The double sheath on cathodes of discharges burning in cathode vapour

The model of a collisionless near-cathode space-charge sheath with ionization of atoms emitted by the cathode surface is considered. Numerical calculations showed that the mathematical problem is solvable and its solution is unique. In the framework of this model, the sheath represents a double layer with a potential maximum, with the ions which are produced before the maximum returning to the cathode surface and those produced after the maximum escaping into the plasma. Numerical results are given in a form to be readily applicable in analysis of discharges burning in cathode vapour, such as vacuum arcs. In particular, the results indicate that the ion backflow coefficient in such discharges exceeds 0.5, in agreement with values extracted from the experiment.info:eu-repo/semantics/publishedVersio

Field to thermo-field to thermionic electron emission: a practical guide to evaluation and electron emission from arc cathodes

This work is concerned with devising a method of evaluation of electron emission in the framework of the Murphy-Good theory, which would be as simple and computationally efficient as possible while being accurate in the full range of conditions of validity of the theory. The method relies on Pad e approximants. A comparative study of electron emission from cathodes of arcs in ambient gas and vacuum arcs is performed with the use of this method. Electron emission from cathodes of arcs in ambient gas is of thermionic nature even for extremely high gas pressures characteristic of projection and automotive arc lamps and is adequately described by the Richardson-Schottky formula. The electron emission from vaporizing (hot) cathodes of vacuum arcs is of thermo-field nature and is adequately described by the Hantzsche fit formula. Since no analytical formulas are uniformly valid for field to thermo-field to thermionic emission, a numerical evaluation of the Murphy-Good formalism is inevitable in cases where a unified description of the full range of conditions is needed, as is the general case of plasma-cathode interaction in vacuum arcs, and the technique proposed in this work may be the method of choice to this end.info:eu-repo/semantics/publishedVersio

Sheath and arc-column voltages in high-pressure arc discharges

Electrical characteristics of a 1 cm-long free-burning atmospheric-pressure argon arc are calculated by means of a model taking into account the existence of a near-cathode space-charge sheath and the discrepancy between the electron and heavy-particle temperatures in the arc column. The computed arc voltage exhibits a variation with the arc current I similar to the one revealed by the experiment and exceeds experimental values by no more than approximately 2 V in the current range 20–175 A. The sheath contributes about two-thirds or more of the arc voltage. The LTE model predicts a different variation of the arc voltage with I and underestimates the experimental values appreciably for low currents but by no more than approximately 2 V for I 120 A. However, the latter can hardly be considered as a proof of unimportance of the space-charge sheath at high currents: the LTE model overestimates both the resistance of the bulk of the arc column and the resistance of the part of the column that is adjacent to the cathode, and this overestimation to a certain extent compensates for the neglect of the voltage drop in the sheath. Furthermore, if the latter resistance were evaluated in the framework of the LTE model in an accurate way, then the overestimation would be still much stronger and the obtained voltage would significantly exceed those observed in the experiment.info:eu-repo/semantics/publishedVersio

Mixing Aβ(1-40) and Aβ(1-42) peptides generates unique amyloid fibrils

Recent structural studies show distinct morphologies for the fibrilsof Ab(1-42) and Ab(1-40), which are believed not to co-fibrillize.We describe here a novel, structurally-uniform 1 : 1 mixed fibrillarspecies, which differs from bothpure fibrils. It forms preferen-tially even when Ab(1-42) : Ab(1-40) peptides are mixed in a non-stoichiometric ratio

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA

Lipocalin 2 modulates the cellular response to amyloid beta

The production, accumulation and aggregation of amyloid beta (Aß) peptides in Alzheimer's disease (AD) are influenced by different modulators. Among these are iron and iron-related proteins, given their ability to modulate the expression of the amyloid precursor protein and to drive Aß aggregation. Herein, we describe that lipocalin 2 (LCN2), a mammalian acute-phase protein involved in iron homeostasis, is highly produced in response to Aß1-42 by choroid plexus epithelial cells and astrocytes, but not by microglia or neurons. Although Aß1-42 stimulation decreases the dehydrogenase activity and survival of wild-type astrocytes, astrocytes lacking the expression of Lcn2 are not affected. This protection results from a lower expression of the proapoptotic gene Bim and a decreased inflammatory response. Altogether, these findings show that Aß toxicity to astrocytes requires LCN2, which represents a novel mechanism to target when addressing AD.Cell Death and Differentiation advance online publication, 23 May 2014; doi:10.1038/cdd.2014.68.We thank Dr. Ioannis Sotiropoulos for reagents and comments. Sandro Da Mesquita and Ana Catarina Ferreira are recipients of PhD fellowships and Fernanda Marques is recipient of a postdoctoral fellowship by the Fundacao para a Ciencia e Tecnologia (FCT, Portugal)/FEDER. This work was supported by a grant from FCT/FEDER (EXPL/NEUOSD/2196/2013)

De novo design of a biologically active amyloid

Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic amyloid peptide, based on an amyloidogenic fragment of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that is not associated to amyloidosis. Vascin recapitulates key biophysical and biochemical characteristics of natural amyloids, penetrates cells, and seeds the aggregation of VEGFR2 through direct interaction. We found that amyloid toxicity is observed only in cells that both express VEGFR2 and are dependent on VEGFR2 activity for survival. Thus, amyloid toxicity here appears to be both protein-specific and conditional—determined by VEGFR2 loss of function in a biological context in which target protein function is essential.This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 Framework Programme, ERC grant agreement 647458 (MANGO) to J.S. The Switch Laboratory was supported by grants from VIB, Industrial Research Funds of KU Leuven (IOF), the Funds for Scientific Research Flanders (FWO), the Flanders Institute for Science and Technology (IWT), and the Federal Office for Scientific Affairs of Belgium (Belspo), IUAP P7/16. G.V.V., F.D.S., and F.C. were supported by postdoctoral fellowships of FWO. G.V.V. was also supported by KU Leuven competitive funding (PF/10/014). L.Y. is funded by a Wellcome Trust Institutional Strategic Support Fund (ISSF) (grant 015615/Z/14/Z). The Synapt high-definition mass spectroscopy mass spectrometer was purchased with funds from the Biotechnology and Biological Sciences Research Council through its Research Equipment Initiative scheme (BB/E012558/1). The Linköping University laboratories were supported by The Göran Gustafsson Foundation, The Swedish Research Council, and The Swedish Alzheimer Foundation. P.C. was supported by FWO, Methusalem funding by the Flemish government, and an AXA Research grant. M.K. is supported by a Marie Skłodowska-Curie Individual Fellowship under the European Union’s Horizon 2020 Framework Programme (grant H2020-MSCA-IF-2014-ST). C.V. was supported by the KU Leuven Stem Cell Programme. F.R. and J.S. are inventors on patent applications WO2007/071789 and WO2012/123419 submitted by VIB vzw, Belgium, that covers the use of targeted protein aggregation for therapeutic or biotechnological applications

Modulation of γ-Secretase Activity by Multiple Enzyme-Substrate Interactions: Implications in Pathogenesis of Alzheimer's Disease

BACKGROUND: We describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease γ-secretase, from the initial interaction with its C99 substrate to the final release of toxic Aβ peptides. RESULTS: The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest Aβ42/Aβ40 ratio is observed in pre-steady-state when Aβ40 is the dominant product. Aβ42 is produced after Aβ40, and therefore Aβ42 is not a precursor for Aβ40. The longer more hydrophobic Aβ products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of γ-secretase with its C99 substrate leads to 30% decrease in Aβ40 with concomitant increase in the longer Aβ products and Aβ42/Aβ40 ratio. To different degree the same changes in Aβ products can be observed with two mutations that lead to an early onset of AD, ΔE9 and G384A. Four different lines of evidence show that γ-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, NotchΔE substrate can activate or inhibit γ-secretase activity on C99 substrate. Multiple C99 molecules bound to γ-secretase can affect processive cleavages of the nascent Aβ catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded Aβ-bundles. CONCLUSIONS: Gradual saturation of γ-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of γ-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded Aβ-bundles generated by γ-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis