmost importance. The method presented in this chapter details a protocol for preparing an Aβ oligomer, with a primarily disordered secondary structure, without the need for chemical modification or amino acid substitution. Due to the stability of these disordered Aβ oligomers and the reproducibility with which they form, they are amenable for biophysical and high-resolution structural characterization.

  8. Post-splenectomy β-amyloid level changes in Rabbit

    International Nuclear Information System (INIS)

    Ji Xueli; Yu Jiwei; Ji Zhe; Zhou Zhengzhong

    2002-01-01

    Objective: To study the effect of splenectomy on serum β-amyloid (Aβ) levels in rabbit. Methods: Thirty 3yr-old rabbits underwent splenectomy and fifteen others underwent a sham-operation of laparectomy only. Serum Aβ levels were determined with RIA before and at regular intervals after operation. Results: In the splenectomy group, the Aβ levels were increased greatly after the operation and reached the peak at 5 th week. The levels then gradually declined but remained significantly higher than the pre-operative value at 6 th month. In the sham operation group, the value was no drastically changed but increased slowly (as an aging process). Conclusion: Splenectomy in rabbit would markedly increase the serum Aβ level, possibly due to a hypoimmune state impairing clearance of the substance

  9. Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment.

    Science.gov (United States)

    Lawrence, James L M; Tong, Mei; Alfulaij, Naghum; Sherrin, Tessi; Contarino, Mark; White, Michael M; Bellinger, Frederick P; Todorovic, Cedomir; Nichols, Robert A

    2014-10-22

    Soluble β-amyloid has been shown to regulate presynaptic Ca(2+) and synaptic plasticity. In particular, picomolar β-amyloid was found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here, we report that a functional N-terminal domain exists within β-amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of α- and β-secretases, and resident carboxypeptidase. The N-terminal β-amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer's patients. Unlike full-length β-amyloid, the N-terminal β-amyloid fragment is monomeric and nontoxic. In Ca(2+) imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse nerve terminals, the N-terminal β-amyloid fragment proved to be highly potent and more effective than full-length β-amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal β-amyloid fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal fragment also rescued LTP inhibited by elevated levels of full-length β-amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal β-amyloid fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal β-amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal β-amyloid fragment may serve as a potent and effective endogenous neuromodulator. Copyright © 2014 the authors 0270-6474/14/3414210-09$15.00/0.

  10. Significant association between renal function and amyloid-positive area in renal biopsy specimens in AL amyloidosis

    Directory of Open Access Journals (Sweden)

    Kuroda Takeshi

    2012-09-01

    Full Text Available Abstract Background The kidney is a major target organ for systemic amyloidosis that often affects the kidney including proteinura, and elevated serum creatinine (Cr. The correlation between amount of amyloid deposits and clinical parameters is not known. The aim of this study was to clarify correlation the amyloid area in all renal biopsy specimen and clinical parameters. Methods Fifty-eight patients with an established diagnosis of AL amyloidosis participated in the study. All patients showed amyloid deposits in renal biopsies. We retrospectively investigated the correlation between clinical data and amyloid occupied area in whole renal biopsy specimens. Results The area occupied by amyloid was less than 10% in 57 of the 58 patients, and was under 2% in 40. For statistical analyses, %amyloid-positive areas were transformed to common logarithmic values (Log10%amyloid. Cr showed significant correlation with Log10%amyloid and estimated glomerular filtration rate (eGFR showed the significant negative correlation. Patient age, cleatinine clearance (Ccr, blood urea nitorogen, and urinary protein was not significantly correlated with Log10%amyloid. The correlation with other clinical factors such as sex, and serum concentrations of total protein, albumin, immunoglobulins, compliments was evaluated. None of these factors significantly correlated with Log10%amyloid. According to sex- and age- adjusted multiple linear regression analysis, Log10%amyloid had significant positive association with Cr and significant negative association with eGFR. Conclusion There is significant association between amyloid-positive area in renal tissue and renal function, especially Cr and eGFR. The level of Cr and eGFR may be a marker of amount of amyloid in renal tissue.

  11. Pathogenesis of lober intracerebral hemorrhage related to cerebral amyloid angiopathy

    International Nuclear Information System (INIS)

    Sakai, Naoto; Namba, Hiroki; Miura, Katsutoshi; Baba, Satoshi; Isoda, Haruo; Yokoyama, Tetsuo

    2010-01-01

    Cerebral amyloid angiopathy (CAA) is an important cause of lober intracerebral hemorrhage in the elderly. Although leptomeningeal and cortical arteries with the deposition of the amyloid β-protein (Aβ) have been thought to rupture in CAA, the pathogenesis of CAA-related hemorrhage still remains obscure. We studied 10 cases of CAA according to the Boston criteria from April 2006 to July 2009 in Omaezaki Municipal Hospital. Based on clinical data, we examined the primary site of hemorrhage and hypothesized the mechanisms of bleeding. Intracerebral hematoma evacuation was performed to alleviate neurological deteriolation in 2 patients and to make diagnosis in 3 patients. The surgical specimens were pathologically examined. The characteristic MR images of CAA related hemorrhage were characterized by microbleeds, superficial siderosis, subpial or subarachnoid hemorrhage, subcortical hemorrhage and lober intracerebral hemorrhage. Chronological images obtained in 1 patient revealed that lober intracerebral hemorrhage developed from microbleed with subpial hemorrhage without subarachnoid hemorrhage in one side of the cortex in the affected facing cerebral sulci. Operative findings showed subpial and subarachnoid hemorrhages around the cortical veins on the affected cerebral sulci in all cases. Abnormal fragile vessels existed in one side of the cortex of the affected sulci but not in the other side of the cortex. Complete hamatoma evacuation was performed in 4 cases. The surgical specimens of the hematoma and the adjacent brain parenchyma were pathologically examined by tissue staining with hematoxylin-eosin and Congo red. Many vessels in subpial, subcortical and subarachnoid space along the cerebral sulci were deposited with Aβ. From these findings, we speculated that the primary hemorrhage related to CAA occurred from the cortical arteries with Aβ deposition in the subpial space along the cerebral sulci and formed a lober intracerebral hematoma. Subarachnoid

  12. A proteomic approach for the diagnosis of bacterial meningitis.

    Directory of Open Access Journals (Sweden)

    Sarah Jesse

    Full Text Available BACKGROUND: The discrimination of bacterial meningitis (BM versus viral meningitis (VM shapes up as a problem, when laboratory data are not equivocal, in particular, when Gram stain is negative. METHODOLOGY/PRINCIPAL FINDINGS: With the aim to determine reliable marker for bacterial or viral meningitis, we subjected cerebrospinal fluid (CSF to a quantitative proteomic screening. By using a recently established 2D-DIGE protocol which was adapted to the individual CSF flow, we compared a small set of patients with proven BM and VM. Thereby, we identified six potential biomarkers out of which Prostaglandin-H2 D-isomerase was already described in BM, showing proof of concept. In the subsequent validation phase on a more comprehensive collective of 80 patients, we could validate that in BM high levels of glial fibrillary acidic protein (GFAP and low levels of soluble amyloid precursor protein alpha/beta (sAPPalpha/beta are present as possible binding partner of Fibulin-1. CONCLUSIONS/SIGNIFICANCE: We conclude that our CSF flow-adapted 2D-DIGE protocol is valid especially in comparing samples with high differences in total protein and suppose that GFAP and sAPPalpha/beta have a high potential as additional diagnostic markers for differentiation of BM from VM. In the clinical setting, this might lead to an improved early diagnosis and to an individual therapy.

  13. Michler’s Hydrol Blue: A Sensitive Probe for Amyloid Fibril Detection

    KAUST Repository

    Kitts, Catherine C.; Beke-Somfai, Tamás; Nordén, Bengt

    2011-01-01

    amyloid probe, can differentiate between insulin and lysozyme fibrils by a more red-shifted excitation spectrum for insulin fibrils. To support the experimental observations, time-dependent density functional theory (TDDFT) calculations were performed

  14. The Tubular Sheaths Encasing Methanosaeta and Methanospirillum Filaments are Functional Amyloids

    DEFF Research Database (Denmark)

    Dueholm, Morten Simonsen; Larsen, Poul; Nielsen, Per Halkjær

    Archaea are well-recognized for their ability to thrive in extreme environments, although they can be found in virtually all habitats. Their adaptive success is linked to their unique cell envelopes, which often display extremely resistant to chemical and thermal denaturation and resist proteolysis...... techniques to show that the extracellular cell wall sheaths of the methanogenic archaea Methanosaeta and Methanospirillum are functional amyloid structures. Depolymerization of sheaths with formic acid and reducing agents and subsequent MS/MS analysis revealed that the sheaths are composed of a single major...... sheath protein (MspA). The amyloidogenic nature of MspA was confirmed by in vitro amyloid formation of recombinant MspA under a wide range of environmental conditions. This is the first report of a functional amyloid from the archaeal domain of life. The amyloid properties explain the extreme resistance...

  15. Long-term effects of amyloid, hypometabolism, and atrophy on neuropsychological functions

    NARCIS (Netherlands)

    Ossenkoppele, R.; van der Flier, W.M.; Verfaillie, S.C.J.; Vrenken, H.; Versteeg, A.; van Schijndel, R.A.; Sikkes, S.A.; Twisk, J.; Adriaanse, S.M.; Zwan, M.D.; Boellaard, R.; Windhorst, A.D.; Barkhof, F.; Scheltens, P.; Lammertsma, A.A.; van Berckel, B.N.M.

    2014-01-01

    Objective: To assess how amyloid deposition, glucose hypometabolism, and cerebral atrophy affect neuropsychological performance in patients with Alzheimer disease (AD) dementia, patients with mild cognitive impairment (MCI), and controls over time. Methods: A total of 41 patients with AD dementia,

  16. Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation

    NARCIS (Netherlands)

    Leuner, K.; Schutt, T.; Kurz, C.; Eckert, S.H.; Schiller, C.; Occhipinti, A.; Mai, S.; Jendrach, M.; Eckert, G.P.; Kruse, S.E.; Palmiter, R.D.; Brandt, U.; Drose, S.; Wittig, I.; Willem, M.; Haass, C.; Reichert, A.S.; Muller, W.E.

    2012-01-01

    AIMS: Intracellular amyloid beta (Abeta) oligomers and extracellular Abeta plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Abeta production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species

  17. Bifunctional fluorescent probes for detection of amyloid aggregates and reactive oxygen species.

    Science.gov (United States)

    Needham, Lisa-Maria; Weber, Judith; Fyfe, James W B; Kabia, Omaru M; Do, Dung T; Klimont, Ewa; Zhang, Yu; Rodrigues, Margarida; Dobson, Christopher M; Ghandi, Sonia; Bohndiek, Sarah E; Snaddon, Thomas N; Lee, Steven F

    2018-02-01

    Protein aggregation into amyloid deposits and oxidative stress are key features of many neurodegenerative disorders including Parkinson's and Alzheimer's disease. We report here the creation of four highly sensitive bifunctional fluorescent probes, capable of H 2 O 2 and/or amyloid aggregate detection. These bifunctional sensors use a benzothiazole core for amyloid localization and boronic ester oxidation to specifically detect H 2 O 2 . We characterized the optical properties of these probes using both bulk fluorescence measurements and single-aggregate fluorescence imaging, and quantify changes in their fluorescence properties upon addition of amyloid aggregates of α-synuclein and pathophysiological H 2 O 2 concentrations. Our results indicate these new probes will be useful to detect and monitor neurodegenerative disease.

  18. Bifunctional fluorescent probes for detection of amyloid aggregates and reactive oxygen species

    Science.gov (United States)

    Needham, Lisa-Maria; Weber, Judith; Fyfe, James W. B.; Kabia, Omaru M.; Do, Dung T.; Klimont, Ewa; Zhang, Yu; Rodrigues, Margarida; Dobson, Christopher M.; Ghandi, Sonia; Bohndiek, Sarah E.; Snaddon, Thomas N.; Lee, Steven F.

    2018-02-01

    Protein aggregation into amyloid deposits and oxidative stress are key features of many neurodegenerative disorders including Parkinson's and Alzheimer's disease. We report here the creation of four highly sensitive bifunctional fluorescent probes, capable of H2O2 and/or amyloid aggregate detection. These bifunctional sensors use a benzothiazole core for amyloid localization and boronic ester oxidation to specifically detect H2O2. We characterized the optical properties of these probes using both bulk fluorescence measurements and single-aggregate fluorescence imaging, and quantify changes in their fluorescence properties upon addition of amyloid aggregates of α-synuclein and pathophysiological H2O2 concentrations. Our results indicate these new probes will be useful to detect and monitor neurodegenerative disease.

  19. Simultaneous measurement of amyloid fibril formation by dynamic light scattering and fluorescence reveals complex aggregation kinetics.

    Directory of Open Access Journals (Sweden)

    Aaron M Streets

    Full Text Available An apparatus that combines dynamic light scattering and Thioflavin T fluorescence detection is used to simultaneously probe fibril formation in polyglutamine peptides, the aggregating subunit associated with Huntington's disease, in vitro. Huntington's disease is a neurodegenerative disorder in a class of human pathologies that includes Alzheimer's and Parkinson's disease. These pathologies are all related by the propensity of their associated protein or polypeptide to form insoluble, β-sheet rich, amyloid fibrils. Despite the wide range of amino acid sequence in the aggregation prone polypeptides associated with these diseases, the resulting amyloids display strikingly similar physical structure, an observation which suggests a physical basis for amyloid fibril formation. Thioflavin T fluorescence reports β-sheet fibril content while dynamic light scattering measures particle size distributions. The combined techniques allow elucidation of complex aggregation kinetics and are used to reveal multiple stages of amyloid fibril formation.

  20. Uptake of raft components into amyloid β-peptide aggregates and membrane damage.

    Science.gov (United States)

    Sasahara, Kenji; Morigaki, Kenichi; Mori, Yasuko

    2015-07-15

    Amyloid aggregation and deposition of amyloid β-peptide (Aβ) are pathologic characteristics of Alzheimer's disease (AD). Recent reports have shown that the association of Aβ with membranes containing ganglioside GM1 (GM1) plays a pivotal role in amyloid deposition and the pathogenesis of AD. However, the molecular interactions responsible for membrane damage associated with Aβ deposition are not fully understood. In this study, we microscopically observed amyloid aggregation of Aβ in the presence of lipid vesicles and on a substrate-supported planar membrane containing raft components and GM1. The experimental system enabled us to observe lipid-associated aggregation of Aβ, uptake of the raft components into Aβ aggregates, and relevant membrane damage. The results indicate that uptake of raft components from the membrane into Aβ deposits induces macroscopic heterogeneity of the membrane structure. Copyright © 2015 Elsevier Inc. All rights reserved.