A reaction-diffusion model for the hydration/setting of cement

We propose a heterogeneous reaction-diffusion model for the hydration and setting of cement. The model is based on diffusional ion transport and on cement specific chemical dissolution/precipitation reactions under spatial heterogeneous solid/liquid conditions. We simulate the spatial and temporal evolution of precipitated micro structures starting from initial random configurations of anhydrous cement particles. Though the simulations have been performed for two dimensional systems, we are able to reproduce qualitatively basic features of the cement hydration problem. The proposed model is also applicable to general water/mineral systems.Comment: REVTeX (12 pages), 4 postscript figures, tarred, gzipped, uuencoded using `uufiles', coming with separate file(s). Figure 1 consists of 6 color plates; if you have no color printer try to send it to a black&white postscript-plotte

Nature and regulation of protein folding on the ribosome

Co-translational protein folding is an essential process by which cells ensure the safe and efficient production and assembly of new proteins in their functional native states following biosynthesis on the ribosome. In this review, we describe recent progress in probing the changes during protein synthesis of the free energy landscapes that underlie co-translational folding and discuss the critical coupling between these landscapes and the rate of translation that ultimately determines the success or otherwise of the folding process. Recent developments have revealed a variety of mechanisms by which both folding and translation can be modulated or regulated, and we discuss how these effects are utilised by the cell to optimise the outcome of protein biosynthesis. [Abstract copyright: Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

The release of toxic oligomers from a-synuclein fibrils induces dysfunction in neuronal cells

The self-assembly of a-synuclein (aS) into intraneuronal inclusion bodies is a key characteristic of Parkinson’s disease. To define the nature of the species giving rise to neuronal damage, we have investigated the mechanism of action of the main aS populations that have been observed to form progressively during fibril growth. The aS fibrils release soluble prefibrillar oligomeric species with cross-ß structure and solvent-exposed hydrophobic clusters. aS prefibrillar oligomers are efficient in crossing and permeabilize neuronal membranes, causing cellular insults. Short fibrils are more neurotoxic than long fibrils due to the higher proportion of fibrillar ends, resulting in a rapid release of oligomers. The kinetics of released aS oligomers match the observed kinetics of toxicity in cellular systems. In addition to previous evidence that aS fibrils can spread in different brain areas, our in vitro results reveal that aS fibrils can also release oligomeric species responsible for an immediate dysfunction of the neurons in the vicinity of these species

Amyloid-ß and a-Synuclein Decrease the Level of Metal-Catalyzed Reactive Oxygen Species by Radical Scavenging and Redox Silencing

The formation of reactive oxygen species (ROS) is linked to the pathogenesis of neurodegenerative diseases. Here we have investigated the effect of soluble and aggregated amyloid-ß (Aß) and a-synuclein (aS), associated with Alzheimer''s and Parkinson''s diseases, respectively, on the Cu2+-catalyzed formation of ROS in vitro in the presence of a biological reductant. We find that the levels of ROS, and the rate by which ROS is generated, are significantly reduced when Cu2+ is bound to Aß or aS, particularly when they are in their oligomeric or fibrillar forms. This effect is attributed to a combination of radical scavenging and redox silencing mechanisms. Our findings suggest that the increase in ROS associated with the accumulation of aggregated Aß or aS does not result from a particularly ROS-active form of these peptides, but rather from either a local increase of Cu2+ and other ROS-active metal ions in the aggregates or as a downstream consequence of the formation of the pathological amyloid structures

Hsp70 oligomerization is mediated by an interaction between the interdomain linker and the substrate-binding domain

Oligomerization in the heat shock protein (Hsp) 70 family has been extensively documented both in vitro and in vivo, although the mechanism, the identity of the specific protein regions involved and the physiological relevance of this process are still unclear. We have studied the oligomeric properties of a series of human Hsp70 variants by means of nanoelectrospray ionization mass spectrometry, optical spectroscopy and quantitative size exclusion chromatography. Our results show that Hsp70 oligomerization takes place through a specific interaction between the interdomain linker of one molecule and the substrate-binding domain of a different molecule, generating dimers and higher-order oligomers. We have found that substrate binding shifts the oligomerization equilibrium towards the accumulation of functional monomeric protein, probably by sequestering the helical lid sub-domain needed to stabilize the chaperone: substrate complex. Taken together, these findings suggest a possible role of chaperone oligomerization as a mechanism for regulating the availability of the active monomeric form of the chaperone and for the control of substrate binding and release

