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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. Using bacterial inclusion bodies to screen for amyloid aggregation inhibitors

    Science.gov (United States)

    2012-01-01

    Background The amyloid-β peptide (Aβ42) is the main component of the inter-neuronal amyloid plaques characteristic of Alzheimer's disease (AD). The mechanism by which Aβ42 and other amyloid peptides assemble into insoluble neurotoxic deposits is still not completely understood and multiple factors have been reported to trigger their formation. In particular, the presence of endogenous metal ions has been linked to the pathogenesis of AD and other neurodegenerative disorders. Results Here we describe a rapid and high-throughput screening method to identify molecules able to modulate amyloid aggregation. The approach exploits the inclusion bodies (IBs) formed by Aβ42 when expressed in bacteria. We have shown previously that these aggregates retain amyloid structural and functional properties. In the present work, we demonstrate that their in vitro refolding is selectively sensitive to the presence of aggregation-promoting metal ions, allowing the detection of inhibitors of metal-promoted amyloid aggregation with potential therapeutic interest. Conclusions Because IBs can be produced at high levels and easily purified, the method overcomes one of the main limitations in screens to detect amyloid modulators: the use of expensive and usually highly insoluble synthetic peptides. PMID:22553999

  3. Thioflavin-S staining of bacterial inclusion bodies for the fast, simple, and inexpensive screening of amyloid aggregation inhibitors.

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    Pouplana, S; Espargaro, A; Galdeano, C; Viayna, E; Sola, I; Ventura, S; Muñoz-Torrero, D; Sabate, R

    2014-01-01

    Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer's disease (AD) or spongiform encephalopathies to non-neuropathic localized diseases as type II diabetes and cataracts. Because the formation of insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown to share mechanistic features with amyloid self-assembly, bacteria have emerged as a tool to study amyloid aggregation. Herein we present a fast, simple, inexpensive and quantitative method for the screening of potential anti-aggregating drugs. This method is based on monitoring the changes in the binding of thioflavin-S to intracellular IBs in intact Eschericchia coli cells in the presence of small chemical compounds. This in vivo technique fairly recapitulates previous in vitro data. Here we mainly use the Alzheimer's related β-amyloid peptide as a model system, but the technique can be easily implemented for screening inhibitors relevant for other conformational diseases simply by changing the recombinant amyloid protein target. Indeed, we show that this methodology can be also applied to the evaluation of inhibitors of the aggregation of tau protein, another amyloidogenic protein with a key role in AD.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Widespread Abundance of Functional Bacterial Amyloid in Mycolata and Other Gram-Positive Bacteria

    DEFF Research Database (Denmark)

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

    2009-01-01

    Until recently, extracellular functional bacterial amyloid (FuBA) has been detected and characterized in only a few bacterial species, including Escherichia coli, Salmonella and Gram-positive Streptomyces coelicolor. Here we have probed Gram-positive bacteria with conformationally specific...... 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....

  9. 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...

  10. Direct Conversion of an Enzyme from Native-like to Amyloid-like Aggregates within Inclusion Bodies.

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    Elia, Francesco; Cantini, Francesca; Chiti, Fabrizio; Dobson, Christopher Martin; Bemporad, Francesco

    2017-06-20

    The acylphosphatase from Sulfolobus solfataricus (Sso AcP) is a globular protein able to aggregate in vitro from a native-like conformational ensemble without the need for a transition across the major unfolding energy barrier. This process leads to the formation of assemblies in which the protein retains its native-like structure, which subsequently convert into amyloid-like aggregates. Here, we investigate the mechanism by which Sso AcP aggregates in vivo to form bacterial inclusion bodies after expression in E. coli. Shortly after the initiation of expression, Sso AcP is incorporated into inclusion bodies as a native-like protein, still exhibiting small but significant enzymatic activity. Additional experiments revealed that this overall process of aggregation is enhanced by the presence of the unfolded N-terminal region of the sequence and by destabilization of the globular segment of the protein. At later times, the Sso AcP molecules in the inclusion bodies lose their native-like properties and convert into β-sheet-rich amyloid-like structures, as indicated by their ability to bind thioflavin T and Congo red. These results show that the aggregation behavior of this protein is similar in vivo to that observed in vitro, and that, at least for a predominant part of the protein population, the transition from a native to an amyloid-like structure occurs within the aggregate state. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  11. 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.

  12. Inclusions of R6/2 Mice Are Not Amyloid and Differ Structurally from Those of Huntington Disease Brain.

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    André, William; Sandt, Christophe; Nondier, Isabelle; Djian, Philippe; Hoffner, Guylaine

    2017-05-16

    R6/2 mice contain an N-terminal fragment of human huntingtin with an expanded polyQ and develop a neurological disease resembling Huntington disease. Although the brain of R6/2 mice contains numerous inclusions, there is very little neuronal death. In that respect, R6/2 mice differ from patients with Huntington disease whose striatum and cerebral cortex develop inclusions associated with extensive neuronal loss. We have previously demonstrated using synchrotron-based infrared microspectroscopy that the striatum and the cortex of patients with Huntington disease contained inclusions specifically enriched in amyloid β-sheets. We had concluded that the presence of an amyloid motif conferred toxicity to the inclusions. We demonstrate here by synchrotron based infrared microspectroscopy in transmission and attenuated total reflectance mode that the inclusions of R6/2 mice possess no detectable amyloid and are composed of proteins whose structure is not distinguishable from that of the surrounding soluble proteins. The difference in structure between the inclusions of patients affected by Huntington disease and those of R6/2 mice might explain why the former but not the latter cause neuronal death.

  13. Purification and Refolding to Amyloid Fibrils of (His)6-tagged Recombinant Shadoo Protein Expressed as Inclusion Bodies in E. coli.

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    Li, Qiaojing; Richard, Charles-Adrien; Moudjou, Mohammed; Vidic, Jasmina

    2015-12-19

    The Escherichia coli expression system is a powerful tool for the production of recombinant eukaryotic proteins. We use it to produce Shadoo, a protein belonging to the prion family. A chromatographic method for the purification of (His)6-tagged recombinant Shadoo expressed as inclusion bodies is described. The inclusion bodies are solubilized in 8 M urea and bound to a Ni(2+)-charged column to perform ion affinity chromatography. Bound proteins are eluted by a gradient of imidazole. Fractions containing Shadoo protein are subjected to size exclusion chromatography to obtain a highly purified protein. In the final step purified Shadoo is desalted to remove salts, urea and imidazole. Recombinant Shadoo protein is an important reagent for biophysical and biochemical studies of protein conformation disorders occurring in prion diseases. Many reports demonstrated that prion neurodegenerative diseases originate from the deposition of stable, ordered amyloid fibrils. Sample protocols describing how to fibrillate Shadoo into amyloid fibrils at acidic and neutral/basic pHs are presented. The methods on how to produce and fibrillate Shadoo can facilitate research in laboratories working on prion diseases, since it allows for production of large amounts of protein in a rapid and low cost manner.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

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    García-Fruitós, Elena; Seras-Franzoso, Joaquín; Vazquez, Esther; Villaverde, Antonio

    2010-05-01

    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.

  20. 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.

  1. Strategies for the recovery of active proteins through refolding of bacterial inclusion body proteins

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    Rinas Ursula

    2004-09-01

    Full Text Available Abstract Recent advances in generating active proteins through refolding of bacterial inclusion body proteins are summarized in conjunction with a short overview on inclusion body isolation and solubilization procedures. In particular, the pros and cons of well-established robust refolding techniques such as direct dilution as well as less common ones such as diafiltration or chromatographic processes including size exclusion chromatography, matrix- or affinity-based techniques and hydrophobic interaction chromatography are discussed. Moreover, the effect of physical variables (temperature and pressure as well as the presence of buffer additives on the refolding process is elucidated. In particular, the impact of protein stabilizing or destabilizing low- and high-molecular weight additives as well as micellar and liposomal systems on protein refolding is illustrated. Also, techniques mimicking the principles encountered during in vivo folding such as processes based on natural and artificial chaperones and propeptide-assisted protein refolding are presented. Moreover, the special requirements for the generation of disulfide bonded proteins and the specific problems and solutions, which arise during process integration are discussed. Finally, the different strategies are examined regarding their applicability for large-scale production processes or high-throughput screening procedures.

  2. 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

  3. 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.

  4. 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.

  5. Amyloid imaging: the court of public opinion.

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    Lerner, Alan J

    2013-09-24

    Human amyloid imaging is one of the great recent translational medicine stories. Beginning with the recognition that Thioflavin T derivatives could be used as PET tracers, through development of Pittsburgh compound B, to Food and Drug Administration (FDA) approval of Florbetapir in 2012, human amyloid imaging has held great promise to allow in vivo inclusive diagnosis of Alzheimer disease (AD), even though the first principle of amyloid PET is that it functions as a surrogate for β-amyloid pathology, and not necessarily as a surrogate for the diagnosis of AD.(1,2.)

  6. [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.

  7. 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.

  8. Functional Amyloids in Reproduction.

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    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.

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    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. A RHIM with a View: FLYing with Functional Amyloids.

    Science.gov (United States)

    Shin, Sunny; Cherry, Sara

    2017-10-17

    Recognition of bacterial peptidoglycan by the Drosophila IMD pathway triggers NF-κB activation and an associated immune response. In this issue of Immunity, Kleino et al. (2017) show that proteins in the IMD pathway form functional amyloids via a cryptic motif resembling the RHIM motif found in mammalian RIPK proteins. Amyloid formation can be negatively regulated, suggesting that it presents a regulatory point in multiple biological processes. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. One-step affinity tag purification of full-length recombinant human AP-1 complexes from bacterial inclusion bodies using a polycistronic expression system.

    Science.gov (United States)

    Wang, Wei-Ming; Lee, A-Young; Chiang, Cheng-Ming

    2008-05-01

    The AP-1 transcription factor is a dimeric protein complex formed primarily between Jun (c-Jun, JunB, JunD) and Fos (c-Fos, FosB, Fra-1, Fra-2) family members. These distinct AP-1 complexes are expressed in many cell types and modulate target gene expression implicated in cell proliferation, differentiation, and stress responses. Although the importance of AP-1 has long been recognized, the biochemical characterization of AP-1 remains limited in part due to the difficulty in purifying full-length, reconstituted dimers with active DNA-binding and transcriptional activity. Using a combination of bacterial coexpression and epitope-tagging methods, we successfully purified all 12 heterodimers (3 Junx4 Fos) of full-length human AP-1 complexes as well as c-Jun/c-Jun, JunD/JunD, and c-Jun/JunD dimers from bacterial inclusion bodies using one-step nickel-NTA affinity tag purification following denaturation and renaturation of coexpressed AP-1 subunits. Coexpression of two constitutive components in a dimeric AP-1 complex helps stabilize the proteins when compared with individual protein expression in bacteria. Purified dimeric AP-1 complexes are functional in sequence-specific DNA binding, as illustrated by electrophoretic mobility shift assays and DNase I footprinting, and are also active in transcription with in vitro-reconstituted human papillomavirus (HPV) chromatin containing AP-1-binding sites in the native configuration of HPV nucleosomes. The availability of these recombinant full-length human AP-1 complexes has greatly facilitated mechanistic studies of AP-1-regulated gene transcription in many biological systems.

  12. 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....

  13. Amyloid Fibril Solubility

    OpenAIRE

    Rizzi, L. G.; Auer, S.

    2015-01-01

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactio...

  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. Amyloid Beta Mediates Memory Formation

    Science.gov (United States)

    Garcia-Osta, Ana; Alberini, Cristina M.

    2009-01-01

    The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid [beta] (1-42) peptide (A[beta][1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated,…

  16. MRI evaluation of amyloid myopathy

    International Nuclear Information System (INIS)

    Metzler, J.P.; Fleckenstein, J.L.; Veterans Affairs Medical Center, Dallas, TX; White, C.L. III; Veterans Affairs Medical Center, Dallas, TX; Haller, R.G.; Greenlee, R.G. Jr.; Veterans Affairs Medical Center, Dallas, TX; Frenkel, E.P.; Veterans Affairs Medical Center, Dallas, TX

    1992-01-01

    Amyloid myopathy is a rare complication of primary amyloidosis. The magnetic resonance imaging (MRI) features of two patients with amyloid myopathy were studied. Slight prolongation of muscle T1 and T2 relaxation times was evident but the striking abnormality was marked reticulation of the subcutaneous fat. The clinical findings of indurated extremities far exceeds the minimal signal intenisty alteration seen in the muscles. The MR appearance of amyloid myopathy differs from that of other neuromuscular conditions in the minimal changes found in muscle, but the striking abnormality seen in subcutaneous fat makes it distinct from many neuromuscular conditions. (orig.)

  17. Inclusive pedagogy

    DEFF Research Database (Denmark)

    Korsgaard, Morten Timmermann; Mortensen, Stig Skov

    With a starting point in the tradition of geisteswissenschaftliche Pädagogik this article presents a challenge to inclusive education research to engage a continental perspective on educational research. The motivation is to entice inclusive education researchers to begin to ask educational...... questions of inclusion, as opposed to inclusive questions of education. Recent years has seen a call to re-think inclusive education research and this paper attempts to answer this call by turning to a Continental perspective and the emphasis on an at least relative autonomy for the theory and practice...... 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....

  18. 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...... 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......, underlining the importance of understanding this relationship. The monomeric C-36 peptide was investigated by liquid-state NMR spectroscopy and found to be intrinsically disordered with minor propensities towards β-sheet structure. The plasticity of such a peptide makes it suitable for a whole range...

  19. Cerebrospinal Fluid Amyloid β40 Is Decreased in Cerebral Amyloid Angiopathy

    Science.gov (United States)

    Verbeek, Marcel M.; Kremer, Berry P. H.; Rikkert, Marcel Olde; van Domburg, Peter H. M. F.; Skehan, Maureen E.; Greenberg, Steven M.

    2013-01-01

    Cerebral amyloid angiopathy is caused by deposition of the amyloid β protein in the cerebral vasculature. In analogy to previous observations in Alzheimer disease, we hypothesized that analysis of amyloid β40 and β42 proteins in the cerebrospinal fluid might serve as a molecular biomarker. We observed strongly decreased cerebrospinal fluid amyloid β40 (p < 0.01 vs controls or Alzheimer disease) and amyloid β42 concentrations (p < 0.001 vs controls and p < 0.05 vs Alzheimer disease) in cerebral amyloid angiopathy patients. The combination of amyloid β42 and total tau discriminated cerebral amyloid angiopathy from controls, with an area under the receiver operator curve of 0.98. Our data are consistent with neuropathological evidence that amyloid β40 as well as amyloid β42 protein are selectively trapped in the cerebral vasculature from interstitial fluid drainage pathways that otherwise transport amyloid β proteins toward the cerebrospinal fluid. PMID:19743453

  20. 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

  1. 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)

  2. 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.

  3. 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...

  4. 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.

  5. 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)

  6. 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.

  7. 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.

  8. 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

  9. 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.

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

    Science.gov (United States)

    Oztug Durer, Zeynep A; Cohlberg, Jeffrey A; Dinh, Phong; Padua, Shelby; Ehrenclou, Krista; Downes, Sean; Tan, James K; Nakano, Yoko; Bowman, Christopher J; Hoskins, Jessica L; Kwon, Chuhee; Mason, Andrew Z; Rodriguez, Jorge A; Doucette, Peter A; Shaw, Bryan F; Valentine, Joan Selverstone

    2009-01-01

    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.

  11. 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.

  12. 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...

  13. Beta-Amyloid Deposition and Alzheimer's Type Changes Induced by Borrelia Spirochetes

    Energy Technology Data Exchange (ETDEWEB)

    Miklossy,J.; Kis, A.; Radenovic, A.; Miller, L.; Forro, L.; Martins, R.; Reiss, K.; Darbinian, N.; Darekar, P.; et al.

    2006-01-01

    The pathological hallmarks of Alzheimer's disease (AD) consist of {beta}-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of {beta}-amyloid presursor protein (A{beta}PP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

  14. Social imaginaries and inclusion

    DEFF Research Database (Denmark)

    Hansen, Janne Hedegaard

    2016-01-01

    , 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...

  15. 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.

  16. 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.

  17. 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.

  18. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits.

    Science.gov (United States)

    Bodin, Karl; Ellmerich, Stephan; Kahan, Melvyn C; Tennent, Glenys A; Loesch, Andrzej; Gilbertson, Janet A; Hutchinson, Winston L; Mangione, Palma P; Gallimore, J Ruth; Millar, David J; Minogue, Shane; Dhillon, Amar P; Taylor, Graham W; Bradwell, Arthur R; Petrie, Aviva; Gillmore, Julian D; Bellotti, Vittorio; Botto, Marina; Hawkins, Philip N; Pepys, Mark B

    2010-11-04

    Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one in a thousand deaths in developed countries. Localized amyloid can also have serious consequences; for example, cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present. There is therefore a major unmet need for therapy that safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor proteins can arrest amyloid accumulation. Unfortunately, control of fibril-protein production is not possible in some forms of amyloidosis and in others it is often slow and hazardous. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar plasma glycoprotein, serum amyloid P component (SAP). Here we show that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers a potent, complement-dependent, macrophage-derived giant cell reaction that swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP-antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-d-proline compound CPHPC, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.

  19. 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.

  20. Bacterial Keratitis

    Science.gov (United States)

    ... Español Eye Health / Eye Health A-Z Bacterial Keratitis Sections What Is Bacterial Keratitis? Bacterial Keratitis Symptoms ... Lens Care Bacterial Keratitis Treatment What Is Bacterial Keratitis? Leer en Español: ¿Qué Es la Queratitis Bacteriana? ...

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. General Amyloid Inhibitors? A Critical Examination of the Inhibition of IAPP Amyloid Formation by Inositol Stereoisomers

    Science.gov (United States)

    Wang, Hui; Raleigh, Daniel P.

    2014-01-01

    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. PMID:25260075

  6. Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism

    Directory of Open Access Journals (Sweden)

    Anckarsäter Henrik

    2010-06-01

    Full Text Available Abstract Background The metabolism of amyloid precursor protein (APP and β-amyloid (Aβ is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB. Methods The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau, phosphorylated tau (P-tau and neurofilament protein (NFL were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers. Results In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up. Conclusions Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.

  7. Magnetic Fluids Have Ability to Decrease Amyloid Aggregation Associated with Amyloid-Related Diseases

    Science.gov (United States)

    Antosova, Andrea; Koneracka, Martina; Siposova, Katarina; Zavisova, Vlasta; Daxnerova, Zuzana; Vavra, Ivo; Fabian, Martin; Kopcansky, Peter; Gazova, Zuzana

    2010-12-01

    At least twenty human proteins can fold abnormally to form pathological deposits that are associated with several amyloid-related diseases. We have investigated the effect of four magnetic fluids (MFs)—electrostatically stabilized Fe3O4 magnetic nanoparticles (MF1) and sterically stabilized Fe3O4 magnetic nanoparticles by sodium oleate (MF2, MF3 and MF4) with adsorbed BSA (MF2) or dextran (MF4)—on amyloid aggregation of two proteins, human insulin and chicken egg lysozyme. The morphology, particle size and size distribution of the prepared magnetic fluids were characterized. We have found that MFs are able to decrease amyloid aggregation of both studied proteins and the extent of depolymerization depended on the MF properties. The most effective reduction was observed for MF4 as 90% decrease of amyloids was detected for insulin and lysozyme amyloid aggregates. Our findings indicate that MFs have potential to be used for treatment of amyloid diseases.

  8. 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.

  9. 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.

  10. 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...

  11. Natural product-based amyloid inhibitors.

    Science.gov (United States)

    Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R; Xu, Bin

    2017-09-01

    Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Hybrid Amyloid Membranes for Continuous Flow Catalysis.

    Science.gov (United States)

    Bolisetty, Sreenath; Arcari, Mario; Adamcik, Jozef; Mezzenga, Raffaele

    2015-12-29

    Amyloid fibrils are promising nanomaterials for technological applications such as biosensors, tissue engineering, drug delivery, and optoelectronics. Here we show that amyloid-metal nanoparticle hybrids can be used both as efficient active materials for wet catalysis and as membranes for continuous flow catalysis applications. Initially, amyloid fibrils generated in vitro from the nontoxic β-lactoglobulin protein act as templates for the synthesis of gold and palladium metal nanoparticles from salt precursors. The resulting hybrids possess catalytic features as demonstrated by evaluating their activity in a model catalytic reaction in water, e.g., the reduction of 4-nitrophenol into 4-aminophenol, with the rate constant of the reduction increasing with the concentration of amyloid-nanoparticle hybrids. Importantly, the same nanoparticles adsorbed onto fibrils surface show improved catalytic efficiency compared to the same unattached particles, pointing at the important role played by the amyloid fibril templates. Then, filter membranes are prepared from the metal nanoparticle-decorated amyloid fibrils by vacuum filtration. The resulting membranes serve as efficient flow catalysis active materials, with a complete catalytic conversion achieved within a single flow passage of a feeding solution through the membrane.

  13. 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.

  14. Immunoprecipitation of amyloid fibrils by the use of an antibody that recognizes a generic epitope common to amyloid fibrils.

    Directory of Open Access Journals (Sweden)

    Erin R Greiner

    Full Text Available Amyloid fibrils are associated with many maladies, including Alzheimer's disease (AD. The isolation of amyloids from natural materials is very challenging because the extreme structural stability of amyloid fibrils makes it difficult to apply conventional protein science protocols to their purification. A protocol to isolate and detect amyloids is desired for the diagnosis of amyloid diseases and for the identification of new functional amyloids. Our aim was to develop a protocol to purify amyloid from organisms, based on the particular characteristics of the amyloid fold, such as its resistance to proteolysis and its capacity to be recognized by specific conformational antibodies. We used a two-step strategy with proteolytic digestion as the first step followed by immunoprecipitation using the amyloid conformational antibody LOC. We tested the efficacy of this method using as models amyloid fibrils produced in vitro, tissue extracts from C. elegans that overexpress Aβ peptide, and cerebrospinal fluid (CSF from patients diagnosed with AD. We were able to immunoprecipitate Aβ(1-40 amyloid fibrils, produced in vitro and then added to complex biological extracts, but not α-synuclein and gelsolin fibrils. This method was useful for isolating amyloid fibrils from tissue homogenates from a C. elegans AD model, especially from aged worms. Although we were able to capture picogram quantities of Aβ(1-40 amyloid fibrils produced in vitro when added to complex biological solutions, we could not detect any Aβ amyloid aggregates in CSF from AD patients. Our results show that although immunoprecipitation using the LOC antibody is useful for isolating Aβ(1-40 amyloid fibrils, it fails to capture fibrils of other amyloidogenic proteins, such as α-synuclein and gelsolin. Additional research might be needed to improve the affinity of these amyloid conformational antibodies for an array of amyloid fibrils without compromising their selectivity before

  15. 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

  16. 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.

  17. Computational Modelling of the Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby

    2014-01-01

    of a specific protein into amyloid fibrils. During this process, a cytotoxic event occurs which can be a serious actor in the evolvement of the disease. This thesis is concerned with elucidating the biological processes concerning amyloid proteins, more specifically, the peptide hormone human islet amyloid...... setup. We have exploited these strengths to study the interactions between an amyloid fibril and amyloid imaging agents. Imaging agents are promising tools for the detection of amyloid deposits in the brain of AD patients. This could aid in the early diagnosis as well as evaluation of new treatments......When proteins do not fold correctly, it can lead to very serious diseases. One such group of diseases is the amyloid diseases, of which Alzheimer’s disease (AD), Parkinson’s disease, and type 2 diabetes mellitus (T2DM) are members. The amyloid diseases are characterized by the aggregation...

  18. Interaction of magnetic nanoparticles with lysozyme amyloid fibrils

    International Nuclear Information System (INIS)

    Gdovinová, Veronika; Tomašovičová, Natália; Batko, Ivan; Batková, Marianna; Balejčíková, Lucia; Garamus, Vasyl M.; Petrenko, Viktor I.; Avdeev, Mikhail V.; Kopčanský, Peter

    2017-01-01

    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.

  19. 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.

  20. Amyloid formation via supramolecular peptide assemblies.

    Science.gov (United States)

    Moore, Roger A; Hayes, Stanley F; Fischer, Elizabeth R; Priola, Suzette A

    2007-06-19

    Amyloid fibrils have been classically defined as linear, nonbranched polymeric proteins with a cross beta-sheet structure and the ability to alter the optical properties of the amyloid-specific dye Congo Red. Mounting evidence suggests that soluble oligomeric peptide assemblies approximately 2-20 nm in diameter are critical intermediates in amyloid formation. Using a pathogenic prion protein peptide comprised of residues 23-144, we demonstrate that, under quiescent but not agitated conditions, much larger globular assemblies up to 1 mum in diameter are made. These globules precede fibril formation and directly interact with growing fibril bundles. Fibrils made via these large spherical peptide assemblies displayed a remarkable diversity of ultrastructural features. Fibrillization of the Abeta1-40 peptide under similar conditions yielded similar results, suggesting a mechanism of general amyloid formation that can proceed through intermediates much larger than those previously described. Our data suggest that simply changing the physical microenvironment can profoundly influence the mechanism of amyloid formation and yield fibrils with novel ultrastructural properties.

  1. 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.

  2. 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.

  3. 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,…

  4. 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

  5. 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.

  6. Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis.

    Science.gov (United States)

    Askanas, Valerie; Engel, W King

    2007-11-01

    Sporadic inclusion-body myositis, the most common muscle disease of older persons, has no known cause or persistently beneficial treatment. The unfolding pathogenesis could lead to new treatment strategies and it is now of growing interest among clinicians and basic scientists. About 100 papers related to the subject were published in 2006 and the first part of 2007 (we cite only articles most relevant to this review). This review focuses on the current concepts of the pathogenesis of sporadic inclusion-body myositis. Both degeneration and mononuclear-cell inflammation are components of the pathology, but how each relates to the pathogenesis remains unclear. We suggest that an intramuscle fiber degenerative component is primary, leading to muscle-fiber destruction, while the lymphocytic inflammatory component may only slightly contribute to sporadic inclusion-body myositis muscle-fiber damage. Intracellular accumulation of amyloid-beta precursor protein, amyloid-beta, and amyloid-beta oligomers in an aging muscle-fiber cellular milieu, and other abnormalities, appear to be key pathogenic factors. We summarize intracellular molecular events and their consequences, and correlate findings in sporadic inclusion-body myositis muscle biopsies with inclusion-body myositis experimental models in tissue culture and in transgenic mice. Treatment of sporadic inclusion-body myositis remains a challenge. Antiinflammatory approaches used so far are without major or enduring benefit. Possible new treatment avenues are suggested.

  7. 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.

  8. 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)

  9. Fibrillar dimer formation of islet amyloid polypeptides

    Science.gov (United States)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    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.

  10. Antimicrobial activity of human islet amyloid polypeptides: an insight into amyloid peptides' connection with antimicrobial peptides.

    Science.gov (United States)

    Wang, Lan; Liu, Qian; Chen, Jin-Chun; Cui, Yi-Xian; Zhou, Bing; Chen, Yong-Xiang; Zhao, Yu-Fen; Li, Yan-Mei

    2012-07-01

    Human islet amyloid polypeptide (hIAPP) shows an antimicrobial activity towards two types of clinically relevant bacteria. The potency of hIAPP varies with its aggregation states. Circular dichroism was employed to determine the interaction between hIAPP and bacteria lipid membrane mimic. The antimicrobial activity of each aggregate species is associated with their ability to induce membrane disruption. Our findings provide new evidence revealing the antimicrobial activity of amyloid peptide, which suggest a possible connection between amyloid peptides and antimicrobial peptides.

  11. 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.)

  12. Designed amyloid fibers as materials for selective carbon dioxide capture.

    Science.gov (United States)

    Li, Dan; Furukawa, Hiroyasu; Deng, Hexiang; Liu, Cong; Yaghi, Omar M; Eisenberg, David S

    2014-01-07

    New materials capable of binding carbon dioxide are essential for addressing climate change. Here, we demonstrate that amyloids, self-assembling protein fibers, are effective for selective carbon dioxide capture. Solid-state NMR proves that amyloid fibers containing alkylamine groups reversibly bind carbon dioxide via carbamate formation. Thermodynamic and kinetic capture-and-release tests show the carbamate formation rate is fast enough to capture carbon dioxide by dynamic separation, undiminished by the presence of water, in both a natural amyloid and designed amyloids having increased carbon dioxide capacity. Heating to 100 °C regenerates the material. These results demonstrate the potential of amyloid fibers for environmental carbon dioxide capture.

  13. 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...... that is higher than that previously reported. The basal cell carcinoma material was further studied regarding the amount of amyloid, mitotic rate, degree of apoptosis and the age of the patients. There was no correlation between the amount of amyloid and the mitotic rate, or the degree of apoptosis...

  14. A novel and convenient method to immunize animals: Inclusion ...

    African Journals Online (AJOL)

    Purified recombinant protein has been routinely used to immunize rabbits to produce polyclonal antibodies. The process of the purification of recombinant proteins from bacterial inclusion bodies is both labor intensive and time consuming. To determine whether whole inclusion bodies can be used as antigen in polyclonal ...

  15. Bacterial Proteasomes.

    Science.gov (United States)

    Jastrab, Jordan B; Darwin, K Heran

    2015-01-01

    Interest in bacterial proteasomes was sparked by the discovery that proteasomal degradation is required for the pathogenesis of Mycobacterium tuberculosis, one of the world's deadliest pathogens. Although bacterial proteasomes are structurally similar to their eukaryotic and archaeal homologs, there are key differences in their mechanisms of assembly, activation, and substrate targeting for degradation. In this article, we compare and contrast bacterial proteasomes with their archaeal and eukaryotic counterparts, and we discuss recent advances in our understanding of how bacterial proteasomes function to influence microbial physiology.

  16. Radiologically Isolated Cerebral Amyloid Angiopathy-Related Inflammation.

    Science.gov (United States)

    Renard, Dimitri; Wacongne, Anne; Thouvenot, Eric

    2017-11-01

    In amyloid β-related angiitis of the central nervous system (also called cerebral amyloid angiopathy-related inflammation), cerebral amyloid angiopathy occurs in association with primary vasculitis of small- and medium-sized leptomeningeal and cortical arteries. To avoid brain biopsy, clinicoradiological criteria (including clinical features due to inflammation-related uni/multifocal white matter hyperintensities) for the diagnosis of cerebral amyloid angiopathy-related inflammation have been validated recently. We report 3 cases with acute symptoms directly related to cerebral amyloid angiopathy in the presence of asymptomatic cerebral amyloid angiopathy-related inflammation hyperintensities on initial magnetic resonance imaging. Recognizing radiological features of cerebral amyloid angiopathy-related inflammation in patients with cerebral amyloid angiopathy is important because radiological isolated cerebral amyloid angiopathy-related inflammation may become symptomatic and immunosuppressive treatment is often effective in cerebral amyloid angiopathy-related inflammation, although optimal treatment regimen is yet unknown. In contrast, apart from hypertension treatment, few therapeutic options exist in cerebral amyloid angiopathy. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  17. Nonpathological extracellular amyloid is present during normal epididymal sperm maturation.

    Directory of Open Access Journals (Sweden)

    Sandra Whelly

    Full Text Available Amyloids are aggregated proteins characterized by a specific cross-β-sheet structure and are typically associated with neurodegenerative diseases including Alzheimer's disease. Recently, however, several nonpathological amyloids have been found in intracellular organelles of normal mammalian tissues suggesting that amyloid may also carry out biological functions. We previously have shown that the epididymal cystatin CRES (cystatin-related epididymal spermatogenic, cst8, a reproductive-specific member of the cystatin superfamily of cysteine protease inhibitors, forms amyloid in vitro suggesting that CRES amyloid may also form in vivo within the epididymal lumen. Here we show that amyloid structures containing CRES are a component of the normal mouse epididymal lumen without any apparent cytotoxic effects on spermatozoa and that these structures change along the length of the tubule. These studies suggest the presence of a functional amyloid structure that may carry out roles in sperm maturation or maintenance of the luminal milieu and which itself may undergo maturational changes along the epididymis. In contrast to previous examples of functional amyloid which were intracellular, our studies now show that nonpathological/functional amyloid can also be extracellular. The presence of an extracellular and nonpathological amyloid in the epididymis suggests that similar amyloid structures may be present in other organ systems and may carry out distinctive tissue-specific functions.

  18. 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...

  19. Genetic Dissection of the Amyloid Precursor Protein in Developmental Function and Amyloid Pathogenesis*♦

    OpenAIRE

    Li, Hongmei; Wang, Zilai; Wang, Baiping; Guo, Qinxi; Dolios, Georgia; Tabuchi, Katsuhiko; Hammer, Robert E.; Südhof, Thomas C.; Wang, Rong; Zheng, Hui

    2010-01-01

    Proteolytic processing of the amyloid precursor protein (APP) generates large soluble APP derivatives, β-amyloid (Aβ) peptides, and APP intracellular domain. Expression of the extracellular sequences of APP or its Caenorhabditis elegans counterpart has been shown to be sufficient in partially rescuing the CNS phenotypes of the APP-deficient mice and the lethality of the apl-1 null C. elegans, respectively, leaving open the question as what is the role of the highly conserved APP intracellular...

  20. 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.

  1. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    Science.gov (United States)

    ... the genes associated with hereditary cerebral amyloid angiopathy APP CST3 ITM2B Related Information What is a gene? What is a gene mutation ... a disorder seems to run in my family? What are the different ways in which a genetic condition can be inherited? More about ... APP-related Genetic Testing Registry: Dementia familial British Genetic ...

  2. Amyloid plaque formation precedes dendritic spine loss.

    Science.gov (United States)

    Bittner, Tobias; Burgold, Steffen; Dorostkar, Mario M; Fuhrmann, Martin; Wegenast-Braun, Bettina M; Schmidt, Boris; Kretzschmar, Hans; Herms, Jochen

    2012-12-01

    Amyloid-beta plaque deposition represents a major neuropathological hallmark of Alzheimer's disease. While numerous studies have described dendritic spine loss in proximity to plaques, much less is known about the kinetics of these processes. In particular, the question as to whether synapse loss precedes or follows plaque formation remains unanswered. To address this question, and to learn more about the underlying kinetics, we simultaneously imaged amyloid plaque deposition and dendritic spine loss by applying two-photon in vivo microscopy through a cranial window in double transgenic APPPS1 mice. As a result, we first observed that the rate of dendritic spine loss in proximity to plaques is the same in both young and aged animals. However, plaque size only increased significantly in the young cohort, indicating that spine loss persists even many months after initial plaque appearance. Tracking the fate of individual spines revealed that net spine loss is caused by increased spine elimination, with the rate of spine formation remaining constant. Imaging of dendritic spines before and during plaque formation demonstrated that spine loss around plaques commences at least 4 weeks after initial plaque formation. In conclusion, spine loss occurs, shortly but with a significant time delay, after the birth of new plaques, and persists in the vicinity of amyloid plaques over many months. These findings hence give further hope to the possibility that there is a therapeutic window between initial amyloid plaque deposition and the onset of structural damage at spines.

  3. Fibrillar amyloid plaque formation precedes microglial activation.

    Science.gov (United States)

    Jung, Christian K E; Keppler, Kevin; Steinbach, Sonja; Blazquez-Llorca, Lidia; Herms, Jochen

    2015-01-01

    In Alzheimer's disease (AD), hallmark β-amyloid deposits are characterized by the presence of activated microglia around them. Despite an extensive characterization of the relation of amyloid plaques with microglia, little is known about the initiation of this interaction. In this study, the detailed investigation of very small plaques in brain slices in AD transgenic mice of the line APP-PS1(dE9) revealed different levels of microglia recruitment. Analysing plaques with a diameter of up to 10 μm we find that only the half are associated with clear morphologically activated microglia. Utilizing in vivo imaging of new appearing amyloid plaques in double-transgenic APP-PS1(dE9)xCX3CR1+/- mice further characterized the dynamic of morphological microglia activation. We observed no correlation of morphological microglia activation and plaque volume or plaque lifetime. Taken together, our results demonstrate a very prominent variation in size as well as in lifetime of new plaques relative to the state of microglia reaction. These observations might question the existing view that amyloid deposits by themselves are sufficient to attract and activate microglia in vivo.

  4. Infectious particles, stress, and induced prion amyloids

    Science.gov (United States)

    2013-01-01

    Transmissible encephalopathies (TSEs) are believed by many to arise by spontaneous conversion of host prion protein (PrP) into an infectious amyloid (PrP-res, PrPSc) without nucleic acid. Many TSE agents reside in the environment, with infection controlled by public health measures. These include the disappearance of kuru with the cessation of ritual cannibalism, the dramatic reduction of epidemic bovine encephalopathy (BSE) by removal of contaminated feed, and the lack of endemic scrapie in geographically isolated Australian sheep with susceptible PrP genotypes. While prion protein modeling has engendered an intense focus on common types of protein misfolding and amyloid formation in diverse organisms and diseases, the biological characteristics of infectious TSE agents, and their recognition by the host as foreign entities, raises several fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environmental metagenome that may cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non-infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging. PMID:23633671

  5. Energetics Underlying Twist Polymorphisms in Amyloid Fibrils

    NARCIS (Netherlands)

    Periole, Xavier; Huber, Thomas; Bonito-Oliva, Alessandra; Aberg, Karina C; van der Wel, Patrick C A; Sakmar, Thomas P; Marrink, Siewert J

    2018-01-01

    Amyloid fibrils are highly ordered protein aggregates associated with more than 40 human diseases. The exact conditions in which the fibrils are grown determine many types of reported fibril polymorphism, including different twist patterns. Twist-based polymorphs display unique mechanical properties

  6. 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

  7. Bacterial adhesion

    NARCIS (Netherlands)

    Loosdrecht, van M.C.M.

    1988-01-01

    As mentioned in the introduction of this thesis bacterial adhesion has been studied from a variety of (mostly practice oriented) starting points. This has resulted in a range of widely divergent approaches. In order to elucidate general principles in bacterial adhesion phenomena, we felt it

  8. 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...

  9. 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' ...

  10. Foresighting for Inclusive Development

    DEFF Research Database (Denmark)

    Andersen, Allan Dahl; Andersen, Per Dannemand

    2017-01-01

    We propose that foresight can contribute to inclusive development by making innovation systems more inclusive. Processes of developing future oriented innovation policies are often unsuccessful and rarely inclusive. We conceptualize such processes as foresighting. We focus on how the ex-ante desi...... 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....

  11. 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

  12. 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

  13. 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

  14. Inclusion : Conceptualization and measurement

    NARCIS (Netherlands)

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

  15. The Full Inclusion Movement.

    Science.gov (United States)

    Machado, Rodney E.; And Others

    1996-01-01

    Overviews background of the movement toward full inclusion of special education students into regular classrooms, including legal issues and successful educational practices. Suggests that full inclusion does not benefit all students and that inclusion should be one of several alternatives to meeting students' educational needs. Of approximately…

  16. 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…

  17. Documenting Your Inclusion Efforts.

    Science.gov (United States)

    Fritz, Marie F.; Miller, Maury

    This paper briefly addresses critical issues in documenting studies of the effectiveness of inclusive education for students with disabilities and includes a summary table of the existing literature and guidelines for problem solving about inclusion. The importance of sound methodology in documenting effects of inclusion and the dangers of value…

  18. Foresighting for Inclusive Development

    DEFF Research Database (Denmark)

    Dahl Andersen, Allan; Andersen, Per Dannemand

    We propose that foresight can contribute to inclusive development by making innovation policy processes more inclusive, which in turn makes innovation systems more inclusive. Processes of developing future-oriented innovation policies are often unsuccessful and rarely inclusive. We conceptualize...... 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...

  19. 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 ( ...

  20. 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.

  1. 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.

  2. 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...

  3. Recurrent Syncope, a Clue in Amyloid Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Julian A. Marin-Acevedo

    2018-01-01

    Full Text Available Infiltrative cardiomyopathies include a variety of disorders that lead to myocardial thickening resulting in a constellation of clinical manifestations and eventually heart failure that could be the first clue to reach the diagnosis. Among the more described infiltrative diseases of the heart is amyloid cardiomyopathy. The disease usually presents with subtle, nonspecific symptoms. Herein, we illustrate a case of recurrent syncope as the initial presenting symptom for systemic amyloid with polyneuropathy and cardiomyopathy as a cause of syncope. The article illustrates the role of advanced cardiac imaging in the diagnosis of the disease with a focused literature review. We also highlight the role of early, shared decision-making between patient, family, and medical team in the management of cardiac amyloidosis.

  4. What is the role of amyloid precursor protein dimerization?

    OpenAIRE

    Khalifa, Naouel Ben; Van Hees, Joanne; Tasiaux, Bernadette; Huysseune, Sandra; Smith, Steven O.; Constantinescu, Stefan N.; Octave, Jean-Noël; Kienlen-Campard, Pascal

    2010-01-01

    Extensive research efforts have been conducted over the past decades to understand the processing of the Amyloid Precursor Protein (APP). APP cleavage leads to the production of the beta-amyloid peptide (Abeta), which is the major constituent of the amyloid core of senile plaques found in the brains of patients with Alzheimer's disease (AD). Abeta is produced by the sequential cleavage of APP by beta- and gamma-secretases. Cleavage of APP by gamma-secretase also generates the APP Intracellula...

  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. Generation of amyloid-β is reduced by the interaction of calreticulin with amyloid precursor protein, presenilin and nicastrin.

    Directory of Open Access Journals (Sweden)

    Nina Stemmer

    Full Text Available Dysregulation of the proteolytic processing of amyloid precursor protein by γ-secretase and the ensuing generation of amyloid-β is associated with the pathogenesis of Alzheimer's disease. Thus, the identification of amyloid precursor protein binding proteins involved in regulating processing of amyloid precursor protein by the γ-secretase complex is essential for understanding the mechanisms underlying the molecular pathology of the disease. We identified calreticulin as novel amyloid precursor protein interaction partner that binds to the γ-secretase cleavage site within amyloid precursor protein and showed that this Ca(2+- and N-glycan-independent interaction is mediated by amino acids 330-344 in the C-terminal C-domain of calreticulin. Co-immunoprecipitation confirmed that calreticulin is not only associated with amyloid precursor protein but also with the γ-secretase complex members presenilin and nicastrin. Calreticulin was detected at the cell surface by surface biotinylation of cells overexpressing amyloid precursor protein and was co-localized by immunostaining with amyloid precursor protein and presenilin at the cell surface of hippocampal neurons. The P-domain of calreticulin located between the N-terminal N-domain and the C-domain interacts with presenilin, the catalytic subunit of the γ-secretase complex. The P- and C-domains also interact with nicastrin, another functionally important subunit of this complex. Transfection of amyloid precursor protein overexpressing cells with full-length calreticulin leads to a decrease in amyloid-β42 levels in culture supernatants, while transfection with the P-domain increases amyloid-β40 levels. Similarly, application of the recombinant P- or C-domains and of a synthetic calreticulin peptide comprising amino acid 330-344 to amyloid precursor protein overexpressing cells result in elevated amyloid-β40 and amyloid-β42 levels, respectively. These findings indicate that the interaction of

  7. Amyloid-hydroxyapatite bone biomimetic composites.

    Science.gov (United States)

    Li, Chaoxu; Born, Anne-Kathrin; Schweizer, Thomas; Zenobi-Wong, Marcy; Cerruti, Marta; Mezzenga, Raffaele

    2014-05-28

    A "bottom up" strategy is proposed to synthesize high aspect ratio hydroxyapatite (and brushite) platelets, and combine them with amyloid fibrils into layered hybrid nanocomposites. Their hierarchical structure, despite the differences from natural bone, confers to the nanocomposites a density and elastic modulus matching those of cancellous bone. Evidence of good adhesion and spreading of human trabecular bone-derived pre-osteoblasts cells on these nanocomposites is provided. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. 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.

  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. Amyloid Beta Peptide Folding in Reverse Micelles.

    Science.gov (United States)

    Eskici, Gözde; Axelsen, Paul H

    2017-07-19

    Previously published experimental studies have suggested that when the 40-residue amyloid beta peptide is encapsulated in a reverse micelle, it folds into a structure that may nucleate amyloid fibril formation (Yeung, P. S.-W.; Axelsen, P. H. J. Am. Chem. Soc. 2012, 134, 6061 ). The factors that induce the formation of this structure have now been identified in a multi-microsecond simulation of the same reverse micelle system that was studied experimentally. Key features of the polypeptide-micelle interaction include the anchoring of a hydrophobic residue cluster into gaps in the reverse micelle surface, the formation of a beta turn at the anchor point that brings N- and C-terminal segments of the polypeptide into proximity, high ionic strength that promotes intramolecular hydrogen bond formation, and deformation of the reverse micelle surface to facilitate interactions with the surface along the entire length of the polypeptide. Together, these features cause the simulation-derived vibrational spectrum to red shift in a manner that reproduces the red-shift previously reported experimentally. On the basis of these findings, a new mechanism is proposed whereby membranes nucleate fibril formation and facilitate the in-register alignment of polypeptide strands that is characteristic of amyloid fibrils.

  11. Design and Construction of Large Amyloid Fibers

    Directory of Open Access Journals (Sweden)

    Devin M. Ridgley

    2015-04-01

    Full Text Available 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 amino acid sequence show that control of the large amyloid fiber morphology is dependent on the amount of glutamine repeats or “Q-blocks” relative to hydrophobic side chained amino acids such as alanine, isoleucine, leucine, and valine in the adder protein. Adder proteins with only hydrophobic groups form low modulus rectangular cross-sections and increasing the Q-block content allows excess hydrogen bonding on amide groups that results in twist and higher modulus. The experimental results show that large amyloid fibers of specific shape and modulus can be designed and controlled at the molecular level.

  12. Amyloid osteoarthropathy in long term hemodialysis patients

    International Nuclear Information System (INIS)

    Orzincolo, C.; Cardona, P.; Vita, G.; Bedani, P.L.; Farinelli, A.; Scutellari, P.N.

    1988-01-01

    The accumulation of amyloid in the bone and joint system has recently been recognized as a peculiar disease in patients undergoing long-term hemodialysis (5 years at least), especially in those who use cuprophan membranes. The pathology of amyloidosis is characterized by deposits of amyloid (β microglobulin mainly) in the bone, in the synovia, and in pericapsular soft tissues. The skeleton of 46 long-term hemodialysis patients (19 males and 27 females) was studied by X-ray; bone and joint abnormalities due to amyloid deposition were observed in 45% of cases. The shoulder, hip, and wrist were the most frequently involved joints. Destructive spondyloarthorapathy was present in 15% of cases. The radiographic patterns of AOD are generally divided into axial and peripheral lesions. In the appendicular skeleton abnormalities include: well-defined lytic areas (geodes), pathologic fractures, marginal erosions, and particular soft tissue swelling. Destructive spondyloarthropathy is frequently present in the cervical spine (85% of our cases) and is characterized by narrowing of the invertebral space, marginal erosion, and subchondral bone sclerosis of the vertebral body

  13. Amyloid goiter: two cases and a review of the Literature

    International Nuclear Information System (INIS)

    Yildiz, Levent; Kefeli, Mehmet; Kose, Behiye; Baris, Sancar

    2007-01-01

    Although involvement of the thyroid gland by amyloid is a relatively common phenomenon, clinically significant enlargement of the thyroid owing to amyloid deposition is an extremely rare occurrence. We describe two cases of amyloid goiter and review the relevant literature. The first case was systemic amylloidosis secondary to familial Mediterranean fever. The second case was a chronic renal failure patient who presented with an enlarged thyroid and upper airway obstructive symptoms. To date, true amyloid goiter secondary to amyloidosis associated with familial Mediterranean fever has only been reported in twelve patients. (author)

  14. 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...

  15. 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 ...

  16. Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta.

    Science.gov (United States)

    Oikonomidi, Aikaterini; Lewczuk, Piotr; Kornhuber, Johannes; Smulders, Yvo; Linnebank, Michael; Semmler, Alexander; Popp, Julius

    2016-10-01

    Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPβ, and amyloid β1-42 (Aβ1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aβ1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPβ were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aβ1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Aβ1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease. © 2016 International Society for Neurochemistry.

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

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

    The research agenda will cover four themes: linkages between trade and inclusive growth; negotiation issues with poorly understood implications, such as labour standards and intellectual property; liberalization of trade in services, and the emerging regional trade policy architecture. The idea is to promote a better ...

  18. 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.

  19. Regional brain hypometabolism is unrelated to regional amyloid plaque burden.

    Science.gov (United States)

    Altmann, Andre; Ng, Bernard; Landau, Susan M; Jagust, William J; Greicius, Michael D

    2015-12-01

    In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting

  20. Amyloid cascade in Alzheimer's disease: Recent advances in medicinal chemistry.

    Science.gov (United States)

    Mohamed, Tarek; Shakeri, Arash; Rao, Praveen P N

    2016-05-04

    Alzheimer's disease is of major concern all over the world due to a number of factors including (i) an aging population (ii) increasing life span and (iii) lack of effective pharmacotherapy options. The past decade has seen intense research in discovering disease-modifying multitargeting small molecules as therapeutic options. The pathophysiology of Alzheimer's disease is attributed to a number of factors such as the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/mitochondrial dysfunction. In recent years, targeting the amyloid cascade has emerged as an attractive strategy to discover novel neurotherapeutics. Formation of beta-amyloid species, with different degrees of solubility and neurotoxicity is associated with the gradual decline in cognition leading to dementia. The two commonly used approaches to prevent beta-amyloid accumulation in the brain include (i) development of beta-secretase inhibitors and (ii) designing direct inhibitors of beta-amyloid (self-induced) aggregation. This review highlights the amyloid cascade hypothesis and the key chemical features required to design small molecules that inhibit lower and higher order beta-amyloid aggregates. Several recent examples of small synthetic molecules with disease-modifying properties were considered and their molecular docking studies were conducted using either a dimer or steric-zipper assembly of beta-amyloid. These investigations provide a mechanistic understanding on the structural requirements needed to design novel small molecules with anti-amyloid aggregation properties. Significantly, this work also demonstrates that the structural requirements to prevent aggregation of various amyloid species differs considerably, which explains the fact that many small molecules do not exhibit similar inhibition profile toward diverse amyloid species such as dimers, trimers, tetramers, oligomers, protofibrils and fibrils. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. 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…

  2. School Inclusion Programmes (SIPS)

    Science.gov (United States)

    Drossinou-Korea, Maria; Matousi, Dimitra; Panopoulos, Nikolaos; Paraskevopoulou, Aikaterini

    2016-01-01

    The purpose of this work was to understand the school inclusion programmes (SIPs) for students with special educational needs (SEN). The methodology was conducted in the field of special education (SE) and focuses on three case studies of students who was supported by SIPs. The Targeted, Individual, Structured, Inclusion Programme for students…

  3. Ladle Metallurgy Kinetics: Inclusion-Inclusion Reactions

    Science.gov (United States)

    Pistorius, P. Chris

    An example is presented to illustrate the joint effect of local reaction equilibria and mass transfer limitations, for reactions during ladle refining of steel. The example relies on some of the kinetic principles that David Robertson has employed to quantify many metallurgical processes. In calcium treatment of alumina inclusions in aluminum-killed steels, solid CaS forms as an intermediate reaction product. During subsequent reaction, CaS disappears and calcium aluminate forms; at the same time, aluminum and sulfur dissolve in the steel. Kinetic analysis shows that the rate of this reaction is not limited by mass transfer of dissolved aluminum and sulfur away from the reacting inclusions. The reaction rate is likely limited by transport of dissolved calcium. This example also illustrates the use of FactSage macros for kinetic modeling.

  4. Bacterial Ecology

    DEFF Research Database (Denmark)

    Fenchel, Tom

    2011-01-01

    Bacterial ecology is concerned with the interactions between bacteria and their biological and nonbiological environments and with the role of bacteria in biogeochemical element cycling. Many fundamental properties of bacteria are consequences of their small size. Thus, they can efficiently exploit...

  5. 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,

  6. 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,

  7. Bacterial Ecology

    DEFF Research Database (Denmark)

    Fenchel, Tom

    2011-01-01

    , 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...

  8. Bacterial Vaginosis

    Science.gov (United States)

    ... that coats the walls of the vagina Vaginal discharge with an unpleasant or fishlike odor Vaginal pain or itching Burning during urination Doctors are unsure of the incubation period for bacterial vaginosis. How Is the Diagnosis Made? Your child’s pediatrician can make the diagnosis ...

  9. 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: ...

  10. 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.

  11. 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...

  12. Beyond Amyloid - Widening the View on Alzheimer's Disease.

    Science.gov (United States)

    Behl, Christian; Ziegler, Christine

    2017-11-01

    For 25 years, the amyloid cascade hypothesis, based on the finding that mutations in the amyloid precursor protein are closely linked to familial forms of Alzheimer's disease (AD), dominated the research on this disease. Recent failures of clinical anti-amyloidogenic trials, however, substantially support the reasoning (i) that the pathomechanisms that trigger familial AD, namely the generation, aggregation, and deposition of amyloid beta, cannot necessarily be extrapolated to sporadic cases and (ii) that amyloid beta represents a prominent histopathological feature in AD but not its exclusive causative factor. In autumn 2016, the Volkswagen Foundation hosted the Herrenhausen Symposium 'Beyond Amyloid - Widening the View on Alzheimer's Disease' in Hannover, Germany, to bring together current knowledge on cellular and molecular processes that contribute to AD pathogenesis independent of or alongside with the amyloid biochemistry. The following mini review series was authored by key speakers at the meeting, and highlights some of the mechanisms potentially involved in AD etiology that provide alternative viewpoints and mechanisms beyond the amyloid cascade hypothesis. This article is part of the series "Beyond Amyloid". © 2017 International Society for Neurochemistry.

  13. 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 ...

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

    Indian Academy of Sciences (India)

    2012-10-27

    Oct 27, 2012 ... To test the above hypothesis, we used ovariectomized with diet-induced hypercholesterolemia (OVX) and hypercholesterolemia (HCL) diet alone mouse models. HPLC analysis reveals the presence of beta amyloid in the OVX and HCL mice brain. Congo red staining analysis revealed the extent of amyloid ...

  15. 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

  16. 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 us...

  17. Specific Triazine Herbicides Induce Amyloid-beta(42) Production

    NARCIS (Netherlands)

    Portelius, Erik; Durieu, Emilie; Bodin, Marion; Cam, Morgane; Pannee, Josef; Leuxe, Charlotte; Mabondzo, Aloise; Oumata, Nassima; Galons, Herve; Lee, Jung Yeol; Chang, Young-Tae; Stuber, Kathrin; Koch, Philipp; Fontaine, Gaelle; Potier, Marie-Claude; Manousopoulou, Antigoni; Garbis, Spiros D.; Covaci, Adrian; Van Dam, Debby; De Deyn, Peter; Karg, Frank; Flajolet, Marc; Omori, Chiori; Hata, Saori; Suzuki, Toshiharu; Blennow, Kaj; Zetterberg, Henrik; Meijer, Laurent

    2016-01-01

    Proteolytic cleavage of the amyloid-beta protein precursor (A beta PP) ecretases leads to extracellular release of amyloid-beta (A beta) peptides. Increased production of A beta(42) over A beta(40) and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark.

  18. 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...

  19. Bacterial Adhesion & Blocking Bacterial Adhesion

    DEFF Research Database (Denmark)

    Vejborg, Rebecca Munk

    2008-01-01

    reduce or delay bacterial biofilm formation of a range of urinary tract infectious E.coli and Klebsiella isolates. Several other proteinaceous coatings were also found to display anti-adhesive properties, possibly providing a measure for controlling the colonization of implant materials. Several other...... components. These substances may both mediate and stabilize the bacterial biofilm. Finally, several adhesive structures were examined, and a novel physiological biofilm phenotype in E.coli biofilms was characterized, namely cell chain formation. The autotransporter protein, antigen 43, was implicated...

  20. 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

  1. Inhibition of Toxic IAPP Amyloid by Extracts of Common Fruits.

    Science.gov (United States)

    Kao, Pei-Yu; Green, Evangeline; Pereira, Catalina; Ekimura, Shauna; Juarez, Dennis; Whyte, Travis; Arhar, Taylor; Malaspina, Bianca; Nogaj, Luiza A; Moffet, David A

    2015-01-01

    The aggregation of the 37-amino acid polypeptide islet amyloid polypeptide (IAPP, amylin), as either insoluble amyloid or as small oligomers, appears to play a direct role in the death of pancreatic β-islet cells in type 2 diabetes. It is believed that inhibiting the aggregation of IAPP may slow down, if not prevent entirely, the progression of this disease. Extracts of thirteen different common fruits were analyzed for their ability to prevent the aggregation of amyloidogenic IAPP. Thioflavin T binding, immuno-detection and circular dichroism assays were performed to test the in vitro inhibitory potential of each extract. Atomic force microscopy was used to visualize the formation of amyloid fibrils with and without each fruit extract. Finally, extracts were tested for their ability to protect living mammalian cells from the toxic effects of amyloid IAPP. Several fruits showed substantial ability to inhibit IAPP aggregation and protect living cells from toxic IAPP amyloid.

  2. 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.

  3. 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...

  4. Imaging of dialysis-related amyloid (AB-amyloid) deposits with 131I-beta 2-microglobulin

    International Nuclear Information System (INIS)

    Floege, J.; Burchert, W.; Brandis, A.; Gielow, P.; Nonnast-Daniel, B.; Spindler, E.; Hundeshagen, H.; Shaldon, S.; Koch, K.M.

    1990-01-01

    The diagnosis of dialysis-related amyloid (AB-amyloid) has been based usually on clinical and radiological criteria. Following the discovery that beta 2-microglobulin was the major protein of this amyloid, we isolated and radiolabelled uremic plasma beta 2-microglobulin. After intravenous injection, gamma-camera images of selected joint areas were obtained from 42 patients who were on regular hemodialysis therapy. Positive scans involving the shoulder, hip, knee and carpal regions were found in 13 of 14 patients treated for more than 10 years and 10 of 16 patients treated for 5 to 10 years. Patients treated for less time had negative scans. Specificity was indicated by negative scans in non-amyloid inflammatory lesions in control hemodialysis patients. Up to 48-fold tracer enrichment was detected in excised AB-amyloid containing tissue as compared to amyloid-free tissue. These findings suggest that circulating radiolabelled beta 2-microglobulin is taken up by the amyloid deposits. This method may non-invasively detect tissue infiltrates of amyloid. It may also permit prospective evaluation of the efficacy of prophylactic dialysis strategies which are designed to prevent or delay the onset of this complication of long-term dialysis

  5. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup

    NARCIS (Netherlands)

    Sperling, R.A.; Jack, C.R.; Black, S.E.; Frosch, M.P.; Greenberg, S.M.; Hyman, B.T.; Scheltens, P.; Carrillo, M.C.; Thies, W.; Bednar, M.M.; Black, R.S.; Brashear, H.R.; Grundman, M.; Siemers, E.R.; Feldman, H.H.; Schindler, R.J.

    2011-01-01

    Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-β burden in Alzheimer's disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened

  6. 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?...

  7. Mapping Inclusive Growth

    OpenAIRE

    Raquel Almeida Ramos; Rafael Ranieri; Jan-Willem Lammes

    2013-01-01

    Since its emergence around the turn of the century the concept of inclusive growth has been substantially debated by researchers and practitioners, has increasingly gained space in domestic and international political circles, has inspired the design of and generated projects and policies, and has impacted the views and the lives of many people. While the conceptual debate and the practical application of various definitions of inclusive growth have taken place simultaneously, they have recen...

  8. 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...

  9. Bacterial lipases

    OpenAIRE

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

    1994-01-01

    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, meaning a sharp increase in lipase activity observed when the substrate starts to form an emulsion, thereby presenting to the enzyme an interfacial area. As a consequence, the kinetics of a lipase rea...

  10. 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.

  11. Animal models of cerebral amyloid angiopathy.

    Science.gov (United States)

    Jäkel, Lieke; Van Nostrand, William E; Nicoll, James A R; Werring, David J; Verbeek, Marcel M

    2017-10-15

    Cerebral amyloid angiopathy (CAA), due to vascular amyloid β (Aβ) deposition, is a risk factor for intracerebral haemorrhage and dementia. CAA can occur in sporadic or rare hereditary forms, and is almost invariably associated with Alzheimer's disease (AD). Experimental (animal) models are of great interest in studying mechanisms and potential treatments for CAA. Naturally occurring animal models of CAA exist, including cats, dogs and non-human primates, which can be used for longitudinal studies. However, due to ethical considerations and low throughput of these models, other animal models are more favourable for research. In the past two decades, a variety of transgenic mouse models expressing the human Aβ precursor protein (APP) has been developed. Many of these mouse models develop CAA in addition to senile plaques, whereas some of these models were generated specifically to study CAA. In addition, other animal models make use of a second stimulus, such as hypoperfusion or hyperhomocysteinemia (HHcy), to accelerate CAA. In this manuscript, we provide a comprehensive review of existing animal models for CAA, which can aid in understanding the pathophysiology of CAA and explore the response to potential therapies. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  12. 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

  13. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Nordberg, Agneta [Karolinska University Hospital Huddinge, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden)

    2008-03-15

    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 {sup 11}C-PIB retention in brain at prodromal stages of AD and a possibility to discriminate AD from other dementia disorders by {sup 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.)

  15. 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.

  16. 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.

  17. 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.)

  18. 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.

  19. Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery.

    Science.gov (United States)

    Jaunmuktane, Zane; Quaegebeur, Annelies; Taipa, Ricardo; Viana-Baptista, Miguel; Barbosa, Raquel; Koriath, Carolin; Sciot, Raf; Mead, Simon; Brandner, Sebastian

    2018-02-15

    Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer's disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). Aβ pathology is transmissible experimentally in animals and through medical procedures in humans, such as contaminated growth hormone or dura mater transplantation in the context of iatrogenic prion disease. Here, we present four patients who underwent neurosurgical procedures during childhood or teenage years and presented with intracerebral haemorrhage approximately three decades later, caused by severe CAA. None of these patients carried pathogenic mutations associated with early Aβ pathology development. In addition, we identified in the literature four patients with a history of neurosurgical intervention and subsequent development of CAA. These findings raise the possibility that Aβ pathology may be transmissible, as prion disease is, through neurosurgical procedures.

  20. Overexpression of heparanase lowers the amyloid burden in amyloid-β precursor protein transgenic mice.

    Science.gov (United States)

    Jendresen, Charlotte B; Cui, Hao; Zhang, Xiao; Vlodavsky, Israel; Nilsson, Lars N G; Li, Jin-Ping

    2015-02-20

    Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-β (Aβ) deposits in Alzheimer disease brain and in Aβ precursor protein (AβPP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of Aβ pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human AβPP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect AβPP processing because the steady-state levels of Aβ1-40, Aβ1-42, and soluble AβPP β were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the Aβ burden, measured by Aβx-40 and Aβx-42 immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the Aβx-42 burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated Aβ1-42-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing Aβ fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with Aβ-HSPG interactions might be a potential strategy for Alzheimer disease treatment. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. 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...... movement is powered by insertional polymerization of ParM. Consistently, we find that segregating plasmids are positioned at the ends of extending ParM filaments. Thus, the process of R1 plasmid segregation in E. coli appears to be mechanistically analogous to the actin-based motility operating...

  2. Silver ions as em marker of congo red ligation sites in amyloids and amyloid-like aggregates.

    Science.gov (United States)

    Rybarska, Janina; Konieczny, Leszek; Jagusiak, Anna; Chłopaś, Katarzyna; Zemanek, Grzegorz; Piekarska, Barbara; Stopa, Barbara; Piwowar, Piotr; Woźnicka, Olga; Roterman, Irena

    2017-01-01

    Congo red (CR) is a known selective amyloid ligand. The focus of our work is identification (by EM imaging) of dye binding sites and their distribution in amyloids and amyloid-like aggregates formed in vitro. In order to produce the required contrast, CR has been indirectly combined with metal via including Titan yellow (TY) by intercalation which exhibits a relatively strong affinity for silver ions. The resulting combined ligand retains its ability to bind to proteins (which it owes to CR) and can easily be detected in EM studies thanks to TY. We have found, however, that in protein aggregates where unfolding is stabilized by aggregation and therefore is irreversible, TY alone may serve as both, the ligand and the metal carrier. The formation of ordered structures in amyloids was studied using IgG light chains with amyloidogenic properties, converted into amyloids by shaking. The resulting EM images were subjected to interpretation on the basis of the authors' earlier research on the CR/light chain complexation process. Our results indicate that dimeric light chains, which are the subject of our study, produce amyloids or amyloid-like complexes with chain-like properties and strong helicalization tendencies. Cursory analysis suggests that the edge polypeptide loops belonging to unstable light chains form intermolecular bridges which promote creation of loose gel deposits, or are otherwise engaged in the swapping processes leading to higher structural ordering.

  3. 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

  4. 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.

  5. Amyloid β Oligomeric Species Present in the Lag Phase of Amyloid Formation.

    Directory of Open Access Journals (Sweden)

    Martin Wolff

    Full Text Available Alzheimer's disease (AD-associated amyloid β peptide (Aβ is one of the main actors in AD pathogenesis. Aβ is characterized by its high tendency to self-associate, leading to the generation of oligomers and amyloid fibrils. The elucidation of pathways and intermediates is crucial for the understanding of protein assembly mechanisms in general and in conjunction with neurodegenerative diseases, e.g., for the identification of new therapeutic targets. Our study focused on Aβ42 and its oligomeric assemblies in the lag phase of amyloid formation, as studied by sedimentation velocity (SV centrifugation. The assembly state of Aβ during the lag phase, the time required by an Aβ solution to reach the exponential growth phase of aggregation, was characterized by a dominant monomer fraction below 1 S and a population of oligomeric species between 4 and 16 S. From the oligomer population, two major species close to a 12-mer and an 18-mer with a globular shape were identified. The recurrence of these two species at different initial concentrations and experimental conditions as the smallest assemblies present in solution supports the existence of distinct, energetically favored assemblies in solution. The sizes of the two species suggest an Aβ42 aggregation pathway that is based on a basic hexameric building block. The study demonstrates the potential of SV analysis for the evaluation of protein aggregation pathways.

  6. Study of Meteoritic Inclusion

    DEFF Research Database (Denmark)

    Olsen, Mia Bjørg Stolberg

    ionization mass spectrometry (SIMS). Moreover, we have shown that combining careful petrological investigations with high-precision isotope measurements of multiple systems on single meteoritic inclusions can potentially provide unique insights into the formation history of the solar system's earliest solids...... and the observation of a reduced initial abundance of 26Al in the accretion regions of chondrules and asteroidal bodies impacts our understanding of the accretion timescales of protoplanets in a significant way. Combining high-precision isotope measurements of multiple systems on individual meteoritic inclusions...

  7. 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.

  8. 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

  9. 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 ...

  10. 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...

  11. Electrochemistry of Alzheimer disease amyloid beta peptides.

    Science.gov (United States)

    Chiorcea-Paquim, Ana-Maria; Enache, Teodor Adrian; Oliveira-Brett, Ana Maria

    2018-02-13

    Alzheimer's disease (AD) is a widespread form of dementia that is estimated to affect 44.4 million people worldwide. AD pathology is closely related to the accumulation of amyloid beta (Aβ) peptides in fibrils and plagues, the small oligomeric intermediate species formed during the Aβ peptides aggregation presenting the highest neurotoxicity. This review discusses the recent advances on the Aβ peptides electrochemical characterisation. The Aβ peptides oxidation at a glassy carbon electrode occurs in one or two steps, depending on the amino acid sequence, length and content. The first electron transfer reaction corresponds to the tyrosine Tyr10 amino acid residue oxidation, and the second to all three histidine (His6, His13 and His14) and one methionine (Met35) amino acid residues. The Aβ peptides aggregation and amyloid fibril formation is electrochemically detected via the electroactive amino acids oxidation peak currents decrease that occurs in a time dependent manner. The Aβ peptides redox behaviour is correlated with changes in the adsorption morphology from initially random coiled structures, corresponding to the Aβ peptide monomers in random coil or in α-helix conformations, to aggregates and protofibrils and two types of fibrils, corresponding to the Aβ peptides in a β-sheet configuration, observed by atomic force microscopy. Electrochemical studies of Aβ peptides aggregation, mediated by the interaction with metal ions, in particular zinc, copper, and iron, and different methodologies concerning the detection of Aβ peptide biomarkers of AD in biological fluids, using electrochemical biosensors, are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. 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.

  13. The effect of tachykinin neuropeptides on amyloid β aggregation.

    Science.gov (United States)

    Flashner, Efrat; Raviv, Uri; Friedler, Assaf

    2011-04-01

    A hallmark of Alzheimer's disease is production of amyloid β peptides resulting from aberrant cleavage of the amyloid precursor protein. Amyloid β assembles into fibrils under physiological conditions, through formation of neurotoxic intermediate oligomers. Tachykinin peptides are known to affect amyloid β neurotoxicity in cells. To understand the mechanism of this effect, we studied how tachykinins affect Aβ(1-40) aggregation in vitro. Fibrils grown in the presence of tachykinins exhibited reduced thioflavin T (ThT) fluorescence, while their morphology, observed in transmission electron microscopy (TEM), did not alter. Cross linking studies revealed that the distribution of low molecular weight species was not affected by tachykinins. Our results suggest that there may be a specific interaction between tachykinins and Aβ(1-40) that allows them to co-assemble. This effect may explain the reduction of Aβ(1-40) neurotoxicity in cells treated with tachykinins. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Prevalence of cerebral amyloid pathology in persons without dementia

    DEFF Research Database (Denmark)

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

    2015-01-01

    or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants...... with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex....... OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified...

  15. Mechanism of prion propagation: amyloid growth occurs by monomer addition.

    Directory of Open Access Journals (Sweden)

    Sean R Collins

    2004-10-01

    Full Text Available Abundant nonfibrillar oligomeric intermediates are a common feature of amyloid formation, and these oligomers, rather than the final fibers, have been suggested to be the toxic species in some amyloid diseases. Whether such oligomers are critical intermediates for fiber assembly or form in an alternate, potentially separable pathway, however, remains unclear. Here we study the polymerization of the amyloidogenic yeast prion protein Sup35. Rapid polymerization occurs in the absence of observable intermediates, and both targeted kinetic and direct single-molecule fluorescence measurements indicate that fibers grow by monomer addition. A three-step model (nucleation, monomer addition, and fiber fragmentation accurately accounts for the distinctive kinetic features of amyloid formation, including weak concentration dependence, acceleration by agitation, and sigmoidal shape of the polymerization time course. Thus, amyloid growth can occur by monomer addition in a reaction distinct from and competitive with formation of potentially toxic oligomeric intermediates.

  16. Imaging amyloid beta peptide oligomeric particles in solution.

    Science.gov (United States)

    Dong, Jijun; Apkarian, Robert P; Lynn, David G

    2005-09-01

    While all protein misfolding diseases are characterized by fibrous amyloid deposits, the favorable free energy and strongly cooperative nature of the self-assembly have complicated the development of therapeutic strategies aimed at preventing their formation. As structural models for the amyloid fibrils approach atomic resolution, increasing evidence suggests that early folding intermediates, rather than the final structure, are more strongly associated with the loss of neuronal function. For that reason we now demonstrate the use of cryo-etch high-resolution scanning electron microscopy (cryo-HRSEM) for the direct observation of pathway intermediates in amyloid assembly. A congener of the Abeta peptide of Alzheimer's disease, Abeta(13-21), samples a variety of time-dependent self-assembles in a manner similar to those seen for larger proteins. A morphological description of these intermediates is the first step towards their structural characterization and the definition of their role in both amyloid assembly and neurotoxicity.

  17. 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…

  18. Interactions driving the collapse of islet amyloid polypeptide: Implications for amyloid aggregation

    Science.gov (United States)

    Cope, Stephanie M.

    Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-residue intrinsically disordered hormone involved in glucose regulation and gastric emptying. The aggregation of hIAPP into amyloid fibrils is believed to play a causal role in type 2 diabetes. To date, not much is known about the monomeric state of hIAPP or how it undergoes an irreversible transformation from disordered peptide to insoluble aggregate. IAPP contains a highly conserved disulfide bond that restricts hIAPP(1-8) into a short ring-like structure: N_loop. Removal or chemical reduction of N_loop not only prevents cell response upon binding to the CGRP receptor, but also alters the mass per length distribution of hIAPP fibers and the kinetics of fibril formation. The mechanism by which N_loop affects hIAPP aggregation is not yet understood, but is important for rationalizing kinetics and developing potential inhibitors. By measuring end-to-end contact formation rates, Vaiana et al. showed that N_loop induces collapsed states in IAPP monomers, implying attractive interactions between N_loop and other regions of the disordered polypeptide chain . We show that in addition to being involved in intra-protein interactions, the N_loop is involved in inter-protein interactions, which lead to the formation of extremely long and stable beta-turn fibers. These non-amyloid fibers are present in the 10 muM concentration range, under the same solution conditions in which hIAPP forms amyloid fibers. We discuss the effect of peptide cyclization on both intra- and inter-protein interactions, and its possible implications for aggregation. Our findings indicate a potential role of N_loop-N_loop interactions in hIAPP aggregation, which has not previously been explored. Though our findings suggest that N_loop plays an important role in the pathway of amyloid formation, other naturally occurring IAPP variants that contain this structural feature are incapable of forming amyloids. For example, hIAPP readily

  19. 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 qua...

  20. 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...

  1. Peer Tutoring for Inclusion

    Science.gov (United States)

    Temple, Viviene A.; Lynnes, Michelle D.

    2008-01-01

    Peer tutoring is a pedagogical technique that has promise to improve outcomes for students with a disability within existing resource constraints. Published empirically-based papers on peer-tutoring were descriptively analysed. Synthesis of these studies revealed that peer tutoring is effective in inclusive physical education contexts. Evidence…

  2. Penile Epidermal Inclusion Cyst

    Directory of Open Access Journals (Sweden)

    M. El-Shazly

    2012-01-01

    Full Text Available We report a case of epidermal inclusion cyst in a 32-year-old male. This was a complication of circumcision that was neglected over years to form stones and urethrocutaneous fistula. Complete excision of the cyst and repair of the fistula were performed successfully. Histopathological examination confirmed our diagnosis.

  3. Supporting Inclusive Growth

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

    msandilands

    2010-10-27

    Oct 27, 2010 ... United Nations Development Programme. WRC. Women's Rights and Citizenship ... The goal of the Supporting Inclusive Growth (SIG) program is to support rigorous and policy-oriented research that ... Exploring synergies with IDRC's Environmental Economics program and other lead players outside the ...

  4. 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

  5. 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.

  6. 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.

  7. PMEL Amyloid Fibril Formation: The Bright Steps of Pigmentation

    Directory of Open Access Journals (Sweden)

    Christin Bissig

    2016-08-01

    Full Text Available In pigment cells, melanin synthesis takes place in specialized organelles, called melanosomes. The biogenesis and maturation of melanosomes is initiated by an unpigmented step that takes place prior to the initiation of melanin synthesis and leads to the formation of luminal fibrils deriving from the pigment cell-specific pre-melanosomal protein (PMEL. In the lumen of melanosomes, PMEL fibrils optimize sequestration and condensation of the pigment melanin. Interestingly, PMEL fibrils have been described to adopt a typical amyloid-like structure. In contrast to pathological amyloids often associated with neurodegenerative diseases, PMEL fibrils represent an emergent category of physiological amyloids due to their beneficial cellular functions. The formation of PMEL fibrils within melanosomes is tightly regulated by diverse mechanisms, such as PMEL traffic, cleavage and sorting. These mechanisms revealed increasing analogies between the formation of physiological PMEL fibrils and pathological amyloid fibrils. In this review we summarize the known mechanisms of PMEL fibrillation and discuss how the recent understanding of physiological PMEL amyloid formation may help to shed light on processes involved in pathological amyloid formation.

  8. Toxic species in amyloid disorders: Oligomers or mature fibrils

    Directory of Open Access Journals (Sweden)

    Meenakshi Verma

    2015-01-01

    Full Text Available Protein aggregation is the hallmark of several neurodegenerative disorders. These protein aggregation (fibrillization disorders are also known as amyloid disorders. The mechanism of protein aggregation involves conformation switch of the native protein, oligomer formation leading to protofibrils and finally mature fibrils. Mature fibrils have long been considered as the cause of disease pathogenesis; however, recent evidences suggest oligomeric intermediates formed during fibrillization to be toxic. In this review, we have tried to address the ongoing debate for these toxic amyloid species. We did an extensive literature search and collated information from Pubmed (http://www.ncbi.nlm.nih.gov and Google search using various permutations and combinations of the following keywords: Neurodegeneration, amyloid disorders, protein aggregation, fibrils, oligomers, toxicity, Alzheimer′s Disease, Parkinson′s Disease. We describe different instances showing the toxicity of mature fibrils as well as oligomers in Alzheimer′s Disease and Parkinson′s Disease. Distinct structural framework and morphology of amyloid oligomers suggests difference in toxic effect between oligomers and fibrils. We highlight the difference in structure and proposed toxicity pathways for fibrils and oligomers. We also highlight the evidences indicating that intermediary oligomeric species can act as potential diagnostic biomarker. Since the formation of these toxic species follow a common structural switch among various amyloid disorders, the protein aggregation events can be targeted for developing broad-range therapeutics. The therapeutic trials based on the understanding of different protein conformers (monomers, oligomers, protofibrils and fibrils in amyloid cascade are also described.

  9. 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.

  10. Detection of amyloid fibrils in Parkinson's disease using plasmonic chirality.

    Science.gov (United States)

    Kumar, Jatish; Eraña, Hasier; López-Martínez, Elena; Claes, Nathalie; Martín, Víctor F; Solís, Diego M; Bals, Sara; Cortajarena, Aitziber L; Castilla, Joaquín; Liz-Marzán, Luis M

    2018-03-27

    Amyloid fibrils, which are closely associated with various neurodegenerative diseases, are the final products in many protein aggregation pathways. The identification of fibrils at low concentration is, therefore, pivotal in disease diagnosis and development of therapeutic strategies. We report a methodology for the specific identification of amyloid fibrils using chiroptical effects in plasmonic nanoparticles. The formation of amyloid fibrils based on α-synuclein was probed using gold nanorods, which showed no apparent interaction with monomeric proteins but effective adsorption onto fibril structures via noncovalent interactions. The amyloid structure drives a helical nanorod arrangement, resulting in intense optical activity at the surface plasmon resonance wavelengths. This sensing technique was successfully applied to human brain homogenates of patients affected by Parkinson's disease, wherein protein fibrils related to the disease were identified through chiral signals from Au nanorods in the visible and near IR, whereas healthy brain samples did not exhibit any meaningful optical activity. The technique was additionally extended to the specific detection of infectious amyloids formed by prion proteins, thereby confirming the wide potential of the technique. The intense chiral response driven by strong dipolar coupling in helical Au nanorod arrangements allowed us to detect amyloid fibrils down to nanomolar concentrations.

  11. 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.

  12. 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...

  13. 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.

  14. 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

  15. 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...... into practice. This lead to forced linguistic assimilation and the elimination of cultural and linguistic heritage. Now, in the present age of globalization, linguistic diversity at the national state level has been recognized and multilingual states have been developing where all types of languages can be used...... 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...

  16. INTEGRATION-INCLUSION

    OpenAIRE

    KERAMITCHIEVSKA-BILJANOVSKA Vesna; MITREVSKA Roberta; SABOLICH Nada

    2015-01-01

    By defining the terms, we would like to show that mentally disabled children cannot follow the regular educational process, in the same way children without learning disabilities can.The process of rehabilitation and education of disabled persons with different kind of disabilities, enables independent social integration and good quality of living in our country in the last 50 years; throw there is no need of changes in the inclusive education.

  17. BACTERIAL PLASMIDS

    Directory of Open Access Journals (Sweden)

    Marina Dinic

    2007-12-01

    Full Text Available Plasmids, extrachromosomal DNA, were identified in bacteria pertaining to family of Enterobacteriacae for the very first time. After that, they were discovered in almost every single observed strain. The structure of plasmids is made of circular double chain DNA molecules which are replicated autonomously in a host cell. Their length may vary from few up to several hundred kilobase (kb. Among the bacteria, plasmids are mostly transferred horizontally by conjugation process. Plasmid replication process can be divided into three stages: initiation, elongation, and termination. The process involves DNA helicase I, DNA gyrase, DNA polymerase III, endonuclease, and ligase.Plasmids contain genes essential for plasmid function and their preservation in a host cell (the beginning and the control of replication. Some of them possess genes whichcontrol plasmid stability. There is a common opinion that plasmids are unnecessary fora growth of bacterial population and their vital functions; thus, in many cases they can be taken up or kicked out with no lethal effects to a plasmid host cell. However,there are numerous biological functions of bacteria related to plasmids. Plasmids identification and classification are based upon their genetic features which are presented permanently in all of them, and these are: abilities to preserve themselves in a host cell and to control a replication process. In this way, plasmids classification among incompatibility groups is performed. The method of replicon typing, which is based on genotype and not on phenotype characteristics, has the same results as in compatibility grouping.

  18. 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…

  19. Inclusion-Body Myositis: Diagnosis

    Science.gov (United States)

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

  20. 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.

  1. 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

    Amyloid diseases are characterized by the misfolding and deposition of proteins in the body in the form of insoluble amyloid fibrils. Alzheimer’s disease and type 2 diabetes mellitus are two examples of amyloid diseases which are closely related both with respect to the atomic structures of the a...... binding modes for imaging agents is proposed to originate from subtle differences in amino acid composition of the surface grooves on an amyloid fibril, resulting in fine tuning of the binding affinities for a specific amyloid fibril....... 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...

  2. 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.

  3. 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.)

  4. Phenolsulfonphthalein, but not phenolphthalein, inhibits amyloid fibril formation: implications for the modulation of amyloid self-assembly.

    Science.gov (United States)

    Levy, Michal; Porat, Yair; Bacharach, Eran; Shalev, Deborah E; Gazit, Ehud

    2008-06-03

    The study of the mechanism of amyloid fibril formation and its inhibition is of key medical importance due to the lack of amyloid assembly inhibitors that are approved for clinical use. We have previously demonstrated the potent inhibitory potential of phenolsulfonphthalein, a nontoxic compound that was approved for diagnostic use in human subjects, on aggregation of islet amyloid polypeptide (IAPP) that is associated with type 2 diabetes. Here, we extend our studies on the mechanism of action of phenolsulfonphthalein by comparing its antiamyloidogenic effect to a very similar compound that is also approved for human use, phenolphthalein. While these compounds have very similar primary chemical structures, they significantly differ in their three-dimensional conformation. Our results clearly demonstrated that these two compounds had completely different inhibitory potencies: While phenolsulfonphthalein was a very potent inhibitor of amyloid fibril formation by IAPP, phenolphthalein did not show significant antiamyloidogenic activity. This behavior was observed with a short amyloid fragment of IAPP and also with the full-length polypeptide. The NMR spectrum of IAPP 20-29 in the presence of phenolsulfonphthalein showed chemical shift deviations that were different from the unbound or phenolphthalein-bound peptide. Differential activity was also observed in the inhibition of insulin amyloid formation by these two compounds, and density-gradient experiments clearly demonstrated the different inhibitory effect of the two compounds on the formation of prefibrillar assemblies. Taken together, our studies suggest that the three-dimensional arrangement of the polyphenol phenolsulfonphthalein has a central role in its amyloid formation inhibition activity.

  5. 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.)

  6. 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...

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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...

  12. Study of Meteoritic Inclusion

    DEFF Research Database (Denmark)

    Olsen, Mia Bjørg Stolberg

    . The manuscripts presented in this thesis have provided critical insights into the origin and distribution of short-lived radioisotopes as well as the formation and transport history of chondrules and, by extension, the precursor material to asteroidal and planetary bodies. The proposal of 26Al heterogeneity...... and the observation of a reduced initial abundance of 26Al in the accretion regions of chondrules and asteroidal bodies impacts our understanding of the accretion timescales of protoplanets in a significant way. Combining high-precision isotope measurements of multiple systems on individual meteoritic inclusions...

  13. 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).

  14. 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.

  15. Intracellular tracing of amyloid vaccines through direct fluorescent labelling.

    Science.gov (United States)

    Mold, Matthew; Kumar, Manpreet; Mirza, Ambreen; Shardlow, Emma; Exley, Christopher

    2018-02-05

    Alzheimer's disease is a debilitating neurodegenerative condition that progressively causes synaptic loss and major neuronal damage. Immunotherapy utilising Aβ as an active immunogen or via passive treatment utilising antibodies raised to amyloid have shown therapeutic promise. The migratory properties of peripheral blood-borne monocytes and their ability to enter the central nervous system, suggests a beneficial role in mediating tissue damage and neuroinflammation. However, the intrinsic phagocytic properties of such cells have pre-disposed them to internalise misfolded amyloidogenic peptides that could act as seeds capable of nucleating amyloid formation in the brain. Mechanisms governing the cellular fate of amyloid therefore, may prove to be key in the development of future vaccination regimes. Herein, we have developed unequivocal and direct conformation-sensitive fluorescent molecular probes that reveal the intracytoplasmic and intranuclear persistence of amyloid in a monocytic T helper 1 (THP-1) cell line. Use of the pathogenic Aβ 42 species as a model antigen in simulated vaccine formulations suggested differing mechanisms of cellular internalisation, in which fibrillar amyloid evaded lysosomal capture, even when co-deposited on particulate adjuvant materials. Taken collectively, direct fluorescent labelling of antigen-adjuvant complexes may serve as critical tools in understanding subsequent immunopotentiation in vaccines directed against amyloidosis and wider dementia.

  16. Amylin under examination. Fibrillogenic polypeptide of pancreatic amyloid

    Directory of Open Access Journals (Sweden)

    Małgorzata Marszałek

    2015-06-01

    Full Text Available In patients or animals affected by 2 type diabetes mellitus (diabetes mellitus type 2, DM2, non-insulin-dependent diabetes mellitus, NIDDM or pancreatic tumor disease e.g., insulinoma, some pathological deposits, called amyloid, are observed among cells of islets of Langerhans. Among other constituents, pancreatic deposits consist of an insoluble, fibrillar form of peptide neurohormone termed amylin, produced by pancreatic beta cells. It is thought that formation of fibrillar deposits of misfolded and aggregated peptide is highly toxic to beta cells and leads to cell dysfunction, cell loss, pancreas destruction and progress of the disease. This relatively small, 37-amino acid peptide constitutes a serious scientific, research and to some extent a medical problem. This article presents amylin as a fibrillating molecule which participates in formation of amyloid deposits in human and animal pancreas, Langerhans islets as a microenvironment of pancreatic amyloid formation, occurrence of amylin and amyloid in animals and humans, and physico-chemical requirements to meet to name amylin deposit as amyloid.

  17. 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.

  18. The effect of tachykinin neuropeptides on amyloid {beta} aggregation

    Energy Technology Data Exchange (ETDEWEB)

    Flashner, Efrat [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel); Raviv, Uri, E-mail: raviv@chem.ch.huji.ac.il [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel); Friedler, Assaf, E-mail: assaf@chem.ch.huji.ac.il [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel)

    2011-04-01

    Research highlights: {yields} Mechanistic explanation of how tachykinin neuropeptides reduce A{beta}-induced neurotoxicity. {yields} Biophysical studies suggest that tachykinins do not modulate the distribution of A{beta} oligomeric states, but rather may incorporate into the fibrils. {yields} A possible strategy to inhibit toxicity of amyloid fibrils. -- Abstract: A hallmark of Alzheimer's disease is production of amyloid {beta} peptides resulting from aberrant cleavage of the amyloid precursor protein. Amyloid {beta} assembles into fibrils under physiological conditions, through formation of neurotoxic intermediate oligomers. Tachykinin peptides are known to affect amyloid {beta} neurotoxicity in cells. To understand the mechanism of this effect, we studied how tachykinins affect A{beta}(1-40) aggregation in vitro. Fibrils grown in the presence of tachykinins exhibited reduced thioflavin T (ThT) fluorescence, while their morphology, observed in transmission electron microscopy (TEM), did not alter. Cross linking studies revealed that the distribution of low molecular weight species was not affected by tachykinins. Our results suggest that there may be a specific interaction between tachykinins and A{beta}(1-40) that allows them to co-assemble. This effect may explain the reduction of A{beta}(1-40) neurotoxicity in cells treated with tachykinins.

  19. 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

  20. 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…

  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. 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.

  3. 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...

  4. Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis

    Directory of Open Access Journals (Sweden)

    Yasmin M. Ramdzan

    2017-05-01

    Full Text Available Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1 inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis.

  5. 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.

  6. 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.

  7. 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.

  8. Destroying activity of magnetoferritin on lysozyme amyloid fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Kopcansky, Peter; Siposova, Katarina [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Melnikova, Lucia, E-mail: melnikova@saske.sk [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Bednarikova, Zuzana [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Institute of Chemical Sciences, Faculty of Sciences, Safarik University, Kosice (Slovakia); Timko, Milan; Mitroova, Zuzana; Antosova, Andrea [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Garamus, Vasil M. [Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal Research, Max-Planck-Street 1, 21502 Geesthacht (Germany); Petrenko, Viktor I. [Joint Institute for Nuclear Research, Joliot-Curie 6, Dubna, 141980 Moscow Region (Russian Federation); Kyiv Taras Shevchenko National University, Volodymyrska Street 64, Kyiv 01033 (Ukraine); Avdeev, Mikhail V. [Joint Institute for Nuclear Research, Joliot-Curie 6, Dubna, 141980 Moscow Region (Russian Federation); Gazova, Zuzana [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Department of Medical and Clinical Biochemistry and LABMED, Tr. SNP 1, 040 11 Kosice (Slovakia)

    2015-03-01

    Presence of protein amyloid aggregates (oligomers, protofilaments, fibrils) is associated with many diseases as diabetes mellitus or Alzheimer's disease. The interaction between lysozyme amyloid fibrils and magnetoferritin loaded with different amount of iron atoms (168 or 532 atoms) has been investigated by small-angle X-rays scattering and thioflavin T fluorescence measurements. Results suggest that magnetoferritin caused an iron atom-concentration dependent reduction of lysozyme fibril size. - Highlights: • The interaction between lysozyme amyloid fibrils and magnetoferritin loaded with different amount of iron atoms (168 or 532 atoms) has been investigated by small-angle X-rays scattering and thioflavin T fluorescence measurements. • Results suggest that magnetoferritin caused an iron atom-concentration dependent reduction of lysozyme fibril size.

  9. 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.

  10. Radiological findings of amyloid arthropathy in long-term haemodialysis

    Energy Technology Data Exchange (ETDEWEB)

    Rios Camacho, C. [Dept. of Nephrology, Hospital Universitario ``Virgen del Rocio``, Sevilla (Spain); Talegon Melendez, A. [Dept. of Radiology, Hospital Universitario ``Virgen del Rocio``, Sevilla (Spain); Valenzuela, A. [Dept. of Rheumatology, Hospital Universitario ``Virgen del Rocio``, Sevilla (Spain); Gonzalez Guirao, M. [Dept. of Radiology, Hospital Universitario ``Virgen del Rocio``, Sevilla (Spain); Gomez Benitez, S. [Dept. of Radiology, Hospital Universitario ``Virgen del Rocio``, Sevilla (Spain); Gil, L. [Dept. of Nephrology, Hospital Universitario ``Virgen del Rocio``, Sevilla (Spain); Palma Alvarez, A. [Dept. of Nephrology, Hospital Universitario ``Virgen Macarena``, Sevilla (Spain); Mateos Aguilar, J. [Dept. of Nephrology, Hospital Universitario ``Virgen del Rocio``, Sevilla (Spain)

    1992-08-01

    Radiological features of cystic lesions due to beta-2-microglobulin-related amyloidosis have been studied in 88 patients receiving haemodialysis for more than 4 years. Amyloid arthropathy was confirmed by demonstration of amyloid-beta-2-microglobulin deposition on different substrates. Plain radiographs of shoulder, spine, pelvis, hands and knees revealed cystic lesions in 31 patients (35.2%), the distribution being: 71% shoulder, 56.7% carpal bones, 25.8% pelvis, 16.5% femur and 13.3% knees. Discitis was found in 34 patients (38.6%). The ocurrence of geodes was frequent in patients suffering from amyloid arthropathy (63% vs. 23%, P = 0.0001). No significant differences were found in the frequency of discitis or erosive arthropathy in the hands of both groups. The former was related to age and the latter to secondary hyperparathyroidism. We stress the radiographic appearance and the high incidence of these lesions in patients on long-term haemodialysis. (orig.)

  11. 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.

  12. Structural origin of polymorphism of Alzheimer's amyloid β-fibrils.

    Science.gov (United States)

    Agopian, Audrey; Guo, Zhefeng

    2012-10-01

    Formation of senile plaques containing amyloid fibrils of Aβ (amyloid β-peptide) is a pathological hallmark of Alzheimer's disease. Unlike globular proteins, which fold into unique structures, the fibrils of Aβ and other amyloid proteins often contain multiple polymorphs. Polymorphism of amyloid fibrils leads to different toxicity in amyloid diseases and may be the basis for prion strains, but the structural origin for fibril polymorphism is still elusive. In the present study we investigate the structural origin of two major fibril polymorphs of Aβ40: an untwisted polymorph formed under agitated conditions and a twisted polymorph formed under quiescent conditions. Using electron paramagnetic resonance spectroscopy, we studied the inter-strand side-chain interactions at 14 spin-labelled positions in the Aβ40 sequence. The results of the present study show that the agitated fibrils have stronger inter-strand spin-spin interactions at most of the residue positions investigated. The two hydrophobic regions at residues 17-20 and 31-36 have the strongest interactions in agitated fibrils. Distance estimates on the basis of the spin exchange frequencies suggest that inter-strand distances at residues 17, 20, 32, 34 and 36 in agitated fibrils are approximately 0.2 Å (1 Å=0.1 nm) closer than in quiescent fibrils. We propose that the strength of inter-strand side-chain interactions determines the degree of β-sheet twist, which then leads to the different association patterns between different cross β-units and thus distinct fibril morphologies. Therefore the inter-strand side-chain interaction may be a structural origin for fibril polymorphism in Aβ and other amyloid proteins.

  13. Cognitive reserve and β-amyloid pathology in Parkinson disease.

    Science.gov (United States)

    Lucero, Carolyn; Campbell, Meghan C; Flores, Hubert; Maiti, Baijayanta; Perlmutter, Joel S; Foster, Erin R

    2015-08-01

    Dementia in Parkinson disease (PD) is associated with abnormal accumulation of proteins, including β-amyloid, in cortical regions. High cognitive reserve capacity may protect cognition from β-amyloid and delay the onset of dementia. We tested the cognitive reserve theory in PD by determining whether educational attainment, a proxy for cognitive reserve, modifies the correlation between cortical β-amyloid accumulation and cognitive impairment. PD participants (N = 155) underwent MRI to quantify brain volume and [(11)C] PiB PET imaging to quantify fibrillar β-amyloid deposition. Mean cortical binding potentials (MCBP) were calculated for each participant, with higher scores indicating more fibrillar β-amyloid. Global cognitive function was assessed using the Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE). Multiple linear regression analysis was used to determine whether education modified the relationship between MCBP and cognitive function after controlling for brain volume. MCBP interacted with educational attainment to predict scores on each of the cognitive outcome measures (ps ≤ 0.02). Post-hoc analysis revealed that the effect of MCBP on cognitive function changed once the level of education reached 16 years. For participants with less than 16 years of education (n = 68), higher MCBP correlated with worse cognitive function, with MCBP accounting for 8-30% of the variance in MMSE and CDR scores (ps ≤ 0.02). For participants with at least 16 years of education (n = 87), MCBP did not correlate with MMSE or CDR scores (R(2)s cognitive reserve theory in PD and suggest that education may protect PD patients' cognition against cortical β-amyloid pathology. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. 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

  15. 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....

  16. 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 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...... - Iranian Female Adolescent Immigrants’ Experiences of the Canadian Physical Education System Bahar Tajrobehkar, University of Toronto (CA) btajro@gmail.co...

  17. 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......, 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...... 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 one specific group are also beneficial for all children...

  18. Between psychopathology and inclusion

    DEFF Research Database (Denmark)

    Hamre, Bjørn Frithiof; Hedegaard-Sørensen, Lotte; Langager, Søren

    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...

  19. 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....

  20. 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...... and practical orientated framework for innovation in education. The paper documents a process where participants situated around the globe worked in collaboration with a group of participants gathered at a workshop on the concept of hybridity in education and on identifying and describing educational patterns...

  1. 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.

  2. Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition.

    Directory of Open Access Journals (Sweden)

    Sandra Arvidsson

    Full Text Available Transthyretin V30M (ATTR V30M amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex.Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness.There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007 and posterior wall thicknesses (p = 0.010, lower median LV mass indexed to height (p = 0.008, and higher septal strain (p = 0.037, as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness.This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

  3. Intratubular amyloid in light chain cast nephropathy is a risk factor for systemic light chain amyloidosis.

    Science.gov (United States)

    Gibier, Jean-Baptiste; Gnemmi, Viviane; Glowacki, François; Boyle, Eileen M; Lopez, Benjamin; MacNamara, Evelyne; Hoffmann, Maxime; Azar, Raymond; Guincestre, Thomas; Bourdon, Franck; Copin, Marie-Christine; Buob, David

    2017-10-20

    Light chain cast nephropathy is the most common form of kidney disease in patients with multiple myeloma. Light chain casts may occasionally show amyloid staining properties, that is, green birefringence after Congo red staining. The frequency and clinical significance of this intratubular amyloid are poorly understood. Here, we retrospectively assessed the clinicopathological features of 60 patients with histologically proven light chain cast nephropathy with a specific emphasis on intratubular amyloid, especially, its association with extrarenal systemic light chain amyloidosis. We found intratubular amyloid in 17 cases (17/60, 28%) and it was more frequent in patients with λ light chain gammopathy (13/17 in the 'intratubular amyloid' group vs 19/43 in the 'no intratubular amyloid' group, P=0.02). Pathological examination of extrarenal specimens showed that intratubular amyloid was significantly associated with the occurrence of systemic light chain amyloidosis (5/13 in the 'intratubular amyloid' group vs 0/30 in the 'no intratubular amyloid' group, P=0.001). Our results indicate that first, intratubular amyloid is not a rare finding in kidney biopsies of patients with light chain cast nephropathy, and, second, it reflects an amyloidogenic capacity of light chains that can manifest as systemic light chain amyloidosis. Thus, intratubular amyloid should be systematically screened for in kidney biopsies from patients with light chain cast nephropathy and, if detected, should prompt a work-up for associated systemic light chain amyloidosis.Modern Pathology advance online publication, 20 October 2017; doi:10.1038/modpathol.2017.124.

  4. 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.

  5. Difference in aggregation between functional and toxic amyloids studied by atomistic simulations

    Science.gov (United States)

    Carballo Pacheco, Martin; Ismail, Ahmed E.; Strodel, Birgit

    Amyloids are highly structured protein aggregates, normally associated with neurodegenerative diseases such as Alzheimer's disease. In recent years, a number of nontoxic amyloids with physiologically normal functions, called functional amyloids, have been found. It is known that soluble small oligomers are more toxic than large fibrils. Thus, we study with atomistic explicit-solvent molecular dynamics simulations the oligomer formation of the amyloid- β peptide Aβ25 - 35, associated with Alzheimer's disease, and two functional amyloid-forming tachykinin peptides: kassinin and neuromedin K. Our simulations show that monomeric peptides in extended conformations aggregate faster than those in collapsed hairpin-like conformations. In addition, we observe faster aggregation by functional amyloids than toxic amyloids, which could explain their lack of toxicity.

  6. Tafamidis for transthyretin familial amyloid polyneuropathy

    Science.gov (United States)

    Maia, Luis F.; Martins da Silva, Ana; Waddington Cruz, Marcia; Planté-Bordeneuve, Violaine; Lozeron, Pierre; Suhr, Ole B.; Campistol, Josep M.; Conceição, Isabel Maria; Schmidt, Hartmut H.-J.; Trigo, Pedro; Kelly, Jeffery W.; Labaudinière, Richard; Chan, Jason; Packman, Jeff; Wilson, Amy; Grogan, Donna R.

    2012-01-01

    Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score–Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life–Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. Conclusions: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. Classification of evidence: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in

  7. Inclusive spectra in hard processes

    International Nuclear Information System (INIS)

    Kiselev, A.V.; Petrov, V.A.

    1985-01-01

    It is shown that the unified mechanism of hadronization in hard processes results in universality of inclusive spectra of soft hadrons. Inclusive spectrum of hadrons in energy share in deep-inelastic lepton-hadron scattering is calculated. The spectrum obtained is calculated with analogous distribution in e + e - annihilation. It is noted that inclusive spectrum of soft hadrons in hard processes is described by a universal function

  8. Financial Stability and Financial Inclusion

    OpenAIRE

    Peter J. Morgan; Victor Pontines

    2014-01-01

    Developing economies are seeking to promote financial inclusion, i.e., greater access to financial services for low-income households and firms, as part of their overall strategies for economic and financial development. This raises the question of whether financial stability and financial inclusion are, broadly speaking, substitutes or complements. In other words, does the move toward greater financial inclusion tend to increase or decrease financial stability? A number of studies have sugge...

  9. 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...

  10. Permanent dysphagia in familial amyloid polyneuropathy (ATTRVal30Met).

    Science.gov (United States)

    Monteiro, Cecília; Magalhães, Marina; Correia, Carlos; Taipa, Ricardo

    2012-06-01

    Gastrointestinal symptoms are frequent in familial amyloid polyneuropathy, mainly resulting from autonomic nervous system involvement. Dysphagia is one of the possible symptoms, although rarely severe or sudden. We describe a case of a sudden onset and severe dysphagia, a rare form of presentation, in a patient whose polyneuropathy was still beeing investigated and turned out to be ATTRVal30Met-polyneuropathy.

  11. 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...

  12. 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 hexapeptide stretch 21DIDLHL26 has been shown to be important in the self-assembly of the Src homology 3 (SH3) domain of p85 subunit of bovine phosphatidylinositol-3-kinase (PI3-SH3). The SH3 domain of ...

  13. Cold denaturation of α-synuclein amyloid fibrils.

    Science.gov (United States)

    Ikenoue, Tatsuya; Lee, Young-Ho; Kardos, József; Saiki, Miyu; Yagi, Hisashi; Kawata, Yasushi; Goto, Yuji

    2014-07-21

    Although amyloid fibrils are associated with numerous pathologies, their conformational stability remains largely unclear. Herein, we probe the thermal stability of various amyloid fibrils. α-Synuclein fibrils cold-denatured to monomers at 0-20 °C and heat-denatured at 60-110 °C. Meanwhile, the fibrils of β2-microglobulin, Alzheimer's Aβ1-40/Aβ1-42 peptides, and insulin exhibited only heat denaturation, although they showed a decrease in stability at low temperature. A comparison of structural parameters with positive enthalpy and heat capacity changes which showed opposite signs to protein folding suggested that the burial of charged residues in fibril cores contributed to the cold denaturation of α-synuclein fibrils. We propose that although cold-denaturation is common to both native proteins and misfolded fibrillar states, the main-chain dominated amyloid structures may explain amyloid-specific cold denaturation arising from the unfavorable burial of charged side-chains in fibril cores. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Outcome markers for clinical trials in cerebral amyloid angiopathy

    NARCIS (Netherlands)

    S.M. Greenberg (Steven); R.A.S. Salman (Rustam Al-Shahi); G.J. Biessels (Geert Jan); M.A. van Buchem (Mark); C. Cordonnier (Charlotte); J.-M. Lee (Jin-Moo); J. Montaner (Joan); J.A. Schneider (Julie); E.E. Smith (Eric); M.W. Vernooij (Meike); D.J. Werring (David)

    2014-01-01

    textabstractEfforts are underway for early-phase trials of candidate treatments for cerebral amyloid angiopathy, an untreatable cause of haemorrhagic stroke and vascular cognitive impairment. A major barrier to these trials is the absence of consensus on measurement of treatment effectiveness. A

  15. 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 chroni...... HS leading to biopsy-verified severe renal AA amyloidosis and dialysis dependency....

  16. Neuronal activity and amyloid plaque pathology: an update.

    Science.gov (United States)

    Ovsepian, Saak V; O'Leary, Valerie B

    2016-01-01

    A breakthrough in Alzheimer's disease (AD) research came with the discovery of the link between activity-dependent release of amyloid-β (Aβ) from neurons and formation of amyloid plaques. Along with elucidating the cellular basis of behavioral-dependent fluctuations in Aβ levels in the brain, insights have been gained toward understanding the mechanisms that warrant selective vulnerability of various forebrain circuits to amyloid pathology. The notion of elevated activity as a source of excessive Aβ production and plaque formation is, however, in conflict with ample electrophysiological data, which demonstrate exceedingly intense activity (both intrinsic and synaptic) of neurons in several brain regions that are spared or marginally affected by amyloid plaques of AD. Thus, the link between the functional load of brain circuits and their vulnerability to amyloidosis, while evident, is also complex and remains poorly understood. Here, we discuss emerging data suggestive of a major role for super-intense synchronous activity of cortical and limbic networks in excessive Aβ production and plaque formation. It is proposed that dense recurrent wiring of associative areas prone to epileptic seizures might be of critical relevance to their higher susceptibility to plaque pathology and related functional impairments.

  17. 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 peptide (Aβ). Recent epidemiological studies suggest that patients with elevated cholesterol and decreased estrogen levels are more susceptible to AD through Aβ accumulation. To test the ...

  18. Cooperativity among short amyloid stretches in long amyloidogenic sequences.

    Directory of Open Access Journals (Sweden)

    Lele Hu

    Full Text Available Amyloid fibrillar aggregates of polypeptides are associated with many neurodegenerative diseases. Short peptide segments in protein sequences may trigger aggregation. Identifying these stretches and examining their behavior in longer protein segments is critical for understanding these diseases and obtaining potential therapies. In this study, we combined machine learning and structure-based energy evaluation to examine and predict amyloidogenic segments. Our feature selection method discovered that windows consisting of long amino acid segments of ~30 residues, instead of the commonly used short hexapeptides, provided the highest accuracy. Weighted contributions of an amino acid at each position in a 27 residue window revealed three cooperative regions of short stretch, resemble the β-strand-turn-β-strand motif in A-βpeptide amyloid and β-solenoid structure of HET-s(218-289 prion (C. Using an in-house energy evaluation algorithm, the interaction energy between two short stretches in long segment is computed and incorporated as an additional feature. The algorithm successfully predicted and classified amyloid segments with an overall accuracy of 75%. Our study revealed that genome-wide amyloid segments are not only dependent on short high propensity stretches, but also on nearby residues.

  19. Infectious particles, stress, and induced prion amyloids: a unifying perspective.

    Science.gov (United States)

    Manuelidis, Laura

    2013-07-01

    Transmissible encephalopathies (TSEs) are believed by many to arise by spontaneous conversion of host prion protein (PrP) into an infectious amyloid (PrP-res, PrP (Sc) ) without nucleic acid. Many TSE agents reside in the environment, with infection controlled by public health measures. These include the disappearance of kuru with the cessation of ritual cannibalism, the dramatic reduction of epidemic bovine encephalopathy (BSE) by removal of contaminated feed, and the lack of endemic scrapie in geographically isolated Australian sheep with susceptible PrP genotypes. While prion protein modeling has engendered an intense focus on common types of protein misfolding and amyloid formation in diverse organisms and diseases, the biological characteristics of infectious TSE agents, and their recognition by the host as foreign entities, raises several fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environmental metagenome that may cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non-infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging.

  20. 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

  1. 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

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

    Indian Academy of Sciences (India)

    A central hypothesis in the study of Alzheimer's disease (AD) is the accumulation and aggregation of -amyloid peptide (A). Recent epidemiological studies suggest that patients with elevated cholesterol and decreased estrogen levels are more susceptible to AD through A accumulation. To test the above hypothesis, we ...

  3. 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...... the number of bands in IEF to two indicating the existence of two types of polypeptide chains....

  4. 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.

  5. Polymorphic structures of Alzheimer's β-amyloid globulomers.

    Directory of Open Access Journals (Sweden)

    Xiang Yu

    Full Text Available BACKGROUND: Misfolding and self-assembly of Amyloid-β (Aβ peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Aβ structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Aβ species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation. METHODS AND FINDINGS: Here, we model a series of molecular structures of Aβ globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD simulations. Structural and energetic analysis shows that although Aβ globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated β-structure in Aβ globulomers make them difficult to convert into other high-order Aβ aggregates and fibrils with dominant β-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Aβ globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR. CONCLUSIONS: Our computationally modeled Aβ globulomers provide useful

  6. Inclusion by Design: Engineering Inclusive Practices in Secondary Schools

    Science.gov (United States)

    Dukes, Charles; Lamar-Dukes, Pamela

    2009-01-01

    In order to help teachers understand the importance of intentional design for inclusive education, this article describes the design process an engineer might use when designing a new project. If teachers learn to think like engineers, it is possible for them to design inclusive education. This conceptual design can then be combined with…

  7. 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. ...

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. Endocytosed 2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils.

    Directory of Open Access Journals (Sweden)

    Tadakazu Okoshi

    Full Text Available Dialysis-related amyloidosis is a major complication in long-term hemodialysis patients. In dialysis-related amyloidosis, β2-microglobulin (β2-m amyloid fibrils deposit in the osteoarticular tissue, leading to carpal tunnel syndrome and destructive arthropathy with cystic bone lesions, but the mechanism by which these amyloid fibrils destruct bone and joint tissue is not fully understood. In this study, we assessed the cytotoxic effect of β2-m amyloid fibrils on the cultured rabbit synovial fibroblasts. Under light microscopy, the cells treated with amyloid fibrils exhibited both necrotic and apoptotic changes, while the cells treated with β2-m monomers and vehicle buffer exhibited no morphological changes. As compared to β2-m monomers and vehicle buffer, β2-m amyloid fibrils significantly reduced cellular viability as measured by the lactate dehydrogenase release assay and the 3-(4,5-di-methylthiazol-2-yl-2,5-diphenyltetrazolium bromide reduction assay and significantly increased the percentage of apoptotic cells as measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. β2-m amyloid fibrils added to the medium adhered to cell surfaces, but did not disrupt artificial plasma membranes as measured by the liposome dye release assay. Interestingly, when the cells were incubated with amyloid fibrils for several hours, many endosomes/lysosomes filled with amyloid fibrils were observed under confocal laser microscopy and electron microscopy, Moreover, some endosomal/lysosomal membranes were disrupted by intravesicular fibrils, leading to the leakage of the fibrils into the cytosol and adjacent to mitochondria. Inhibition of actin-dependent endocytosis by cytochalasin D attenuated the toxicity of amyloid fibrils. These results suggest that endocytosed β2-m amyloid fibrils induce necrosis and apoptosis by disrupting endosomal/lysosomal membranes, and this novel mechanism on the cytotoxicity of amyloid

  13. Bacterial Cholangitis, Cholecystitis, or both in Dogs.

    Science.gov (United States)

    Tamborini, A; Jahns, H; McAllister, H; Kent, A; Harris, B; Procoli, F; Allenspach, K; Hall, E J; Day, M J; Watson, P J; O'Neill, E J

    2016-07-01

    Bacterial cholangitis and cholecystitis are rarely reported, poorly characterized diseases in the dog. To characterize the clinical features of these conditions. Twenty-seven client-owned dogs with bacterial cholangitis, cholecystitis, or both. Multicenter, retrospective cases series of dogs with bacterial cholangitis, cholecystitis, or both, presenting January 2000 to June 2011 to 4 Veterinary Schools in Ireland/United Kingdom. Interrogation of hospital databases identified all cases with the inclusion criteria; histopathologically confirmed cholangitis or cholecystitis and bile culture/cytology results supporting a bacterial etiology. Twenty-seven dogs met the inclusion criteria with approximately 460 hepatitis cases documented over the same study period. Typical clinical pathology findings were increases in liver enzyme activities (25/26), hyperbilirubinemia (20/26), and an inflammatory leukogram (21/24). Ultrasound findings, although nonspecific, aided decision-making in 25/26 cases. The most frequent hepatobiliary bacterial isolates were Escherichia coli (n = 17; 16 cases), Enterococcus spp. (n = 8; 6 cases), and Clostridium spp. (n = 5; 5 cases). Antimicrobial resistance was an important feature of aerobic isolates; 10/16 E. coli isolates resistant to 3 or more antimicrobial classes. Biliary tract rupture complicated nearly one third of cases, associated with significant mortality (4/8). Discharged dogs had a guarded to fair prognosis; 17/18 alive at 2 months, although 5/10 re-evaluated had persistent liver enzyme elevation 2-12 months later. Bacterial cholangitis and cholecystitis occur more frequently than suggested by current literature and should be considered in dogs presenting with jaundice and fever, abdominal pain, or an inflammatory leukogram or with ultrasonographic evidence of gallbladder abnormalities. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of

  14. Creative Educational Practices for Inclusion

    Science.gov (United States)

    Piske, Fernanda Hellen Ribeiro; Stoltz, Tania; Machado, Jarci

    2014-01-01

    Inclusion of gifted students depends on several aspects to happen in the school context, and one of the most important aspects to include these children at school is creative educational practices. Teaching with art is a good possibility to make children feel motivated to attend school. In the school context, the inclusion of these children could…

  15. 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…

  16. 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…

  17. 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.

  18. 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…

  19. 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…

  20. Secreted amyloid precursor protein β and secreted amyloid precursor protein α induce axon outgrowth in vitro through Egr1 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Stéphanie Chasseigneaux

    Full Text Available BACKGROUND: sAPPα released after α secretase cleavage of Amyloid Precursor Protein (APP has several functions including the stimulation of neurite outgrowth although detailed morphometric analysis has not been done. Two domains involved in this function have been described and are present in sAPPβ released at the first step of amyloid peptide cleavage, raising the possibility that sAPPβ could also stimulate neurite outgrowth. We investigated the morphological effects of sAPPα and sAPPβ on primary neurons and identified a key signaling event required for the changes observed. METHODOLOGY/PRINCIPAL FINDINGS: Final concentrations of 50 to 150 nM bacterial recombinant sAPPα or sAPPβ added to primary neuronal cultures after 1 day in vitro decreased cell adhesion 24 hours later and primary dendrite length 96 hours later. 150 nM sAPPα and sAPPβ induced a similar increase of axon outgrowth, although this increase was already significant at 100 nM sAPPα. These morphological changes induced by sAPPs were also observed when added to differentiated neurons at 5 days in vitro. Real time PCR and immunocytochemistry showed that sAPPα and sAPPβ stimulated Egr1 expression downstream of MAPK/ERK activation. Furthermore, in primary neurons from Egr1 -/- mice, sAPPs affected dendritic length but did not induce any increase of axon length. CONCLUSION/SIGNIFICANCE: sAPPα and sAPPβ decrease cell adhesion and increase axon elongation. These morphological changes are similar to what has been observed in response to heparan sulfate. The sAPPα/sAPPβ stimulated increase in axon growth requires Egr1 signaling. These data suggest that sAPPβ is not deleterious per se. Since sAPPβ and sAPPα are present in the embryonic brain, these two APP metabolites might play a role in axon outgrowth during development and in response to brain damage.

  1. 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.

  2. Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease.

    Science.gov (United States)

    Helmfors, Linda; Boman, Andrea; Civitelli, Livia; Nath, Sangeeta; Sandin, Linnea; Janefjord, Camilla; McCann, Heather; Zetterberg, Henrik; Blennow, Kaj; Halliday, Glenda; Brorsson, Ann-Christin; Kågedal, Katarina

    2015-11-01

    The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease. Copyright © 2015. Published by Elsevier Inc.

  3. 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...

  4. 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

  5. Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation

    NARCIS (Netherlands)

    Månsson, Cecilia; Arosio, Paolo; Hussein, Rasha; Kampinga, Harm H; Hashem, Reem M; Boelens, Wilbert C; Dobson, Christopher M; Knowles, Tuomas P J; Linse, Sara; Emanuelsson, Cecilia

    2014-01-01

    The human molecular chaperone protein DNAJB6 was recently found to inhibit the formation of amyloid fibrils from polyglutamine peptides associated with neurodegenerative disorders such as Huntington's disease. We show in the present study that DNAJB6 also inhibits amyloid formation by an even more

  6. The infidelity of melt inclusions?

    Science.gov (United States)

    Kent, A. J.

    2008-12-01

    Melt inclusions provide important information about magmatic systems and represent unique records of magma composition and evolution. However, it is also clear that melt inclusions do not necessarily constitute a petrological 'magic bullet', and potential exists for trapped melt compositions to be modified by a range of inclusion-specific processes. These include trapping of diffusional boundary layers, crystallization of the host mineral after trapping and dissolution of co-trapped minerals during homogenization, diffusional exchange between trapped liquid and the host mineral and external melt, and cryptic alteration of trapped material during weathering or hydrothermal alteration. It clearly important to identify when melt inclusions are unmodified, and which compositional indices represent the most robust sources of petrogenetic information. In this presentation I review and discuss various approaches for evaluating compositions and compositional variations in inclusion suites. An overriding principle is that the variations evident in melt inclusions should be able to be understood in terms of petrological processes that are known, or can be reasonably inferred to also effect bulk magma compositions. One common approach is to base petrological conclusions on species that should be more robust, and many workers use variations in incompatible trace elements for this purpose. However important information may also be obtained from a comparison of variations in melt inclusions and the lavas that host them, and in most cases this comparison is the key to identifying inclusions and suites that are potentially suspect. Comparisons can be made between individual inclusions and lavas, although comparison of average inclusion composition and the host lava, after correction for differences in crystal fractionation, may also be valuable. An important extension of this is the comparison of the variability of different species in inclusions and host lavas. This also provides

  7. Prevention of bacterial adhesion

    DEFF Research Database (Denmark)

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

    2010-01-01

    Management of bacterial infections is becoming increasingly difficult due to the emergence and increasing prevalence of bacterial pathogens that are resistant to available antibiotics. Conventional antibiotics generally kill bacteria by interfering with vital cellular functions, an approach...... that imposes selection pressure for resistant bacteria. New approaches are urgently needed. Targeting bacterial virulence functions directly is an attractive alternative. An obvious target is bacterial adhesion. Bacterial adhesion to surfaces is the first step in colonization, invasion, and biofilm formation....... 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...

  8. 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

  9. Feasibility and acceptance of simultaneous amyloid PET/MRI.

    Science.gov (United States)

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

    2016-11-01

    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 diagnostic and progression biomarkers. The patient/caregiver survey revealed a gain of convenience in

  10. 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)

  11. 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.

  12. Politics of Inclusion and Empowerment

    DEFF Research Database (Denmark)

    Andersen, John; Siim, Birte

    2004-01-01

    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...

  13. Neurotrophic and Neurotoxic Effects of Amyloid |beta Protein: Reversal by Tachykinin Neuropeptides

    Science.gov (United States)

    Yankner, Bruce A.; Duffy, Lawrence K.; Kirschner, Daniel A.

    1990-10-01

    The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid β protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid β protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid β protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid β protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.

  14. 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)

  15. 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

  16. 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.

  17. 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.

  18. Cerebral Amyloid Angiopathy: A Case Report and Literature ...

    Directory of Open Access Journals (Sweden)

    Orkide Kutlu

    2015-03-01

    Full Text Available Cerebral amyloid angiopathy (CAA is a condition characterized by accumulation of amyloid-beta peptide in the walls of the small and medium-sized arteries of the brain and leptomeninges. This condition disrupts the structure of the vessel wall and makes it prone to bleeding. This is an important cause of intracerebral hemorrhage in elderly accompanying to Alzheimer’s disease or to a familial syndrome. Clinically, it usually presents with spontaneous lobar hemorrhage, as well as transient neurological signs, seizures, cognitive disorders, headache, incidental findings like microhaemorrhages and hemosiderosis observed on magnetic resonance (MR imaging. Herein, we report a hypertensive patient diagnosed with CAA who presented with the complaints of balance disorder while walking. CAA should be suspected in patients with lobar hemorrhage aged 65 years and over. Surgical treatment should not be performed because it could worsen the condition. Clinical improvement can be expected from supportive management, monitoring hypertension, and steroid - immunosuppressive therapies.

  19. Evolutionary perspectives on amyloid and inflammatory features of Alzheimer disease.

    Science.gov (United States)

    Finch, C E; Marchalonis, J J

    1996-01-01

    We propose that the amyloid deposits in senile plaques of Alzheimer's Disease (AD) result from ancient mechanisms in wound-healing and inflammatory processes that preceded the evolution of the inducible combinatorial immune responses characteristic of jawed vertebrates. AD plaques are unlike active plaques in MS, because antibodies, T-cells and, B cells are not conspicuous components of senile plaques or other loci of degeneration. However, senile plaques contain amyloids and other inflammatory proteins of ancient origin that appear to be made by local brain cells, including neurons, astrocytes, and microglia. We describe a highly conserved 16-mer found in pentrakins from mammals and from the horseshoe crab. The senile plaque thus provides a novel opportunity to study primitive features of complement-mediated inflammatory responses in the absence of immunoglobulins.

  20. Inclusão e governamentalidade Inclusion and governmentality

    Directory of Open Access Journals (Sweden)

    Alfredo Veiga-Neto

    2007-10-01

    Full Text Available O artigo parte dos conceitos de governamento, biopoder, norma e governamentalidade para argumentar no sentido de que as políticas de inclusão - especialmente as políticas de inclusão escolar - são dispositivos biopolíticos para o governamento e o controle das populações. Tomam-se esses e outros conceitos foucaultianos como ferramentas analíticas para argumentar que é preciso examinar as políticas e práticas inclusivas sem assumir antecipadamente qualquer juízo de valor sobre elas. Entendendo a diferença como manifestação da diversidade, e o diferente como um exótico, um portador de algo que os outros não possuem, as políticas de inclusão - nos modos como vêm sendo formuladas e em parte executadas no Brasil - parecem ignorar a própria diferença. Assim, ao invés de promoverem uma educação para todos, elas correm o risco de realizar uma inclusão excludente das diferenças. Discute-se a distinção entre campanhas públicas e políticas de inclusão em termos dos âmbitos em que ambas se efetivam.Based on the concepts of government, biopower, norm and governmentality, this paper argues that the inclusion policies - especially those of school inclusion - are biopolitical devices to govern and control the populations. These and other concepts by Foucault are used as analytical tools to argue that we have to explore the including policies and practices without any previous value judgment on them. Since they understand the difference as a manifestation of diversity, and the different as the exotic, what carries something the others do not have, the inclusion policies - as they are being formulated and partly enforced in Brazil - seem to ignore difference itself. Thus, instead of promoting education for all, they may lead to an inclusion that excludes the differences. The text finally discusses the distinction between public campaigns and inclusion policies in terms of the settings in which both take place.

  1. Screening for Amyloid Aggregation by Semi-Denaturing Detergent-Agarose Gel Electrophoresis

    OpenAIRE

    Halfmann, Randal; Lindquist, Susan

    2008-01-01

    Amyloid aggregation is associated with numerous protein misfolding pathologies and underlies the infectious properties of prions, which are conformationally self-templating proteins that are thought to have beneficial roles in lower organisms. Amyloids have been notoriously difficult to study due to their insolubility and structural heterogeneity. However, resolution of amyloid polymers based on size and detergent insolubility has been made possible by Semi-Denaturing Detergent-Agarose Gel El...

  2. Primary amyloid heart disease presenting as hypertrophic obstructive cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Weston, L.T.; Raybuck, B.D.; Robinowitz, M.; Brinker, J.A.; Oetgen, W.J.

    1986-01-01

    This report describes the unusual presentation of a patient with primary cardiac amyloidosis. Initial clinical symptoms and hemodynamic studies, including Technetium-99m-pyrophosphate scintigraphy, suggested hypertrophic obstructive cardiomyopathy, but endomyocardial biopsy revealed diffuse amyloid infiltration. Only two other cases of left ventricular outflow tract obstruction due to cardiac amyloidosis have been reported. The false-negative technetium-99m-pyrophosphate scintigram in this patient argues for the use of endomyocardial biopsy to aid in the diagnosis of left ventricular hypertrophy.

  3. Crowding alone cannot account for cosolute effect on amyloid aggregation.

    Directory of Open Access Journals (Sweden)

    Shahar Sukenik

    Full Text Available Amyloid fiber formation is a specific form of protein aggregation, often resulting from the misfolding of native proteins. Aimed at modeling the crowded environment of the cell, recent experiments showed a reduction in fibrillation halftimes for amyloid-forming peptides in the presence of cosolutes that are preferentially excluded from proteins and peptides. The effect of excluded cosolutes has previously been attributed to the large volume excluded by such inert cellular solutes, sometimes termed "macromolecular crowding". Here, we studied a model peptide that can fold to a stable monomeric β-hairpin conformation, but under certain solution conditions aggregates in the form of amyloid fibrils. Using Circular Dichroism spectroscopy (CD, we found that, in the presence of polyols and polyethylene glycols acting as excluded cosolutes, the monomeric β-hairpin conformation was stabilized with respect to the unfolded state. Stabilization free energy was linear with cosolute concentration, and grew with molecular volume, as would also be predicted by crowding models. After initiating the aggregation process with a pH jump, fibrillation in the presence and absence of cosolutes was followed by ThT fluorescence, transmission electron microscopy, and CD spectroscopy. Polyols (glycerol and sorbitol increased the lag time for fibril formation and elevated the amount of aggregated peptide at equilibrium, in a cosolute size and concentration dependent manner. However, fibrillation rates remained almost unaffected by a wide range of molecular weights of soluble polyethylene glycols. Our results highlight the importance of other forces beyond the excluded volume interactions responsible for crowding that may contribute to the cosolute effects acting on amyloid formation.

  4. 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

  5. Inclusion for Customer with Disabilities

    OpenAIRE

    Murphy, James Peter

    2010-01-01

    For many people with disabilities, licensed premises design and lack of sufficient staff training can act as powerful barriers to their full inclusion in the activities of bars, restaurants and nightclubs.

  6. EDUCATIONAL INCLUSION AND CRITICAL PEDAGOGY

    Directory of Open Access Journals (Sweden)

    Silvia Molina

    2009-11-01

    Full Text Available This article outlines the basic principles of educational inclusion, focusingspecifically on the inclusion of disabled students in mainstream classrooms, and arguesthat inclusive education should be understood as a process of transforming traditionalschools into spaces of learning for all students. The article uses the lens of critical pedagogyto argue that exclusionary educational practices have been developed through themedicalization of learning disabilities which focused on the disability rather than theabilities of disabled students. Following the same line of thinking, the article providesscientific evidence to debunk myths related to the education of disabled students; especiallymyths that contributed to their exclusion from mainstream classrooms. Finally,based on the Learning Communities model, we provide some concrete strategies fortransforming mainstream classrooms into fully inclusive environments.

  7. PSYCHOANALYSIS, ETHICS AND INCLUSIVE EDUCATION

    OpenAIRE

    Ana Beatriz Coutinho Lerner; Rinaldo Voltolini

    2016-01-01

    This paper aims to investigate the central ways in which the discourse on Inclusive Education assumes in contemporary times and some the effects of this discourse on the subjectivity of children, parents and school professionals. In order to accomplish this goal, we first review the literature concerning Inclusive Education, showing the origins of this movement, the main legal frameworks that organize this subject and the current theoretical perspectives. We then analyze discursive elements c...

  8. 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.

  9. 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.

  10. Curcumin Binding to Beta Amyloid: A Computational Study.

    Science.gov (United States)

    Rao, Praveen P N; Mohamed, Tarek; Teckwani, Karan; Tin, Gary

    2015-10-01

    Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease. While curcumin is known to bind directly to various amyloid aggregates, no systematic investigations have been carried out to understand its ability to bind to the amyloid aggregates including oligomers and fibrils. In this study, we constructed computational models of (i) Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper β-sheet assembly and (ii) full-length Aβ fibril β-sheet assembly. Curcumin binding in these models was evaluated by molecular docking and molecular dynamics (MD) simulation studies. In both the models, curcumin was oriented in a linear extended conformation parallel to fiber axis and exhibited better stability in the Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper model (Ebinding  = -10.05 kcal/mol) compared to full-length Aβ fibril model (Ebinding  = -3.47 kcal/mol). Analysis of MD trajectories of curcumin bound to full-length Aβ fibril shows good stability with minimum Cα-atom RMSD shifts. Interestingly, curcumin binding led to marked fluctuations in the (14) HQKLVFFA(21) region that constitute the fibril spine with RMSF values ranging from 1.4 to 3.6 Å. These results show that curcumin binding to Aβ shifts the equilibrium in the aggregation pathway by promoting the formation of non-toxic aggregates. © 2015 John Wiley & Sons A/S.

  11. 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.

  12. MetAmyl: a METa-predictor for AMYLoid proteins.

    Directory of Open Access Journals (Sweden)

    Mathieu Emily

    Full Text Available The aggregation of proteins or peptides in amyloid fibrils is associated with a number of clinical disorders, including Alzheimer's, Huntington's and prion diseases, medullary thyroid cancer, renal and cardiac amyloidosis. Despite extensive studies, the molecular mechanisms underlying the initiation of fibril formation remain largely unknown. Several lines of evidence revealed that short amino-acid segments (hot spots, located in amyloid precursor proteins act as seeds for fibril elongation. Therefore, hot spots are potential targets for diagnostic/therapeutic applications, and a current challenge in bioinformatics is the development of methods to accurately predict hot spots from protein sequences. In this paper, we combined existing methods into a meta-predictor for hot spots prediction, called MetAmyl for METapredictor for AMYLoid proteins. MetAmyl is based on a logistic regression model that aims at weighting predictions from a set of popular algorithms, statistically selected as being the most informative and complementary predictors. We evaluated the performances of MetAmyl through a large scale comparative study based on three independent datasets and thus demonstrated its ability to differentiate between amyloidogenic and non-amyloidogenic polypeptides. Compared to 9 other methods, MetAmyl provides significant improvement in prediction on studied datasets. We further show that MetAmyl is efficient to highlight the effect of point mutations involved in human amyloidosis, so we suggest this program should be a useful complementary tool for the diagnosis of these diseases.

  13. Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade

    Directory of Open Access Journals (Sweden)

    Huntington Potter

    2012-01-01

    Full Text Available The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE. Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.

  14. 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.

  15. Amyloid Goiter: A Diagnosis to Consider in Diffuse Fatty Infiltration of the Thyroid.

    Science.gov (United States)

    Bakan, Selim; Kandemirli, Sedat Giray; Akbas, Serkan; Cingoz, Mehmet; Ozcan Guzelbey, Burcu; Kantarci, Fatih; Akman, Canan

    2017-05-01

    An amyloid goiter is the presence of amyloid protein in the thyroid in sufficient amounts to produce enlargement of the gland, accompanied by fat deposition of varying extents. It can be seen in long-standing inflammatory disorders such as familial Mediterranean fever. Imaging findings depend on the amount of fat and amyloid deposition; however, the main imaging finding is diffuse fatty infiltration of the thyroid. Herein, the multimodality imaging features in 3 cases of amyloid goiters secondary to familial Mediterranean fever are presented. © 2017 by the American Institute of Ultrasound in Medicine.

  16. A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging.

    Science.gov (United States)

    Tanifum, Eric A; Ghaghada, Ketan; Vollert, Craig; Head, Elizabeth; Eriksen, Jason L; Annapragada, Ananth

    2016-01-01

    Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits.

  17. 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.

  18. Molecular understanding of a potential functional link between antimicrobial and amyloid peptides.

    Science.gov (United States)

    Zhang, Mingzhen; Zhao, Jun; Zheng, Jie

    2014-10-14

    Antimicrobial and amyloid peptides do not share common sequences, typical secondary structures, or normal biological activity but both the classes of peptides exhibit membrane-disruption ability to induce cell toxicity. Different membrane-disruption mechanisms have been proposed for antimicrobial and amyloid peptides, individually, some of which are not exclusive to either peptide type, implying that certain common principles may govern the folding and functions of different cytolytic peptides and associated membrane disruption mechanisms. Particularly, some antimicrobial and amyloid peptides have been identified to have dual complementary amyloid and antimicrobial properties, suggesting a potential functional link between amyloid and antimicrobial peptides. Given that some similar structural and membrane-disruption characteristics exist between the two classes of peptides, this review summarizes major findings, recent advances, and future challenges related to antimicrobial and amyloid peptides and strives to illustrate the similarities, differences, and relationships in the sequences, structures, and membrane interaction modes between amyloid and antimicrobial peptides, with a special focus on direct interactions of the peptides with the membranes. We hope that this review will stimulate further research at the interface of antimicrobial and amyloid peptides - which has been studied less intensively than either type of peptides - to decipher a possible link between both amyloid pathology and antimicrobial activity, which can guide drug design and peptide engineering to influence peptide-membrane interactions important in human health and diseases.

  19. [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.

  20. Serum and Synovial Fluid Serum Amyloid A Response in Equine Models of Synovitis and Septic Arthritis.

    Science.gov (United States)

    Ludwig, Elsa K; Brandon Wiese, R; Graham, Megan R; Tyler, Amelia J; Settlage, Julie M; Werre, Stephen R; Petersson-Wolfe, Christina S; Kanevsky-Mullarky, Isis; Dahlgren, Linda A

    2016-10-01

    To investigate the serum and synovial fluid serum amyloid A (SAA) response in equine models of synovitis and septic arthritis and to compare handheld and validated immunoturbidometric assays for SAA quantification. Controlled, experimental study. Healthy adult horses (n = 9). Synovitis (n = 4) and septic arthritis (n = 5) were induced using lipopolysaccharide and Staphylococcus aureus, respectively, and serial serum and synovial fluid samples were collected. Serial synovial fluid cytology was performed for both models and synovial fluid from the septic arthritis model was submitted for bacterial culture. Serum and synovial fluid SAA were quantified by handheld test and immunoturbidometric assay. Cytologic and SAA data were compared within and between models (mixed model ANOVA) and results of SAA assays were compared using category-by-category analysis (weighted kappa coefficient). Synovial fluid total nucleated cell counts and total protein increased significantly following induction of both models. Serum and synovial fluid SAA remained normal in synovitis horses and increased significantly in septic arthritis horses. Serum SAA increased more rapidly than synovial fluid SAA. Agreement was 98% when SAA concentrations were low (septic arthritis in horses. SAA concentrations for the assays diverged and examination using a larger sample size is needed before direct numeric comparisons between the assays can be made. © Copyright 2016 by The American College of Veterinary Surgeons.

  1. 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

    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...... 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...

  2. Studying bacterial multispecies biofilms

    DEFF Research Database (Denmark)

    Røder, Henriette Lyng; Sørensen, Søren Johannes; Burmølle, Mette

    2016-01-01

    , but the identity and significance of interspecies bacterial interactions is neglected in these analyses. There is therefore an urgent need for bridging the gap between metagenomic analysis and in vitro models suitable for studies of bacterial interactions.Bacterial interactions and coadaptation are important......The high prevalence and significance of multispecies biofilms have now been demonstrated in various bacterial habitats with medical, industrial, and ecological relevance. It is highly evident that several species of bacteria coexist and interact in biofilms, which highlights the need for evaluating...

  3. 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.

  4. 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.

  5. 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.

  6. Pro-inflammatory Effects of Bacterial Recombinant Human C-Reactive Protein are Caused by Contamination with Bacterial Products not by C-Reactive Protein Itself

    Science.gov (United States)

    Pepys, Mark B.; Hawkins, Philip N.; Kahan, Melvyn C.; Tennent, Glenys A.; Gallimore, J. Ruth; Graham, David; Sabin, Caroline A.; Zychlinsky, Arturo; de Diego, Juana

    2006-01-01

    Intravenous administration to human volunteers of a commercial preparation of recombinant human C-reactive protein (CRP) produced in E. coli was recently reported in this journal to induce an acute phase response of serum amyloid A protein (SAA) and of CRP itself, and to activate the coagulation system. The authors concluded that CRP is probably a mediator of atherothrombotic disease. Here we confirm that this recombinant CRP preparation was pro-inflammatory both for mouse macrophages in vitro and for mice in vivo, but show that pure natural human CRP had no such activity. Furthermore mice transgenic for human CRP, and expressing it throughout their lives, maintained normal concentrations of their most sensitive endogenous acute phase reactants, SAA and serum amyloid P component (SAP). The patterns of in vitro cytokine induction and of in vivo acute phase stimulation by the recombinant CRP preparation were consistent with contamination by bacterial products, and there was 46.6 EU of apparent endotoxin activity per mg of CRP in the bacterial product, compared to 0.9 EU per mg of our isolated natural human CRP preparation. The absence of any pro-inflammatory activity in natural CRP for macrophages or healthy mice strongly suggests that the in vivo effects of the recombinant preparation observed in humans were due to pro-inflammatory bacterial products and not human CRP. PMID:16254214

  7. 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.

  8. 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

  9. Effect of creatine supplementation on cognitive performance and apoptosis in a rat model of amyloid-beta-induced Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Malek Alimohammadi-Kamalabadi

    2016-11-01

    Conclusion: Cr supplementation before and after β-amyloid injection into the CA1 area of hippocampus deteriorates the learning and memory impairment of rats and it does not protect neuronal apoptosis caused by β-amyloid.

  10. 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.

  11. 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.

  12. The Sociology of Social Inclusion

    Directory of Open Access Journals (Sweden)

    Dan Allman

    2013-01-01

    Full Text Available This article looks at social inclusion from a sociological perspective. It argues that sociology complements biological and other natural order explanations of social stratification. The article interrogates a variety of forms of social integration, including ostracism within 5th century b.c. Greece, 19th-century solidarism, and Goffman’s mid-20th-century work on stigma. It does so to demonstrate how in each of these contexts, social inclusion and exclusion can function as apparati that problematize people on the margins, and by extension, contribute to their governance and control. The article proposes that sociology provides a valuable orientation from which to consider social inclusion because it illuminates how social integration maintains and manages the ways in which people move about and through their socially stratified worlds.

  13. 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.…

  14. 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…

  15. 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.

  16. 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

  17. 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. 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    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

  18. 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

  19. 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

  20. Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes

    NARCIS (Netherlands)

    Lee, Jiyeon; Retamal, Claudio; Cuitino, Loreto; Caruano-Yzermans, Amy; Shin, Jung-Eun; van Kerkhof, Peter; Marzolo, Maria-Paz; Bu, Guojun

    2008-01-01

    Accumulation of extracellular amyloid beta peptide (A beta), generated from amyloid precursor protein (APP) processing by beta- and gamma-secretases, is toxic to neurons and is central to the pathogenesis of Alzheimer disease. Production of A beta from APP is greatly affected by the subcellular

  1. alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells

    NARCIS (Netherlands)

    Kazmierczak, Anna; Strosznajder, Joanna B.; Adamczyk, Agata

    2008-01-01

    alpha-Synuclein is the fundamental component of Lewy bodies which occur in the brain of 60% of sporadic and familial Alzheimer's disease patients. Moreover, a proteolytic fragment of alpha-synuclein, the so-called non-amyloid component of Alzheimer's disease amyloid, was found to be an integral part

  2. Between Amyloids and Aggregation Lies a Connection with Strength and Adhesion

    Directory of Open Access Journals (Sweden)

    Peter N. Lipke

    2014-01-01

    Full Text Available We tell of a journey that led to discovery of amyloids formed by yeast cell adhesins and their importance in biofilms and host immunity. We begin with the identification of the adhesin functional amyloid-forming sequences that mediate fiber formation in vitro. Atomic force microscopy and confocal microscopy show 2-dimensional amyloid “nanodomains” on the surface of cells that are activated for adhesion. These nanodomains are arrays of adhesin molecules that bind multivalent ligands with high avidity. Nanodomains form when adhesin molecules are stretched in the AFM or under laminar flow. Treatment with anti-amyloid perturbants or mutation of the amyloid sequence prevents adhesion nanodomain formation and activation. We are now discovering biological consequences. Adhesin nanodomains promote formation and maintenance of biofilms, which are microbial communities. Also, in abscesses within candidiasis patients, we find adhesin amyloids on the surface of the fungi. In both human infection and a Caenorhabditis elegans infection model, the presence of fungal surface amyloids elicits anti-inflammatory responses. Thus, this is a story of how fungal adhesins respond to extension forces through formation of cell surface amyloid nanodomains, with key consequences for biofilm formation and host responses.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. Characterizing Structural Stability of Amyloid Motif Fibrils Mediated by Water Molecules.

    Science.gov (United States)

    Choi, Hyunsung; Chang, Hyun Joon; Lee, Myeongsang; Na, Sungsoo

    2017-04-05

    In biological systems, structural confinements of amyloid fibrils can be mediated by the role of water molecules. However, the underlying effect of the dynamic behavior of water molecules on structural stabilities of amyloid fibrils is still unclear. By performing molecular dynamics simulations, we investigate the dynamic features and the effect of interior water molecules on conformations and mechanical characteristics of various amyloid fibrils. We find that a specific mechanism induced by the dynamic properties of interior water molecules can affect diffusion of water molecules inside amyloid fibrils, inducing their different structural stabilities. The conformation of amyloid fibrils induced by interior water molecules show the fibrils' different mechanical features. We elucidate the role of confined and movable interior water molecules in structural stabilities of various amyloid fibrils. Our results offer insights not only in further understanding of mechanical features of amyloids as mediated by water molecules, but also in the fine-tuning of the functional abilities of amyloid fibrils for applications. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. 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 bas...

  10. 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

  11. Depletion of spleen macrophages delays AA amyloid development: a study performed in the rapid mouse model of AA amyloidosis.

    Directory of Open Access Journals (Sweden)

    Katarzyna Lundmark

    Full Text Available AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM, marginal zone macrophages (MZM, metallophilic marginal zone macrophages (MMZM. MMZM and MZM are located in the marginal zone and express a unique collection of scavenger receptors that are involved in the uptake of blood-born particles. The murine AA amyloid model that resembles the human form of the disease has been used to study amyloid effects on different macrophage populations. Amyloid was induced by intravenous injection of amyloid enhancing factor and subcutaneous injections of silver nitrate and macrophages were identified with specific antibodies. We show that MZMs are highly sensitive to amyloid and decrease in number progressively with increasing amyloid load. Total area of MMZMs is unaffected by amyloid but cells are activated and migrate into the white pulp. In a group of mice spleen macrophages were depleted by an intravenous injection of clodronate filled liposomes. Subsequent injections of AEF and silver nitrate showed a sustained amyloid development. RPMs that constitute the majority of macrophages in spleen, appear insensitive to amyloid and do not participate in amyloid formation.

  12. Effects of kelp Ecklonia maxima inclusion in formulated feed on the ...

    African Journals Online (AJOL)

    The effect of kelp Ecklonia maxima inclusion in formulated feeds on abalone growth and gut bacterial communities has not been previously investigated in South Africa. An eight-month on-farm growth trial was conducted with sub-adult Haliotis midae (~43 mm shell length) fed graded levels of kelp in formulated feeds.

  13. 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

  14. 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

  15. 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

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

    DEFF Research Database (Denmark)

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

    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...... that have been studied so far have already provided an astonishing demonstration of how the amyloids can be exploited with roles ranging structural components of biofilms, cell envelopes and spore coats to cytotoxins and as reservoirs for quorum-sensing signaling molecules. The identification of novel...... 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...

  17. Identification of Plant Extracts that Inhibit the Formation of Diabetes-Linked IAPP Amyloid.

    Science.gov (United States)

    Fuentes, Ana Lucia; Hennessy, Kathleen; Pascual, Jacob; Pepe, Nicole; Wang, In; Santiago, Alexander; Chaggan, Cynthia; Martinez, Jessica; Rivera, Evelyn; Cota, Paola; Cunha, Christina; Nogaj, Luiza A; Moffet, David A

    2016-03-01

    The extracts of 27 vegetables, spices and herbs were screened for their functional ability to inhibit the aggregation of islet amyloid polypeptide (IAPP, amylin) into toxic amyloid aggregates. The aggregation of IAPP has been directly linked to the death of pancreatic β-islet cells in type 2 diabetes. Inhibiting the aggregation of IAPP is believed to have the potential to slow, if not prevent entirely, the progression of this disease. As vegetables, spices and herbs are known to possess many different positive health effects, the extracts of 27 plants (abundant within the United States and spanning several plant families) were screened for their ability to inhibit the formation of toxic IAPP aggregates. Their anti-amyloid activities were assessed through (1) thioflavin T binding assays, (2) visualization of amyloid fibers using atomic force microscopy and (3) cell rescue studies. From this research, mint, peppermint, red bell pepper and thyme emerged as possessing the greatest anti-amyloid activity.

  18. 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...... trials. Objective: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53.......28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid...

  19. 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.

  20. 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...

  1. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia.

    Science.gov (United States)

    Buhimschi, Irina A; Nayeri, Unzila A; Zhao, Guomao; Shook, Lydia L; Pensalfini, Anna; Funai, Edmund F; Bernstein, Ira M; Glabe, Charles G; Buhimschi, Catalin S

    2014-07-16

    Preeclampsia is a pregnancy-specific disorder of unknown etiology and a leading contributor to maternal and perinatal morbidity and mortality worldwide. Because there is no cure other than delivery, preeclampsia is the leading cause of iatrogenic preterm birth. We show that preeclampsia shares pathophysiologic features with recognized protein misfolding disorders. These features include urine congophilia (affinity for the amyloidophilic dye Congo red), affinity for conformational state-dependent antibodies, and dysregulation of prototype proteolytic enzymes involved in amyloid precursor protein (APP) processing. Assessment of global protein misfolding load in pregnancy based on urine congophilia (Congo red dot test) carries diagnostic and prognostic potential for preeclampsia. We used conformational state-dependent antibodies to demonstrate the presence of generic supramolecular assemblies (prefibrillar oligomers and annular protofibrils), which vary in quantitative and qualitative representation with preeclampsia severity. In the first attempt to characterize the preeclampsia misfoldome, we report that the urine congophilic material includes proteoforms of ceruloplasmin, immunoglobulin free light chains, SERPINA1, albumin, interferon-inducible protein 6-16, and Alzheimer's β-amyloid. The human placenta abundantly expresses APP along with prototype APP-processing enzymes, of which the α-secretase ADAM10, the β-secretases BACE1 and BACE2, and the γ-secretase presenilin-1 were all up-regulated in preeclampsia. The presence of β-amyloid aggregates in placentas of women with preeclampsia and fetal growth restriction further supports the notion that this condition should join the growing list of protein conformational disorders. If these aggregates play a pathophysiologic role, our findings may lead to treatment for preeclampsia. Copyright © 2014, American Association for the Advancement of Science.

  2. 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.

  3. 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.)

  4. Amyloid PET Positivity in Different Primary Progressive Aphasia Phenotypes.

    Science.gov (United States)

    Beaufils, Emilie; Vercouillie, Johnny; Vierron, Emilie; Cottier, Jean-Philippe; Camus, Vincent; Mondon, Karl; Guilloteau, Denis; Hommet, Caroline; Ribeiro, Maria Joao

    2018-04-01

    Primary progressive aphasia (PPA) is a neurological syndrome in which language functions become progressively impaired with relative sparing of memory and other instrumental functions. The pathologic causes of PPA are heterogeneous, but studies suggest that logopenic PPA (LPA) is underpinned by Alzheimer disease (AD) pathology in a high proportion of cases. The purposes of this descriptive and retrospective study were to characterize F-florbetapir PET imaging in a group of patients with a clinical syndrome of PPA, to determine the value of clinical characterization based on language phenotype in predicting the underlying pathology of PPA with F-florbetapir, and to quantify amyloid load in PPA subjects classified as "positive" F-florbetapir scans. Then, we compare the quantification and distribution of F-florbetapir uptake with those of typical, predominantly amnestic AD patients. We conducted a PET study with F-florbetapir in a cohort of 12 right-handed patients diagnosed with PPA: 3 patients with semantic-variant PPA, 5 with nonfluent PPA, 1 with LPA, and 3 unclassifiable patients. We evaluated amyloid deposition between APP groups and 11 patients with typical amnestic AD. Among the 12 patients with PPA syndrome, 8 (66.7%) were considered as amyloid positive. One of the 3 patients with semantic-variant PPA was F-florbetapir positive. In contrast, 4 of the 5 nonfluent-variant PPA, 2 of the 3 unclassifiable cases and the single patient with LPA were F-florbetapir positive. A significantly higher F-florbetapir uptake was observed in PPA F-florbetapir-positive patients compared with typical AD patients. This difference was observed in all regions of interest, except in posterior cingulate and temporal cortex. These results suggest that F-florbetapir PET may be useful in a routine clinical procedure to improve the reliability of identifying AD pathology in patients with PPA syndrome, with different clinical subtypes of the PPA syndrome.

  5. Specific Triazine Herbicides Induce Amyloid-β42 Production.

    Science.gov (United States)

    Portelius, Erik; Durieu, Emilie; Bodin, Marion; Cam, Morgane; Pannee, Josef; Leuxe, Charlotte; Mabondzo, Aloϊse; Oumata, Nassima; Galons, Hervé; Lee, Jung Yeol; Chang, Young-Tae; Stϋber, Kathrin; Koch, Philipp; Fontaine, Gaëlle; Potier, Marie-Claude; Manousopoulou, Antigoni; Garbis, Spiros D; Covaci, Adrian; Van Dam, Debby; De Deyn, Peter; Karg, Frank; Flajolet, Marc; Omori, Chiori; Hata, Saori; Suzuki, Toshiharu; Blennow, Kaj; Zetterberg, Henrik; Meijer, Laurent

    2016-10-18

    Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2-10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.

  6. [Spontaneous bacterial peritonitis].

    Science.gov (United States)

    Strauss, Edna; Caly, Wanda Regina

    2003-01-01

    Spontaneous bacterial peritonitis occurs in 30% of patients with ascites due to cirrhosis leading to high morbidity and mortality rates. The pathogenesis of spontaneous bacterial peritonitis is related to altered host defenses observed in end-stage liver disease, overgrowth of microorganisms, and bacterial translocation from the intestinal lumen to mesenteric lymph nodes. Clinical manifestations vary from severe to slight or absent, demanding analysis of the ascitic fluid. The diagnosis is confirmed by a number of neutrophils over 250/mm3 associated or not to bacterial growth in culture of an ascites sample. Enterobacteriae prevail and Escherichia coli has been the most frequent bacterium reported. Mortality rates decreased markedly in the last two decades due to early diagnosis and prompt antibiotic treatment. Third generation intravenous cephalosporins are effective in 70% to 95% of the cases. Recurrence of spontaneous bacterial peritonitis is common and can be prevented by the continuous use of oral norfloxacin. The development of bacterial resistance demands the search for new options in the prophylaxis of spontaneous bacterial peritonitis; probiotics are a promising new approach, but deserve further evaluation. Short-term antibiotic prophylaxis is recommended for patients with cirrhosis and ascites shortly after an acute episode of gastrointestinal bleeding.

  7. Social Inclusion and Integrative Practices

    Directory of Open Access Journals (Sweden)

    David Cappo

    2014-06-01

    Full Text Available With the passage of time valuable lessons have been learnt about both effective practices for program and system integration and the sizable barriers, including the challenges in sustaining constructive integration. This paper is a reflection on sustainable integrative practices and is grounded in the direct experience of one of the authors, who held the post of the South Australian Social Inclusion Commissioner. We reflect upon the structure and mechanism of the South Australian Social Inclusion Initiative (2002–2011 as well as using a case study of a successful integrative program of the Social Inclusion Initiative, a program in South Australia’s School Retention Action Plan 2004 Making the Connections (South Australian Social Inclusion Board, 2004 that was implemented to improve school retention. The case study draws out salient factors of clear rationale, coordination, collaboration, communication, team work and trust as skills and ingredients to bring about integration in policy and programs. While the integration literature affirms that these ingredients are primary skills for the development of an integrative framework, we also assert that they are not enough for successful and sustained integration. Absent from much of the literature is a discussion about the use of power and the manner in which horizontal integrative work occurs. We take up this theme to draw out some implications for analysis of sustainable integrative practices.

  8. 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...

  9. 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

  10. 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.

  11. 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…

  12. Teacher preparedness for inclusive education

    African Journals Online (AJOL)

    lynette

    Since the report of the National Department of Education, “Quality. Education for All” was published in 1997, it has became evident that inclusive education is going to be the way forward in special (and regular) education. Both the Consultative Paper on Special Educa- tion (30 August 1999) and the Draft White Paper on ...

  13. 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…

  14. Isoforms of murine and human serum amyloid P component

    DEFF Research Database (Denmark)

    Nybo, Mads; Hackler, R; Kold, B

    1998-01-01

    Isoelectric focusing (IEF) and immunofixation of murine serum amyloid P component (SAP), purified and in serum, showed a distinct and strain-dependent isoform pattern with up to seven bands (pI 5.1-5.7). Neuraminidase treatment caused a shift of the isoforms to more basic pI values, but did...... of isoforms of human SAP required the presence of urea and higher SAP concentrations. TEF and immunofixation of SAP monomers showed five to eight isoforms, ranging from pI 4.7-5.7. IEF of SAP in human serum resulted in a less distinct pattern and more acidic isoforms. As with murine SAP, neuraminidase...

  15. 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...

  16. Heteromers of amyloid precursor protein in cerebrospinal fluid

    OpenAIRE

    Cuchillo-Iba?ez, Inmaculada; Lopez-Font, Inmaculada; Boix-Amor?s, Alba; Brinkmalm, Gunnar; Blennow, Kaj; Molinuevo, Jose-Luis; S?ez-Valero, Javier

    2015-01-01

    Background Soluble fragments of the amyloid precursor protein (APP) generated by ?- and ?-secretases, sAPP? and sAPP?, have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for the clinical diagnosis of Alzheimer?s disease (AD). However, the capacity of these soluble proteins to assemble has not been explored and could be relevant. Our aim is to characterize possible sAPP oligomers that could contribute to the quantification of sAPP? and sAPP? in CSF by ELISA, as well as ...

  17. Ten Challenges of the Amyloid Hypothesis of Alzheimer's Disease

    DEFF Research Database (Denmark)

    Kepp, Kasper Planeta

    2017-01-01

    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......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...

  18. 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....

  19. Interfering with bacterial gossip

    DEFF Research Database (Denmark)

    Bjarnsholt, Thomas; Tolker-Nielsen, Tim; Givskov, Michael

    2011-01-01

    defense. Antibiotics exhibit a rather limited effect on biofilms. Furthermore, antibiotics have an ‘inherent obsolescence’ because they select for development of resistance. Bacterial infections with origin in bacterial biofilms have become a serious threat in developed countries. Pseudomonas aeruginosa...... 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......, resistance and QS inhibition as future antimicrobial targets, in particular those that would work to minimize selection pressures for the development of resistant bacteria....

  20. Large proteins have a great tendency to aggregate but a low propensity to form amyloid fibrils.

    Directory of Open Access Journals (Sweden)

    Hassan Ramshini

    Full Text Available The assembly of soluble proteins into ordered fibrillar aggregates with cross-β structure is an essential event of many human diseases. The polypeptides undergoing aggregation are generally small in size. To explore if the small size is a primary determinant for the formation of amyloids under pathological conditions we have created two databases of proteins, forming amyloid-related and non-amyloid deposits in human diseases, respectively. The size distributions of the two protein populations are well separated, with the systems forming non-amyloid deposits appearing significantly larger. We have then investigated the propensity of the 486-residue hexokinase-B from Saccharomyces cerevisiae (YHKB to form amyloid-like fibrils in vitro. This size is intermediate between the size distributions of amyloid and non-amyloid forming proteins. Aggregation was induced under conditions known to be most effective for amyloid formation by normally globular proteins: (i low pH with salts, (ii pH 5.5 with trifluoroethanol. In both situations YHKB aggregated very rapidly into species with significant β-sheet structure, as detected using circular dichroism and X-ray diffraction, but a weak Thioflavin T and Congo red binding. Moreover, atomic force microscopy indicated a morphology distinct from typical amyloid fibrils. Both types of aggregates were cytotoxic to human neuroblastoma cells, as indicated by the MTT assay. This analysis indicates that large proteins have a high tendency to form toxic aggregates, but low propensity to form regular amyloid in vivo and that such a behavior is intrinsically determined by the size of the protein, as suggested by the in vitro analysis of our sample protein.

  1. 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.

  2. Primordial Compositions of Refractory Inclusions

    Energy Technology Data Exchange (ETDEWEB)

    Grossman, L; Simon, S B; Rai, V K; Thiemens, M H; Hutcheon, I D; Williams, R W; Galy, A; Ding, T; Fedkin, A V; Clayton, R N; Mayeda, T K

    2008-02-20

    Bulk chemical and oxygen, magnesium and silicon isotopic compositions were measured for each of 17 Types A and B refractory inclusions from CV3 chondrites. After bulk chemical compositions were corrected for non-representative sampling in the laboratory, the Mg and Si isotopic compositions of each inclusion were used to calculate its original chemical composition assuming that the heavy-isotope enrichments of these elements are due to Rayleigh fractionation that accompanied their evaporation from CMAS liquids. The resulting pre-evaporation chemical compositions are consistent with those predicted by equilibrium thermodynamic calculations for high-temperature nebular condensates but only if different inclusions condensed from nebular regions that ranged in total pressure from 10{sup -6} to 10{sup -1} bar, regardless of whether they formed in a system of solar composition or in one enriched in OC dust relative to gas by a factor of ten relative to solar composition. This is similar to the range of total pressures predicted by dynamic models of the solar nebula for regions whose temperatures are in the range of silicate condensation temperatures. Alternatively, if departure from equilibrium condensation and/or non-representative sampling of condensates in the nebula occurred, the inferred range of total pressure could be smaller. Simple kinetic modeling of evaporation successfully reproduces observed chemical compositions of most inclusions from their inferred pre-evaporation compositions, suggesting that closed-system isotopic exchange processes did not have a significant effect on their isotopic compositions. Comparison of pre-evaporation compositions with observed ones indicates that 80% of the enrichment in refractory CaO + Al{sub 2}O{sub 3} relative to more volatile MgO + SiO{sub 2} is due to initial condensation and 20% due to subsequent evaporation for both Type A and Type B inclusions.

  3. Inclusive teaching strategies - dimensions and agendas

    DEFF Research Database (Denmark)

    Molbæk, Mette

    2017-01-01

    will contribute to an enrichment of the two research fields and give teachers and researchers new opportunities for developing more inclusive schools. Based on research focused on teaching strategies that support students’ opportunities for learning, four dimensions of inclusive teaching strategies are presented...... those teachers working with inclusion can be supported with more tangible and meaningful ways of understanding and developing inclusive classrooms. This article argues that seeing research in inclusion in close connection with research in effective teaching strategies and classroom management...

  4. 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)

  5. Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses.

    Science.gov (United States)

    Willén, Katarina; Sroka, Agnieszka; Takahashi, Reisuke H; Gouras, Gunnar K

    2017-01-01

    Alzheimer's disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aβ/AβPP. We demonstrate that Aβ binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aβ42 accumulates in both glutamatergic and GABAergic AβPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ-secretase AβPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AβPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aβ/AβPP in AD can be important for the development of more effective new therapies for this major disease of aging.

  6. Heterogeneous Association of Alzheimer’s Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses

    Science.gov (United States)

    Willén, Katarina; Sroka, Agnieszka; Takahashi, Reisuke H.; Gouras, Gunnar K.

    2017-01-01

    Alzheimer’s disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aβ/AβPP. We demonstrate that Aβ binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aβ42 accumulates in both glutamatergic and GABAergic AβPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ-secretase AβPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AβPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aβ/AβPP in AD can be important for the development of more effective new therapies for this major disease of aging. PMID:28869466

  7. 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.

  8. Bacterial Meningitis in Infants

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2004-04-01

    Full Text Available A retrospective study of 80 infantile patients (ages 30-365 days; 47 male, 33 female with culture-proven bacterial meningitis seen over a 16 year period (1986-2001 is reported from Taiwan.

  9. Factitious Bacterial Meningitis Revisited

    Science.gov (United States)

    Peterson, E.; Thrupp, L.; Uchiyama, N.; Hawkins, B.; Wolvin, B.; Greene, G.

    1982-01-01

    Nonviable gram-negative bacilli were seen in smears of cerebrospinal fluid from eight infants in whom bacterial meningitis was ruled out. Tubes from commercial kits were the source of the factitious organisms. PMID:7153328

  10. Vimentin in Bacterial Infections

    DEFF Research Database (Denmark)

    Mak, Tim N; Brüggemann, Holger

    2016-01-01

    filaments (IFs). IFs have not only roles in maintaining the structural integrity of the cell, but they are also involved in many cellular processes including cell adhesion, immune signaling, and autophagy, processes that are important in the context of bacterial infections. Here, we summarize the knowledge...... about the role of IFs in bacterial infections, focusing on the type III IF protein vimentin. Recent studies have revealed the involvement of vimentin in host cell defenses, acting as ligand for several pattern recognition receptors of the innate immune system. Two main aspects of bacteria......-vimentin interactions are presented in this review: the role of vimentin in pathogen-binding on the cell surface and subsequent bacterial invasion and the interaction of cytosolic vimentin and intracellular pathogens with regards to innate immune signaling. Mechanistic insight is presented involving distinct bacterial...

  11. 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.

  12. Sleep-wake cycle and diurnal fluctuation of amyloid-β as biomarkers of brain amyloid pathology

    OpenAIRE

    Roh, Jee Hoon; Huang, Yafei; Bero, Adam W.; Kasten, Tom; Stewart, Floy R.; Bateman, Randall J.; Holtzman, David M.

    2012-01-01

    Aggregation of amyloid-β (Aβ) in the brain begins to occur years prior to the clinical onset of Alzheimer’s disease (AD). Prior to Aβ aggregation, levels of extracellular, soluble interstitial fluid (ISF) Aβ, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep declines with aging and to a greater extent in AD. How sleep quality amount as well as the diurnal fluctuation in Aβ chan...

  13. 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

  14. [Diagnosis of bacterial vaginosis].

    Science.gov (United States)

    Djukić, Slobodanka; Ćirković, Ivana; Arsić, Biljana; Garalejić, Eliana

    2013-01-01

    Bacterial vaginosis is a common, complex clinical syndrome characterized by alterations in the normal vaginal flora. When symptomatic, it is associated with a malodorous vaginal discharge and on occasion vaginal burning or itching. Under normal conditions, lactobacilli constitute 95% of the bacteria in the vagina. Bacterial vaginosis is associated with severe reduction or absence of the normal H2O2-producing lactobacilli and overgrowth of anaerobic bacteria and Gardnerella vaginalis, Atopobium vaginae, Mycoplasma hominis and Mobiluncus species. Most types of infectious disease are diagnosed by culture, by isolating an antigen or RNA/DNA from the microbe, or by serodiagnosis to determine the presence of antibodies to the microbe. Therefore, demonstration of the presence of an infectious agent is often a necessary criterion for the diagnosis of the disease. This is not the case for bacterial vaginosis, since the ultimate cause of the disease is not yet known. There are a variety of methods for the diagnosis of bacterial vaginosis but no method can at present be regarded as the best. Diagnosing bacterial vaginosis has long been based on the clinical criteria of Amsel, whereby three of four defined criteria must be satisfied. Nugent's scoring system has been further developed and includes validation of the categories of observable bacteria structures. Up-to-date molecular tests are introduced, and better understanding of vaginal microbiome, a clear definition for bacterial vaginosis, and short-term and long-term fluctuations in vaginal microflora will help to better define molecular tests within the broader clinical context.

  15. Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease.

    Science.gov (United States)

    Cai, Zhiyou; Hussain, M Delwar; Yan, Liang-Jun

    2014-05-01

    Compelling evidence from basic molecular biology has demonstrated the dual roles of microglia in the pathogenesis of Alzheimer's disease (AD). On one hand, microglia are involved in AD pathogenesis by releasing inflammatory mediators such as inflammatory cytokines, complement components, chemokines, and free radicals that are all known to contribute to beta-amyloid (Aβ) production and accumulation. On the other hand, microglia are also known to play a beneficial role in generating anti-Aβ antibodies and stimulating clearance of amyloid plaques. Aβ itself, an inducer of microglia activation and neuroinflammation, has been considered as an underlying and unifying factor in the development of AD. A vicious cycle of inflammation has been formed between Aβ accumulation, activated microglia, and microglial inflammatory mediators, which enhance Aβ deposition and neuroinflammation. Thus, inhibiting the vicious cycle seems to be a promising treatment to restrain further development of AD. With increasing research efforts on microglia in AD, intervention of microglia activation and neuroinflammation in AD may provide a potential target for AD therapy in spite of the provisional failure of nonsteroidal antiinflammatory drugs in clinical trials.

  16. 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

    2017-01-01

    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. DOI: http://dx.doi.org/10.7554/eLife.24888.001 PMID:28653619

  17. 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.

  18. Ferulic acid destabilizes preformed β-amyloid fibrils in vitro

    International Nuclear Information System (INIS)

    Ono, Kenjiro; Hirohata, Mie; Yamada, Masahito

    2005-01-01

    Inhibition of the formation of β-amyloid fibrils (fAβ), as well as the destabilization of preformed fAβ in the CNS, would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). We reported previously that curcumin (Cur) inhibits fAβ formation from Aβ and destabilizes preformed fAβ in vitro. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of ferulic acid (FA) on the formation, extension, and destabilization of fAβ at pH 7.5 at 37 deg C in vitro. We next compared the anti-amyloidogenic activities of FA with Cur, rifampicin, and tetracycline. Ferulic acid dose-dependently inhibited fAβ formation from amyloid β-peptide, as well as their extension. Moreover, it destabilized preformed fAβs. The overall activity of the molecules examined was in the order of: Cur > FA > rifampicin = tetracycline. FA could be a key molecule for the development of therapeutics for AD

  19. Biomathematical screening of amyloid radiotracers with clinical usefulness index.

    Science.gov (United States)

    Nai, Ying-Hwey; Shidahara, Miho; Seki, Chie; Watabe, Hiroshi

    2017-11-01

    To facilitate radiotracers' development, a screening methodology using a biomathematical model and clinical usefulness index (CUI) was proposed to evaluate radiotracers' diagnostic capabilities. A total of 31 amyloid positron emission tomography radiotracers were evaluated. A previously developed biomathematical model was used to simulate 1000 standardized uptake value ratios with population and noise simulations, which were used to determine the integrated receiver operating characteristics curve (Az), effect size (Es), and standardized uptake value ratio (Sr) of conditions-pairs of healthy control-mild cognitive impaired and mild cognitive impaired-Alzheimer's disease. CUI was obtained from the product of averaged [Formula: see text], [Formula: see text], and [Formula: see text]. The relationships of [Formula: see text], [Formula: see text], and [Formula: see text] with CUI were different, suggesting that they assessed different radiotracer properties. The combination of Az, Es, and Sr complemented each other and resulted in CUI of 0.10 to 5.72, with clinically applied amyloid positron emission tomography radiotracers having CUI greater than 3.0. The CUI rankings of clinically applied radiotracers were close to their reported clinical results, attesting to the applicability of the screening methodology.

  20. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET.

    Science.gov (United States)

    Klunk, William E; Koeppe, Robert A; Price, Julie C; Benzinger, Tammie L; Devous, Michael D; Jagust, William J; Johnson, Keith A; Mathis, Chester A; Minhas, Davneet; Pontecorvo, Michael J; Rowe, Christopher C; Skovronsky, Daniel M; Mintun, Mark A

    2015-01-01

    Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤ 45 years) and typical Alzheimer's disease patients. The units of this scale have been named "Centiloids." Basically, we describe a "standard" method of analyzing PiB PET data and then a method for scaling any "nonstandard" method of PiB PET analysis (or any other tracer) to the Centiloid scale. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  1. Amyloid Beta Peptides Differentially Affect Hippocampal Theta Rhythms In Vitro

    Directory of Open Access Journals (Sweden)

    Armando I. Gutiérrez-Lerma

    2013-01-01

    Full Text Available Soluble amyloid beta peptide (Aβ is responsible for the early cognitive dysfunction observed in Alzheimer's disease. Both cholinergically and glutamatergically induced hippocampal theta rhythms are related to learning and memory, spatial navigation, and spatial memory. However, these two types of theta rhythms are not identical; they are associated with different behaviors and can be differentially modulated by diverse experimental conditions. Therefore, in this study, we aimed to investigate whether or not application of soluble Aβ alters the two types of theta frequency oscillatory network activity generated in rat hippocampal slices by application of the cholinergic and glutamatergic agonists carbachol or DHPG, respectively. Due to previous evidence that oscillatory activity can be differentially affected by different Aβ peptides, we also compared Aβ25−35 and Aβ1−42 for their effects on theta rhythms in vitro at similar concentrations (0.5 to 1.0 μM. We found that Aβ25−35 reduces, with less potency than Aβ1−42, carbachol-induced population theta oscillatory activity. In contrast, DHPG-induced oscillatory activity was not affected by a high concentration of Aβ25−35 but was reduced by Aβ1−42. Our results support the idea that different amyloid peptides might alter specific cellular mechanisms related to the generation of specific neuronal network activities, instead of exerting a generalized inhibitory effect on neuronal network function.

  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. The butter flavorant, diacetyl, exacerbates β-amyloid cytotoxicity.

    Science.gov (United States)

    More, Swati S; Vartak, Ashish P; Vince, Robert

    2012-10-15

    Diacetyl (DA), an ubiquitous butter-flavoring agent, was found to influence several aspects of amyloid-β (Aβ) aggregation--one of the two primary pathologies associated with Alzheimer's disease. Thioflavin T fluorescence and circular dichroism spectroscopic measurements revealed that DA accelerates Aβ¹⁻⁴² aggregation into soluble and ultimately insoluble β-pleated sheet structures. DA was found to covalently bind to Arg⁵ of Aβ¹⁻⁴² through proteolytic digestion-mass spectrometric experiments. These biophysical and chemical effects translated into the potentiation of Aβ¹⁻⁴² cytotoxicity by DA toward SH-SY5Y cells in culture. DA easily traversed through a MDR1-MDCK cell monolayer, an in vitro model of the blood-brain barrier. Additionally, DA was found not only to be resistant to but also inhibitory toward glyoxalase I, the primary initiator of detoxification of amyloid-promoting reactive dicarbonyl species that are generated naturally in large amounts by neuronal tissue. In light of the chronic exposure of industry workers to DA, this study raises the troubling possibility of long-term neurological toxicity mediated by DA.

  4. Polymorphism of Protein Aggregation: From Amyloid Fibrils to Crystallization

    Science.gov (United States)

    Safari, Mohammad S.; Conrad, Jacinta C.; Vekilov, Peter G.

    Protein aggregation is commonly observed in neurological diseases and in different types of cancer. Despite the established mechanism of amyloid formation, the polymorphism of aggregation is not very well understood; improved knowledge of mechanisms for aggregation that operate in vivo or under physiological conditions is likely to inform therapeutic design. Here we show that reduction of disulfide bonds in lysozyme can lead to formation of gel-like oligomers that are precursors for protein crystal nucleation events. The growth in size of oligomers follows slow first-order kinetics, suggesting that monomers with free thiol contribute to formation of clusters. Free thiol concentration measurements showed that the thiol concentration was relatively stable over 12 hr, confirming the slow kinetics was due to gelation inside the clusters. We probed the hydrophobicity of the clusters using ANS and ThT assays, and showed that the protein conformation in these clusters differs from that of thermally denatured aggregates. Although partial unfolding aids the formation of precursors to both amyloids and crystals, our results suggest that these pathways exhibit distinct signatures even at the earliest stages. NASA.

  5. 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

  6. STUDENTS’ RESPONSES TO INCLUSIVE DESIGN

    DEFF Research Database (Denmark)

    Herriott, Richard; Geert Jensen, Birgitte

    2012-01-01

    . This technology is designed help to citizens to be 'master of his or her own life' while off-setting capability changes due declining physical ability. Welfare technology includes smarter working practices or service concepts, which frees up labor resources and it also covers robotics, telemedicine, IT solutions...... and intelligent devices. This paper will show the results of students' work with the problem of changed demographics and emerging needs in products and services. In so doing it looks at how the use of inclusive design methods affects students´work processes. This is done by the use of work diaries which provided......This paper looks at how students’ design process responds to the requirements of inclusive design. The background to the students´ brief was the concept of welfare technology. People wish to retain their customary life-style even as ageing brings with it a reduction in physical capability: loss...

  7. The HLT inclusive B triggers

    CERN Document Server

    Gligorov, Vladimir V; Williams, Michael

    2011-01-01

    The inclusive HLT strategy relies on triggering any B decay based on two signatures: a single significantly displaced, high transverse momentum track, and a significantly displaced vertex containing this track and 1-3 other tracks, with high total transverse momentum. In order to provide optimal signal efficiency and background rejection the displaced vertex selection is implemented in a novel boosted decision tree algorithm incorporating information about the experimental resolution in the boosting procedure to protect against overtraining. The performance of these triggers has been commissioned using data taken during 2011 LHCb running and is evaluated here in a data-driven manner. The HLT inclusive triggers are found to have a rejection factor of around 1000 with respect to events selected by the L0 hardware trigger and a bbar purity close to 100%.

  8. Interprofessional development in inclusive schools

    DEFF Research Database (Denmark)

    Hansen, Britt Blaabjerg; Højholdt, Andy; Arndal, Lars Stubbe

    circles (Persson, 2007). The design development was theory oriented, with our introducing theories about the different aspects of professional collaboration, co-creation and social innovation (Conger, S. 2002, Edwall et. al. 2008)).In accordance with the processes of design-based research (iteration...... required to work with these students. This paper describes the challenges [education/school] professionals (teachers and child and youth educators) face in striving to develop inclusive school practice, and how these challenges relate to differences in skills and competencies between the professions....... The knowledge for the paper was generated in a research project entitled “Interprofessional development in inclusive schools”. The project worked from a basic understanding that we need to develop preventive educational strategies for children and young people with learning difficulties and in social risk...

  9. 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.

  10. Social inclusion and integrative practices

    OpenAIRE

    Cappo, David; Verity, Fiona

    2014-01-01

    With the passage of time valuable lessons have been learnt about both effective practices for program and system integration and the sizable barriers, including the challenges in sustaining constructive integration. This paper is a reflection on sustainable integrative practices and is grounded in the direct experience of one of the authors, who held the post of the South Australian Social Inclusion Commissioner. We reflect upon the structure and mechanism of the South Australian Social Inclu...

  11. Student' responses to inclusive design

    DEFF Research Database (Denmark)

    Herriott, Richard; Geert Jensen, Birgitte

    2013-01-01

    ” and “disordered”, this study visualises it and finds patterns underlying a process which is perceived to be chaotic. It provides a rough measure of the dynamics of a project in the form of the “switch between” ratio: how many changes in activity take place from the start to the finish of a project. The article...... was originally written for the DRTS 2012 conference "Articulating Design Thinking" and proposed for inclusion in a special edition of Design Issues....

  12. The Sociology of Social Inclusion

    OpenAIRE

    Dan Allman

    2013-01-01

    This article looks at social inclusion from a sociological perspective. It argues that sociology complements biological and other natural order explanations of social stratification. The article interrogates a variety of forms of social integration, including ostracism within 5th century b.c. Greece, 19th-century solidarism, and Goffman’s mid-20th-century work on stigma. It does so to demonstrate how in each of these c...

  13. 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....

  14. Inclusive fitness theory and eusociality

    DEFF Research Database (Denmark)

    Abbot, Patrick; Abe, Jun; Alcock, John

    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......, we believe that their arguments are based upon a misunderstanding of evolutionary theory and a misrepresentation of the empirical literature. We will focus our comments on three general issues....

  15. 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.

  16. Cross-seeding of fibrils from two types of insulin induces new amyloid strains.

    Science.gov (United States)

    Surmacz-Chwedoruk, Weronika; Nieznańska, Hanna; Wójcik, Sławomir; Dzwolak, Wojciech

    2012-11-27

    The irreversibility and autocatalytic character of amyloidogenesis and the polymorphism of amyloid fibrils underlie the phenomenon of self-propagating strains, wherein the mother seed, rather than the seeding environment, determines the properties of daughter fibrils. Here we study the formation of amyloid fibrils from bovine insulin and the recombinant Lys(B31)-Arg(B32) human insulin analog. The two polypeptides are similar enough to cross-seed but, upon spontaneous aggregation, form amyloid fibrils with distinct spectral features in the infrared amide I' band region. When bovine insulin is cross-seeded with the analog amyloid (and vice versa), the shape, absorption maximum, and even fine fingerprint features of the amide I' band are passed from the mother to daughter fibrils with a high degree of fidelity. Although the differences in primary structure between bovine insulin and the Lys(B31)-Arg(B32) analog of human insulin lie outside of the polypeptide's critical amyloidogenic regions, they affect the secondary structure of fibrils, possibly the formation of intermolecular salt bridges, and the susceptibility to dissection and denaturation with dimethyl sulfoxide (DMSO). All these phenotypic features of mother fibrils are imprinted in daughter amyloid upon cross-seeding. Analysis of noncooperative DMSO-induced denaturation of daughter fibrils suggests that the self-propagating polymorphism underlying the emergence of new amyloid strains is encoded on the level of secondary structure. Our findings have been discussed in the context of polymorphism of fibrils, amyloid strains, and possible implications for mechanisms of amyloidogenesis.

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

    Science.gov (United States)

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

    2017-04-01

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

  18. 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.

  19. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.; Zhao, Anni; Jiang, Lin; Zirafi, Onofrio; Stevens, Jason T.; Münch, Jan; Baker, David; Eisenberg, David (UCLA); (UWASH); (UL); (Kansas); (Ulm)

    2011-09-20

    Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-{beta}-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.

  20. Infrared Probe Technique Reveals a Millipede-like Structure for Aβ(8-28) Amyloid Fibril.

    Science.gov (United States)

    Gao, Yachao; Zou, Ye; Ma, Yan; Wang, Dan; Sun, Ying; Ma, Gang

    2016-02-02

    Amyloid fibrils are unique fibrous polypeptide aggregates. They have been associated with more than 20 serious human diseases including Alzheimer's disease and Parkinson's disease. Besides their pathological significance, amyloid fibrils are also gaining increasing attention as emerging nanomaterials with novel functions. Structural characterization of amyloid fibril is no doubt fundamentally important for the development of therapeutics for amyloid-related diseases and for the rational design of amyloid-based materials. In this study, we explored to use side-chain-based infrared (IR) probe to gain detailed structural insights into the amyloid fibril by a 21-residue model amyloidogenic peptide, Aβ(8-28). We first proposed an approach to incorporate thiocyanate (SCN) IR probe in a site-specific manner into amyloidogenic peptide using 1-cyano-4-dimethylaminopyridinium tetrafluoroborate as cyanylating agent. Using this approach, we obtained three Aβ(8-28) variants, labeled with SCN probe at three different positions. We then showed with thioflavin T fluorescence assay, Congo red assay, and atomic force microscopy that the three labeled Aβ(8-28) peptides can quickly form amyloid fibrils under high concentration and high salt conditions. Finally, we performed a detailed IR spectral analysis of the Aβ(8-28) fibril in both amide I and probe regions and proposed a millipede-like structure for the Aβ(8-28) fibril.

  1. 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

  2. Amyloid β Is Not the Major Factor Accounting for Impaired Adult Hippocampal Neurogenesis in Mice Overexpressing Amyloid Precursor Protein.

    Science.gov (United States)

    Pan, Hongyu; Wang, Dongpi; Zhang, Xiaoqin; Zhou, Dongming; Zhang, Heng; Qian, Qi; He, Xiao; Liu, Zhaoling; Liu, Yunjin; Zheng, Tingting; Zhang, Ling; Wang, Mingkai; Sun, Binggui

    2016-10-11

    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. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. 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......-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect...... Abeta plaque burden and Abeta42 levels in mice treated intranasally with Abeta peptide versus controls treated with myelin basic protein or left untreated. This lower Abeta burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti...

  4. 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.

  5. 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.

  6. 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.

  7. 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.)

  8. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease.

    Science.gov (United States)

    Rasmussen, Jay; Mahler, Jasmin; Beschorner, Natalie; Kaeser, Stephan A; Häsler, Lisa M; Baumann, Frank; Nyström, Sofie; Portelius, Erik; Blennow, Kaj; Lashley, Tammaryn; Fox, Nick C; Sepulveda-Falla, Diego; Glatzel, Markus; Oblak, Adrian L; Ghetti, Bernardino; Nilsson, K Peter R; Hammarström, Per; Staufenbiel, Matthias; Walker, Lary C; Jucker, Mathias

    2017-12-05

    The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.

  9. 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.)

  10. Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis.

    Science.gov (United States)

    Xiao, Qingli; Gil, So-Chon; Yan, Ping; Wang, Yan; Han, Sharon; Gonzales, Ernie; Perez, Ronaldo; Cirrito, John R; Lee, Jin-Moo

    2012-06-15

    One of the pathological hallmarks of Alzheimer disease is the accumulation of amyloid plaques in the extracellular space in the brain. Amyloid plaques are primarily composed of aggregated amyloid β peptide (Aβ), a proteolytic fragment of the transmembrane amyloid precursor protein (APP). For APP to be proteolytically cleaved into Aβ, it must be internalized into the cell and trafficked to endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs) in the phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) gene were significantly associated with Alzheimer disease, suggesting a role in APP endocytosis and Aβ generation. Here, we show that PICALM co-localizes with APP in intracellular vesicles of N2a-APP cells after endocytosis is initiated. PICALM knockdown resulted in reduced APP internalization and Aβ generation. Conversely, PICALM overexpression increased APP internalization and Aβ production. In vivo, PICALM was found to be expressed in neurons and co-localized with APP throughout the cortex and hippocampus in APP/PS1 mice. PICALM expression was altered using AAV8 gene transfer of PICALM shRNA or PICALM cDNA into the hippocampus of 6-month-old APP/PS1 mice. PICALM knockdown decreased soluble and insoluble Aβ levels and amyloid plaque load in the hippocampus. Conversely, PICALM overexpression increased Aβ levels and amyloid plaque load. These data indicate that PICALM, an adaptor protein involved in clathrin-mediated endocytosis, regulates APP internalization and subsequent Aβ generation. PICALM contributes to amyloid plaque load in brain likely via its effect on Aβ metabolism.

  11. Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis*

    Science.gov (United States)

    Xiao, Qingli; Gil, So-Chon; Yan, Ping; Wang, Yan; Han, Sharon; Gonzales, Ernie; Perez, Ronaldo; Cirrito, John R.; Lee, Jin-Moo

    2012-01-01

    One of the pathological hallmarks of Alzheimer disease is the accumulation of amyloid plaques in the extracellular space in the brain. Amyloid plaques are primarily composed of aggregated amyloid β peptide (Aβ), a proteolytic fragment of the transmembrane amyloid precursor protein (APP). For APP to be proteolytically cleaved into Aβ, it must be internalized into the cell and trafficked to endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs) in the phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) gene were significantly associated with Alzheimer disease, suggesting a role in APP endocytosis and Aβ generation. Here, we show that PICALM co-localizes with APP in intracellular vesicles of N2a-APP cells after endocytosis is initiated. PICALM knockdown resulted in reduced APP internalization and Aβ generation. Conversely, PICALM overexpression increased APP internalization and Aβ production. In vivo, PICALM was found to be expressed in neurons and co-localized with APP throughout the cortex and hippocampus in APP/PS1 mice. PICALM expression was altered using AAV8 gene transfer of PICALM shRNA or PICALM cDNA into the hippocampus of 6-month-old APP/PS1 mice. PICALM knockdown decreased soluble and insoluble Aβ levels and amyloid plaque load in the hippocampus. Conversely, PICALM overexpression increased Aβ levels and amyloid plaque load. These data indicate that PICALM, an adaptor protein involved in clathrin-mediated endocytosis, regulates APP internalization and subsequent Aβ generation. PICALM contributes to amyloid plaque load in brain likely via its effect on Aβ metabolism. PMID:22539346

  12. 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

  13. Combined determination of copper ions and β-amyloid peptide by a single ratiometric electrochemical biosensor.

    Science.gov (United States)

    Yu, Yanyan; Wang, Peng; Zhu, Xiaodan; Peng, Qiwen; Zhou, Yi; Yin, Tianxiao; Liang, Yixin; Yin, Xiaoxing

    2017-12-18

    Copper ions (Cu 2+ ) play a critical role in biological processes and are directly involved in β-amyloid peptide (Aβ) aggregation, which is responsible for the occurrence and development of Alzheimer's disease (AD). Therefore, combined determination of Cu 2+ and Aβ in one analytical system is of great significance to understand the exact nature of the AD event. This work presents a novel ratiometric electrochemical biosensor for the dual determination of Cu 2+ and Aβ 1-42 . This unique sensor is based on a 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) (ABTS) and poly(diallyldimethylammonium chloride) (PDDA)-bi functionalized single-walled carbon nanotubes (ABTS-PDDA/CNTs) composite. The inclusion of ABTS not only enhanced the sensitivity, but it also acted as an inner reference molecule to improve detection accuracy. The specific recognition of Cu 2+ was realized by neurokinin B (NKB) coatings on the ABTS-PDDA/CNTs surface to form a [Cu II (NKB) 2 ] complex with Cu 2+ . The ABTS-PDDA/CNTs-NKB modified electrode also displayed an excellent electrochemical response toward the Aβ 1-42 monomer, when a certain amount of the Aβ 1-42 monomer was added to Cu 2+ -contained PBS buffer, which was due to the release of Cu 2+ from the [Cu II (NKB) 2 ] complex through Aβ binding to Cu 2+ . Meanwhile, our work showed that Cu 2+ bound Aβ 1-42 was concentration-dependent. Consequently, the presented electrochemical approach was capable of quantifying two important biological species associated with AD by one single biosensor, with the detection limits of 0.04 μM for Cu 2+ and 0.5 ng mL -1 for Aβ 1-42 , respectively. Finally, the ratiometric electrode was successfully applied for monitoring Cu 2+ and Aβ 1-42 variations in plasma and hippocampus of normal and AD rats.

  14. Inclusive and semi-inclusive hadron interactions at ISR energies

    International Nuclear Information System (INIS)

    Giacomelli, G.

    1987-01-01

    Experiments at the CERN proton-antiproton collider and at the ISR have recently provided a wealth of information on high-energy, low-transverse momentum hadron-hadron interactions. These data are changing the picture of inelastic collisions at high-energies. In this paper will be mainly discussed high-statistics data from the ABCDHW collaboration using the Split Field Magnet (SFM) detector at the CERN-ISR. In particular will be discussed inclusive distributions as functions of x and y, the multiplicity and rapidity dependence of the mean transverse momentum, its fluctuations, correlations in rapidity, Bose-Einstein correlations, charged multiplicity distributions and rapidity fluctuations

  15. Extended analysis of AL-amyloid protein from abdominal wall subcutaneous fat biopsy

    DEFF Research Database (Denmark)

    Olsen, K E; Sletten, K; Westermark, Per

    1998-01-01

    In AL-amyloidosis the cause of amyloid fibril formation in beta-pleated sheets from the precursor protein immunoglobulin light chain is not established, but studies of AL-proteins indicate that amino acid substitutions are important in the pathogenesis. Amyloid material was extracted from...... a subcutaneous fat tissue biopsy and submitted to extended protein separation, typing and amino acid sequence analyses. The AL-protein belonged to the rare immunoglobulin light chain kappa, subtype kappa IV and contained unique amino acid substitutions, mostly in the highly preserved framework regions. The study...... shows that subcutaneous fat biopsies are useful sources of amyloid material for biochemical studies....

  16. 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...

  17. Cerebral amyloid angiopathy presenting as nonhemorrhagic diffuse encephalopathy: neuropathologic and neuroradiologic manifestations in one case.

    Science.gov (United States)

    Caulo, M; Tampieri, D; Brassard, R; Christine Guiot, M; Melanson, D

    2001-01-01

    A case of cerebral amyloid angiopathy is presented with MR imaging findings of high intense signal on T2-weighted sequences at the level of the white and gray matter of both hemispheres in the absence of neuroradiologic signs of cerebral hemorrhage. The biopsy specimen revealed deposition of amyloid in the walls of the intracranial arterial branches and focal ischemic changes and gliosis in the gray and white matter. We consider this presentation to be very unusual in patients affected by cerebral amyloid angiopathy.

  18. 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...... nanomechnical microscopy (DNM) provides the availability to link topography and corresponding nanomechnical properties. This nanomechnical mapping improves the understanding of amyloid self-assembly mechanisms, and it also assists to design the amyloid structure based nanomaterials. In my PhD thesis, I...

  19. 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.

  20. 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

  1. 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

  2. Specific chlamydial inclusion membrane proteins associate with active Src family kinases in microdomains that interact with the host microtubule network.

    Science.gov (United States)

    Mital, Jeffrey; Miller, Natalie J; Fischer, Elizabeth R; Hackstadt, Ted

    2010-09-01

    Chlamydiae are Gram-negative obligate intracellular bacteria that cause diseases with significant medical and economic impact. Chlamydia trachomatis replicates within a vacuole termed an inclusion, which is extensively modified by the insertion of a number of bacterial effector proteins known as inclusion membrane proteins (Incs). Once modified, the inclusion is trafficked in a dynein-dependent manner to the microtubule-organizing centre (MTOC), where it associates with host centrosomes. Here we describe a novel structure on the inclusion membrane comprised of both host and bacterial proteins. Members of the Src family of kinases are recruited to the chlamydial inclusion in an active form. These kinases display a distinct, localized punctate microdomain-like staining pattern on the inclusion membrane that colocalizes with four chlamydial inclusion membrane proteins (Incs) and is enriched in cholesterol. Biochemical studies show that at least two of these Incs stably interact with one another. Furthermore, host centrosomes associate with these microdomain proteins in C. trachomatis-infected cells and in uninfected cells exogenously expressing one of the chlamydial effectors. Together, the data suggest that a specific structure on the C. trachomatis inclusion membrane may be responsible for the known interactions of chlamydiae with the microtubule network and resultant effects on centrosome stability.

  3. Event by Event fluctuations and Inclusive Distribution

    OpenAIRE

    Bialas, A.; Koch, V.

    1999-01-01

    Event-by-event observables are compared with conventional inclusive measurements. We find that moments of event-by-event fluctuations are closely related to inclusive correlation functions. Implications for upcomming heavy ion experiments are discussed.

  4. A study of the cytoplasmic expression of a form of human prolactin and of its solubilization and renaturation from bacterial inclusion bodies; Estudo da expressao citoplasmatica bacteriana de uma forma de prolactina humana e de sua solubilizacao e renaturacao a partir de corpos de inclusao

    Energy Technology Data Exchange (ETDEWEB)

    Affonso, Regina

    2000-07-01

    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 {mu}g/mL.A{sub 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 ({lambda}P{sub L} or tac) and of the antibiotic resistance gene (amp{sup r} or kan{sup 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{sup r} and kan{sup 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)

  5. 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)

  6. Interfering with bacterial gossip

    DEFF Research Database (Denmark)

    Bjarnsholt, Thomas; Tolker-Nielsen, Tim; Givskov, Michael

    2011-01-01

    Biofilm resilience poses major challenges to the development of novel antimicrobial agents. Biofilm bacteria can be considered small groups of “Special Forces” capable of infiltrating the host and destroying important components of the cellular defense system with the aim of crippling the host...... defense. Antibiotics exhibit a rather limited effect on biofilms. Furthermore, antibiotics have an ‘inherent obsolescence’ because they select for development of resistance. Bacterial infections with origin in bacterial biofilms have become a serious threat in developed countries. Pseudomonas aeruginosa...... 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...

  7. Inclusive outreach practices in Palaeontology: Inclusive-Coworking

    Science.gov (United States)

    García-Frank, Alejandra; Gomez-Heras, Miguel; Fesharaki, Omid

    2017-04-01

    Previous experiences with people with both physical and intellectual functional diversity around palaeontological issues have demonstrated the important value of science outreach directed to people with disabilities. The aforementioned practices act twofold: as a learning tool and also improving the quality of life of the participants and thus, their self-image. All these pioneer experiences were the first step in a process of developing new attitudes contributing the 2030 Agenda for Sustainable Development of United Nations, where among the 17 goals proposed an effective social inclusion of people with disabilities is required. For this, real inclusive practices in geological outreach are imperious. A close cooperation with all the parts (researchers and participants), in a kind of coworking attitude is needed. This Inclusive-Coworking is considered in the sense of social gathering in order to share equal values and look for the synergy that this different outlook implies. And what is more important: the change of role of the previously learners into an active part of the scientific outreach, providing the adequate methodology for that. The offer of non-formal learning activities normally includes the participation of university professors and researchers in Science Week editions. During the 2016 session in Madrid, four adults with intellectual disability who were participants in the previous edition, contributed in the palaeontological workshop. They were in charge of four of the eight modules explaining the origin of fossils and how to collect them, the evolution of equids' limbs, and the main dentition types in vertebrates to the twenty 16 year old secondary students who attended the workshop. During the development of the experience all the students were pleased with the inclusive approach, and the interaction of all participants was fruitful. Although the explanations took a bit more time when made by our functional diverse fellows, all the abstracts concepts

  8. Deficiency in either COX-1 or COX-2 genes does not affect amyloid beta protein burden in amyloid precursor protein transgenic mice.

    Science.gov (United States)

    Park, Sun Ah; Chevallier, Nathalie; Tejwani, Karishma; Hung, Mary M; Maruyama, Hiroko; Golde, Todd E; Koo, Edward H

    2016-09-09

    Epidemiologic studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk for developing Alzheimer's disease (AD). Because the primary mode of action of NSAIDs is to inhibit cyclooxygenase (COX) activity, it has been proposed that perturbed activity of COX-1 or COX-2 contributes to AD pathogenesis. To test the role of COX-1 or COX-2 in amyloid deposition and amyloid-associated inflammatory changes, we examined amyloid precursor protein (APP) transgenic mice in the context of either COX-1 or COX-2 deficiency. Our studies showed that loss of either COX-1 or COX-2 gene did not alter amyloid burden in brains of the APP transgenic mice. However, one marker of microglial activation (CD45) was decreased in brains of COX-1 deficient/APP animals and showed a strong trend in reduction in COX-2 deficient/APP animals. These results suggest that COX activity and amyloid deposition in brain are likely independent processes. Further, if NSAIDs do causally reduce the risks of AD, then our findings indicate that the mechanisms are likely not due primarily to their inhibition on COX or γ-secretase modulation activity, the latter reported recently after acute dosing of ibuprofen in humans and nonhuman primates. Copyright © 2016. Published by Elsevier Inc.

  9. 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.

  10. A disulfide-linked amyloid-beta peptide dimer forms a protofibril-like oligomer through a distinct pathway from amyloid fibril formation.

    Science.gov (United States)

    Yamaguchi, Takahiro; Yagi, Hisashi; Goto, Yuji; Matsuzaki, Katsumi; Hoshino, Masaru

    2010-08-24

    The conversion of the soluble, nontoxic amyloid-beta (Abeta) peptide into an aggregated, toxic form rich in beta-sheets is considered a key step in the development of Alzheimer's disease. Whereas growing evidence indicates that the Abeta amyloid fibrils consist of in-register parallel beta-sheets, little is known about the structure of soluble oligomeric intermediates because of their transient nature. To understand the mechanism by which amyloid fibrils form, especially the initial development of the "nucleus" oligomeric intermediates, we prepared covalently linked dimeric Abeta peptides and analyzed the kinetics of the fibril-forming process. A covalent bond introduced between two Abeta molecules dramatically facilitated the spontaneous formation of aggregates with a beta-sheet structure and affinity for thioflavin T. Transmission electron microscopy revealed, however, that these aggregates differed in morphology from amyloid fibrils, more closely resembling protofibrils. The protofibril-like aggregates were not the most thermodynamically stable state but were a kinetically trapped state. The results emphasize the importance of the conformational flexibility of the Abeta molecule and a balance in the association and dissociation rate for the formation of rigid amyloid fibrils.

  11. Diagnosis of bacterial vaginosis

    Directory of Open Access Journals (Sweden)

    Đukić Slobodanka

    2013-01-01

    Full Text Available Bacterial vaginosis is a common, complex clinical syndrome characterized by alterations in the normal vaginal flora. When symptomatic, it is associated with a malodorous vaginal discharge and on occasion vaginal burning or itching. Under normal conditions, lactobacilli constitute 95% of the bacteria in the vagina. Bacterial vaginosis is associated with severe reduction or absence of the normal H2O2­producing lactobacilli and overgrowth of anaerobic bacteria and Gardnerella vaginalis, Atopobium vaginae, Mycoplasma hominis and Mobiluncus species. Most types of infectious disease are diagnosed by culture, by isolating an antigen or RNA/DNA from the microbe, or by serodiagnosis to determine the presence of antibodies to the microbe. Therefore, demonstration of the presence of an infectious agent is often a necessary criterion for the diagnosis of the disease. This is not the case for bacterial vaginosis, since the ultimate cause of the disease is not yet known. There are a variety of methods for the diagnosis of bacterial vaginosis but no method can at present be regarded as the best. Diagnosing bacterial vaginosis has long been based on the clinical criteria of Amsel, whereby three of four defined criteria must be satisfied. Nugent’s scoring system has been further developed and includes validation of the categories of observable bacteria structures. Up­to­date molecular tests are introduced, and better understanding of vaginal microbiome, a clear definition for bacterial vaginosis, and short­term and long­term fluctuations in vaginal microflora will help to better define molecular tests within the broader clinical context.

  12. Microvillous inclusion disease (microvillous atrophy

    Directory of Open Access Journals (Sweden)

    Goulet Olivier

    2006-06-01

    Full Text Available Abstract Microvillous inclusion disease (MVID or microvillous atrophy is a congenital disorder of the intestinal epithelial cells that presents with persistent life-threatening watery diarrhea and is characterized by morphological enterocyte abnormalities. MVID manifests either in the first days of life (early-onset form or in the first two months (late-onset form of life. MVID is a very rare disorder of unknown origin, probably transmitted as an autosomal recessive trait. To date, no prevalence data are available. Ultrastructural analyses reveal: 1 a partial to total atrophy of microvilli on mature enterocytes with apical accumulation of numerous secretory granules in immature enterocytes; 2 the highly characteristic inclusion bodies containing rudimentary or fully differentiated microvilli in mature enterocytes. Light microscopy shows accumulation of PAS-positive granules at the apical pole of immature enterocytes, together with atrophic band indicating microvillus atrophy and, in parallel, an intracellular PAS or CD10 positive line (marking the microvillous inclusion bodies seen on electron microscopy. Intestinal failure secondary to diarrhea is definitive. To date, no curative therapy exists and children with MVID are totally dependent on parenteral nutrition. Long-term outcome is generally poor, due to metabolic decompensation, repeated states of dehydration, infectious and liver complications related to the parenteral nutrition. As MVID is a very rare disorder, which is extremely difficult to diagnose and manage, children with MVID should be transferred to specialized pediatric gastro-intestinal centers, if possible, a center equipped to perform small bowel transplantation. Early small bowel transplantation resulting in intestinal autonomy gives new hope for disease management and outcome.

  13. 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...

  14. Bacterial blight of cotton

    Directory of Open Access Journals (Sweden)

    Aïda JALLOUL

    2015-04-01

    Full Text Available Bacterial blight of cotton (Gossypium ssp., caused by Xanthomonas citri pathovar malvacearum, is a severe disease occurring in all cotton-growing areas. The interactions between host plants and the bacteria are based on the gene-for-gene concept, representing a complex resistance gene/avr gene system. In light of the recent data, this review focuses on the understanding of these interactions with emphasis on (1 the genetic basis for plant resistance and bacterial virulence, (2 physiological mechanisms involved in the hypersensitive response to the pathogen, including hormonal signaling, the oxylipin pathway, synthesis of antimicrobial molecules and alteration of host cell structures, and (3 control of the disease.

  15. Bacterial meningitis in infants.

    Science.gov (United States)

    Ku, Lawrence C; Boggess, Kim A; Cohen-Wolkowiez, Michael

    2015-03-01

    Neonatal bacterial meningitis is uncommon but devastating. Morbidity among survivors remains high. The types and distribution of pathogens are related to gestational age, postnatal age, and geographic region. Confirming the diagnosis is difficult. Clinical signs are often subtle, lumbar punctures are frequently deferred, and cerebrospinal fluid (CSF) cultures can be compromised by prior antibiotic exposure. Infants with bacterial meningitis can have negative blood cultures and normal CSF parameters. Promising tests such as the polymerase chain reaction require further study. Prompt treatment with antibiotics is essential. Clinical trials investigating a vaccine for preventing neonatal Group B Streptococcus infections are ongoing. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Regge cuts in inclusive reactions

    International Nuclear Information System (INIS)

    Paige, F.E.; Trueman, T.L.

    1975-01-01

    The contribution of Regge cuts to single-particle inclusive processes is analyzed using the techniques of Gribov. The dependence of these contributions on the polarization state of the target is emphasized. A general formula is obtained and certain contributions to it are calculated. It is not possible, however, to reduce this to a simple, powerful formula expressing the total cut contribution in terms of other measurable quantities, as can be done for the cut contribution to the total cross section. The reasons for this are discussed in detail. The single-particle intermediate states, analogous to the absorption model for elastic scattering, are explicitly calculated as an illustration

  17. Teaching Competences and Inclusive Education

    Directory of Open Access Journals (Sweden)

    José María Fernández Batanero

    2013-08-01

    Full Text Available This paper focuses on teaching competencies that are conducive to good educational practices in relation to inclusion, from the perspective of teachers. The methodology employed in the study is descriptive/comprehensive, and of an exploratory nature. By means of four case studies, the perceptions of teachers from two secondary schools—characterized by the Spanish Educational Administration as having “good practices”— are examined. The techniques used for information collection in this study include documentary analysis, in-depth interviews and focus groups. The findings emphasize the importance of strategic skills, combined with innovation and creativity, among others.

  18. 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

  19. Metal-Dependent Amyloid β-Degrading Catalytic Antibody Construct

    Science.gov (United States)

    Nishiyama, Yasuhiro; Taguchi, Hiroaki; Hara, Mariko; Planque, Stephanie A.; Mitsuda, Yukie; Paul, Sudhir

    2015-01-01

    Catalytic antibodies (catabodies) that degrade target antigens rapidly are rare. We describe the metal-dependence of catabody construct 2E6, an engineered heterodimer of immunoglobulin light chain variable domains that hydrolyzes amyloid β peptides (Aβ) specifically. In addition to the electrophilic phosphonate inhibitor of serine proteases, the metal chelators ethylenediaminetetraacetic acid (EDTA) and 1,10-phenanthroline completely inhibited the hydrolysis of Aβ by catabody 2E6. Formation of catabody-electrophilic phosphonate inhibitor adducts was unaffected by EDTA, suggesting that the metal exerts a favorable effect on a catalytic step after the initial catabody nucleophilic attack on Aβ. The EDTA inactivated catabody failed to disaggregate fibrillar Aβ, indicating the functional importance of the Aβ hydrolytic activity. Treating the EDTA-inactivated catabody with Zn2+ or Co2+ restored the Aβ hydrolytic activity, and Zn2+-induced catabody conformational transitions were evident by fluorescence emission spectroscopy. The studies reveal the absolute catabody dependence on a metal cofactor. PMID:24698848

  20. 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...

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. Expression of serum amyloid a in equine wounds

    DEFF Research Database (Denmark)

    Sørensen, Mette Aamand; Jacobsen, Stine; Berg, Lise Charlotte

    2010-01-01

    OBJECTIVES Aberrant wound healing with formation of exuberant granulation tissue (EGT) occurs frequently in horses and may affect their athletic career and quality of life. The objective of the study was to determine mRNA expression levels of serum amyloid A (SAA) in normal and aberrant wound...... healing in horses. METHODS Experimental wounds were made in six horses on both metatarsi and on regio brachii. One limb was bandaged to provoke formation of EGT. Biopsies were collected on day 21 and were divided in three groups: body wounds (regio brachii), unbandaged limb wounds (normal healing......), and bandaged limb wounds (aberrant healing with formation of EGT). All biopsies were examined for the relative mRNA expression level of SAA using qRT-PCR. Differences in SAA expression levels between the three groups were analyzed by Kruskal-Wallis test and Dunns test. RESULTS SAA mRNA level was significantly...

  6. Recurrent craniospinal subarachnoid hemorrhage in cerebral amyloid angiopathy

    Directory of Open Access Journals (Sweden)

    Mathew Alexander

    2013-01-01

    Full Text Available Cerebral amyloid angiopathy (CAA usually manifests as cerebral hemorrhage, especially as nontraumatic hemorrhages in normotensive elderly patients. Other manifestations are subarachnoid (SAH, subdural, intraventricular hemorrhage (IVH and superficial hemosiderosis. A 52-year-old hypertensive woman presented with recurrent neurological deficits over a period of 2 years. Her serial brain magnetic resonance imaging and computed tomography scans showed recurrent SAH hemorrhage, and also intracerebral, IVH and spinal hemorrhage, with superficial siderosis. Cerebral angiograms were normal. Right frontal lobe biopsy showed features of CAA. CAA can present with unexplained recurrent SAH hemorrhage, and may be the initial and prominent finding in the course of disease in addition to superficial cortical siderosis and intracerebal and spinal hemorrhages.

  7. The SAXS and Rheological Studies of HEWL Amyloid Formation

    International Nuclear Information System (INIS)

    Szymanska, A.; Slosarek, G.; Hornowski, T.; Kozak, M.

    2008-01-01

    We performed small angle X-ray scattering and rheological experiments in order to analyze the aggregation and denaturation processes of hen egg white lysozyme initiated by the presence of ethanol molecule. At low ethanol concentrations (below 60% (v/v)) we did not observe any change of the radius of gyration of lysozyme and no drastic changes in viscosity of the protein solution. With the increase in ethanol concentration up to the final concentration of 85% (v/v) the viscosity of protein solution dramatically increased. For high ethanol concentration a pseudoplastic behavior of lysozyme solution was observed, indicating a process of aggregation and reorientation of the protein molecules. Similar effects were observed in small angle X-ray scattering experiments. We assume that the analysis of the aggregation processes of the hen egg white lysozyme could contribute to our understanding of the mechanism of lysozyme amyloid formation. (authors)

  8. Amyloid arthropathy revealed by RS3PE syndrome.

    Science.gov (United States)

    Magy, N; Michel, F; Auge, B; Toussirot, E; Wendling, D

    2000-01-01

    Amyloid arthropathy is a form of primary AL amyloidosis with a monoclonal component in the blood and/or urine, and RS3PE syndrome is acute edematous polysynovitis in subjects older than 60 years. A 74-year-old man was diagnosed with both disorders. He was admitted for benign acute polyarthritis of the hands and feet and reported carpal tunnel symptoms predominating on the right. A synovial biopsy at the right wrist disclosed deposits that stained with Congo red even after potassium permanganate treatment (positive Wright's test). Articular AL amyloidosis was diagnosed. The symptoms resolved under glucocorticoid therapy alone, casting some doubt on their relationship with the amyloidosis. Roentgenograms showed geodes, a feature not present in RS3PE. Whether RS3PE may be among the possible presentations of articular amyloidosis is discussed.

  9. 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

  10. Principals' Knowledge of and Attitudes toward Inclusion.

    Science.gov (United States)

    Barnett, Carol; Monda-Amaya, Lisa E.

    1998-01-01

    A survey of 65 elementary, junior, and high school principals investigated attitudes toward and knowledge of inclusion. No clear definition of inclusion emerged, but principals generally viewed inclusion as most appropriate for students with mild disabilities. Also, results indicated that teachers were not adequately prepared to implement…

  11. Inclusive Education: Examining Equity on Five Continents

    Science.gov (United States)

    Artiles, Alfredo J., Ed.; Kozleski, Elizabeth B., Ed.; Waitoller, Federico R., Ed.

    2011-01-01

    Despite the impressive growth of inclusive education around the world, questions and considerations about equity have been neglected. This edited volume makes a major contribution to the field of inclusive education by analyzing equity concerns that have emerged from the implementation of inclusive education models in nine nations on five…

  12. 75 FR 81395 - Minority and Women Inclusion

    Science.gov (United States)

    2010-12-28

    ... 2590-AA28 Minority and Women Inclusion AGENCIES: Federal Housing Finance Board; Federal Housing Finance... and the inclusion of women and minorities in all activities. The final rule implements the provisions.... It also requires each regulated entity to establish an Office of Minority and Women Inclusion, or...

  13. 75 FR 10446 - Minority and Women Inclusion

    Science.gov (United States)

    2010-03-08

    ... 2590-AA28 Minority and Women Inclusion AGENCIES: Federal Housing Finance Board; Federal Housing Finance... minority and women inclusion. Section 1116 of the Housing and Economic Recovery Act of 2008 amended section... Loan Banks to promote diversity and the inclusion of women and minorities in all activities...

  14. Teachers' Experience with Inclusive Education in Singapore

    Science.gov (United States)

    Yeo, Lay See; Chong, Wan Har; Neihart, Maureen F.; Huan, Vivien S.

    2016-01-01

    Teachers' positive attitude is most critically and consistently associated with successful inclusion. However, little is known about teachers' first-hand encounters with inclusive education in Singapore. We present findings from a qualitative study on inclusion based on focus group interviews with 202 teachers from 41 resourced primary schools.…

  15. "Inclusion in Practice": Does Practice Make Perfect?

    Science.gov (United States)

    Slee, Roger

    2001-01-01

    Discusses four issues raised in this special issue: (1) problems with the term "inclusion"; (2) reductionist approaches to inclusive education; (3) politics of special education research and the need to include parent and student voices; and (4) preparation of teachers for inclusive education. (Contains 53 references.) (SK)

  16. Inclusive Classes in Physical Education: Teachers' Difficulties

    Science.gov (United States)

    Toloi, Gabriela Gallucci; Manzini, Eduardo José; Spoldaro, Diego Machado; Zacarias, Lucas Ventura

    2016-01-01

    The successful inclusion of students with special needs in physical education classes requires much planning and preparation. Lack of preparation of physical education teachers working in inclusive settings in Brazil has demonstrated the need for specialized training in strategies for implementing inclusion. The goal of this study was to identify,…

  17. Ultrastructural cytochemical analysis of intranuclear arsenic inclusions

    Energy Technology Data Exchange (ETDEWEB)

    Sorensen, E.M.B.

    1987-01-01

    To establish the chemical composition of the arsenic inclusion, freshly isolated preparations of inclusions and epon-embedded thin sections of inclusions were subjected to ultrastructural cytochemical analysis. Intranuclear inclusions are composed of amorphous, arsenic-containing subunits aligned linearly to form a coiled complex. Lipase, ribonuclease, deoxyribonuclease, trypsin, pepsin, protease, amylase, or ethylenediaminetetraacetic acid (EDTA) was used to digest or chelate these inclusions. Following enzymatic digestion or chelation, the electron opacity of inclusions was compared with that of control sections exposed for equal times to equivalent solutions lacking the enzymes. Exposure to amylase caused a consistent reduction in the electron opacity of thin sections of inclusions and almost complete digestion of the freshly isolated preparations of inclusions. This was indicative of the presence of a carbohydrate moiety within arsenic inclusions. Incubation of inclusions with EDTA resulted in solubilization of freshly isolated and thin-sectioned embedded material. These data indicated that the intranuclear arsenic inclusion is composed of both metallic and carbohydrate moieties, confirming earlier studies which identified arsenic within inclusions using instrumental neutron activation analysis and x-ray microprobe analysis.

  18. Full averaging of fuzzy impulsive differential inclusions

    Directory of Open Access Journals (Sweden)

    Natalia V. Skripnik

    2010-09-01

    Full Text Available In this paper the substantiation of the method of full averaging for fuzzy impulsive differential inclusions is studied. We extend the similar results for impulsive differential inclusions with Hukuhara derivative (Skripnik, 2007, for fuzzy impulsive differential equations (Plotnikov and Skripnik, 2009, and for fuzzy differential inclusions (Skripnik, 2009.

  19. Elements of Inclusion: Findings from the Field

    Science.gov (United States)

    McMaster, Christopher

    2014-01-01

    The Ministry of Education has set the target of 100% of New Zealand schools to be "mostly" inclusive by 2014. But what are the essential elements of inclusion? This paper explores essential core elements that allow inclusion to flourish. Based on an extensive time in the field as part of a year-long doctoral research project, these…

  20. Curcumin-Hydroxypropyl-β-Cyclodextrin Inclusion Complex ...

    African Journals Online (AJOL)

    Purpose: To evaluate the effect of the preparation method on the inclusion complex of curcumin and hydroxypropyl-β-cyclodextrin Methods: HP-β-CD was selected to prepare an inclusion complex with curcumin at a molar ratio of 1:1. The inclusion complexes were prepared using three different methods: common solvent ...