On the global hydration kinetics of tricalcium silicate cement

We reconsider a number of measurements for the overall hydration kinetics of tricalcium silicate pastes having an initial water to cement weight ratio close to 0.5. We find that the time dependent ratio of hydrated and unhydrated silica mole numbers can be well characterized by two power-laws in time, $x/(1-x)\sim (t/t_x)^\psi$. For early times $t < t_x$ we find an `accelerated' hydration ($\psi = 5/2$) and for later times $t > t_x$ a `deaccelerated' behavior ($\psi = 1/2$). The crossover time is estimated as $t_x \approx 16 hours$. We interpret these results in terms of a global second order rate equation indicating that (a) hydrates catalyse the hydration process for $t<t_x$, (b) they inhibit further hydration for $t > t_x$ and (c) the value of the associated second order rate constant is of magnitude 6x10^{-7} - 7x10^{-6} liter mol^{-1} s^{-1}. We argue, by considering the hydration process actually being furnished as a diffusion limited precipitation that the exponents $\psi = 5/2$ and $\psi = 1/2$ directly indicate a preferentially `plate' like hydrate microstructure. This is essentially in agreement with experimental observations of cellular hydrate microstructures for this class of materials.Comment: RevTeX macros, 6 pages, 4 postscript figure

Retailing in the United Kingdom - a synopsis

This paper illustrates the structure of, and trends in, the retail market of the United Kingdom (UK). This industry analysis describes the retail environment compared to continental Europe and considers the regulatory issues which have helped form this retail environment. By using secondary data we describe concentration and consolidation tendencies and explain specific features of the UK retail market. Major trends are identified and discussed, concluding with an outlook on future developments

Protein sequence and structure: Is one more fundamental than the other?

We argue that protein native state structures reside in a novel "phase" of matter which confers on proteins their many amazing characteristics. This phase arises from the common features of all globular proteins and is characterized by a sequence-independent free energy landscape with relatively few low energy minima with funnel-like character. The choice of a sequence that fits well into one of these predetermined structures facilitates rapid and cooperative folding. Our model calculations show that this novel phase facilitates the formation of an efficient route for sequence design starting from random peptides.Comment: 7 pages, 4 figures, to appear in J. Stat. Phy

Viral discovery and diversity in trypanosomatid protozoa with a focus on relatives of the human parasite <i>Leishmania</i>.

Knowledge of viral diversity is expanding greatly, but many lineages remain underexplored. We surveyed RNA viruses in 52 cultured monoxenous relatives of the human parasite &lt;i&gt;Leishmania&lt;/i&gt; ( &lt;i&gt;Crithidia&lt;/i&gt; and &lt;i&gt;Leptomonas&lt;/i&gt; ), as well as plant-infecting &lt;i&gt;Phytomonas&lt;/i&gt; &lt;i&gt;Leptomonas pyrrhocoris&lt;/i&gt; was a hotbed for viral discovery, carrying a virus (Leptomonas pyrrhocoris ostravirus 1) with a highly divergent RNA-dependent RNA polymerase missed by conventional BLAST searches, an emergent clade of tombus-like viruses, and an example of viral endogenization. A deep-branching clade of trypanosomatid narnaviruses was found, notable as &lt;i&gt;Leptomonas seymouri&lt;/i&gt; bearing Narna-like virus 1 (LepseyNLV1) have been reported in cultures recovered from patients with visceral leishmaniasis. A deep-branching trypanosomatid viral lineage showing strong affinities to bunyaviruses was termed " &lt;i&gt;Leishbunyavirus&lt;/i&gt; " (LBV) and judged sufficiently distinct to warrant assignment within a proposed family termed " &lt;i&gt;Leishbunyaviridae&lt;/i&gt; " Numerous relatives of trypanosomatid viruses were found in insect metatranscriptomic surveys, which likely arise from trypanosomatid microbiota. Despite extensive sampling we found no relatives of the totivirus &lt;i&gt;Leishmaniavirus&lt;/i&gt; (LRV1/2), implying that it was acquired at about the same time the &lt;i&gt;Leishmania&lt;/i&gt; became able to parasitize vertebrates. As viruses were found in over a quarter of isolates tested, many more are likely to be found in the &gt;600 unsurveyed trypanosomatid species. Viral loss was occasionally observed in culture, providing potentially isogenic virus-free lines enabling studies probing the biological role of trypanosomatid viruses. These data shed important insights on the emergence of viruses within an important trypanosomatid clade relevant to human disease

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-ß (Aß) in Alzheimer’s disease and a-synuclein (aS) in Parkinson’s disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of aS, Aß and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases