With the increasing use of self-compacting concrete (SCC) its durability has come into focus. Concerning the microstructure of concrete, the porosity in the interfacial transition zone (ITZ) is ...regarded as a key feature for permeability and durability. Generally, a combination of cement and mineral admixtures is used for the production of SCC. In the present study, ITZ porosity of four SCC mixtures produced with ordinary Portland cement, Portland limestone cement, slag cement and ordinary Portland cement combined with fly ash is analyzed. Additionally, the chloride migration coefficient is determined. ITZ porosity and width of the SCC mixtures are similar. The substantial differences in the chloride migration coefficients show that the binder type has a stronger influence on permeability than the pore volume in the ITZ.
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized histopathologically by the extracellular deposition of beta-amyloid peptide in senile plaques, as well as intracellular ...neurofibrillary tangles (NFT) of hyperphosphorylated tau protein, extensive neuronal loss and synaptic changes in the hippocampus and cerebral cortex. In addition, the AD brain shows chronic inflammation characterized by an abundance of reactive astrocytes and activated microglia. In the healthy brain, astrocytes provide essential services for brain homeostasis and neuronal function, including metabolic support for neurons in the form of lactate, glutamate uptake and conversion into glutamine, and synthesis of glutathione and its precursors. In AD, a large body of evidence now suggests that by transforming from a basal to a reactive state, astrocytes neglect their neurosupportive functions, thus rendering neurons vulnerable to neurotoxins including pro-inflammatory cytokines and reactive oxygen species. This review will explain the normal functions of astrocytes, and how these cells might be activated to turn into inflammatory cells, actively contributing to neurodegeneration and neglecting their neurosupportive roles ("neuro-neglect hypothesis"). Furthermore, it is proposed that astrocytes might be promising target of therapeutic intervention for Alzheimer's disease, if these compromised functions can be normalized with pharmacological agents that are specifically designed to return astrocytes to a quiescent phenotype or supplement factors which activated astrocytes lack to produce.
FIB‐nanotomography (FIB‐nt) is applied to record high‐resolution 3D pore networks from cementitious materials. Based on these data, it is examined as to why the pore size distribution (PSD), which is ...obtained from traditional analysis by mercury intrusion porosimetry (MIP), principally deviates from the findings that are achieved by common back‐scattered electron image analysis. The paper does not reflect the vulnerability of the physical model assumptions, but merely focuses on the fundamental issues of the geometrical definition of a PSD. A computationally fast approach for the PSD assessment from 3D data as well as for the simulation of MIP is presented and the varying concepts for the definition of a PSD are compared with each other.
Abstract Alzheimer's disease (AD) is the most common dementing disorder of late life. Although there might be various different triggering events in the early stages of the disease, they seem to ...converge on a few characteristic final pathways in the late stages, characterized by inflammation and neurodegeneration. In this review, we revisit the hypothesis that advanced glycation endproducts (AGEs) and their receptor RAGE may play an important role in disease pathogenesis. Accumulation of AGEs in cells and tissues is a normal feature of aging, but is accelerated in AD. In AD, AGEs can be detected in pathological deposits such as amyloid plaques and neurofibrillary tangles. AGEs explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking, glial induction of oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade. RAGE and its decoy receptor soluble RAGE, may contribute to or protect against AD pathogenesis by influencing transport of β-amyloid into the brain or by manipulating inflammatory mechanisms. Targeted pharmacological interventions using AGE-inhibitors, RAGE-antagonists, RAGE-antibodies, soluble RAGE or RAGE signalling inhibitors such as membrane-permeable antioxidants may be promising therapeutic strategies to slow down the progression of AD.
Through analysis of the Drosophila ionotropic receptors (IRs), a family of variant ionotropic glutamate receptors, we reveal that most IRs are expressed in peripheral neuron populations in diverse ...gustatory organs in larvae and adults. We characterise IR56d, which defines two anatomically-distinct neuron classes in the proboscis: one responds to carbonated solutions and fatty acids while the other represents a subset of sugar- and fatty acid-sensing cells. Mutational analysis indicates that IR56d, together with the broadly-expressed co-receptors IR25a and IR76b, is essential for physiological responses to carbonation and fatty acids, but not sugars. We further demonstrate that carbonation and fatty acids both promote IR56d-dependent attraction of flies, but through different behavioural outputs. Our work provides a toolkit for investigating taste functions of IRs, defines a subset of these receptors required for carbonation sensing, and illustrates how the gustatory system uses combinatorial expression of sensory molecules in distinct neurons to coordinate behaviour.
•At current costs, SOFC is economically convenient only with subsidies.•Germany, Italy and UK seem are the most suitable markets for this technology.•At target costs SOFC becomes the most attractive ...solutions to produce energy.•At target cost, RPBT is 5 years in Italy and Germany and 4 years in UK.•With 1 stack replacement in 15 years, there is a reduction in RPBT up to 7 years.
This work studies the technical and economic feasibility of the introduction of a SOFC-based cogeneration system to supply non-residential buildings with electricity and heat. The techno-economic evaluation is performed for the hotel and hospital sectors, by introducing real hourly load profiles (electrical and thermal) for the buildings. The analysis considers different countries in terms of energy intensity (and load profiles), cost of energy and regulations/incentives. Results are achieved by comparing the SOFC scenario with a benchmark one where electricity is supplied by the grid and heat by a natural gas fed boiler and evaluating the relative payback time between the two solutions.
The analysis showed that, despite the current high investment cost of the SOFC system, in countries such as Germany, Italy and UK (where electricity prices are among the highest in Europe), the option is yet advisable if supported by effective subsidies (already existing for cogeneration systems), and it could offer a competitive alternative to traditional systems, especially in the hospital sector, where the relative payback time is achieved in the 10th year for UK, and in the 14th year for Germany and Italy. A cost reduction scenario has also been analyzed: results show that the SOFC is the best option in most of the locations, both economically and in terms of environmental impact (pollutants emissions reduction).
Abstract
Neointima hyperplasia is a crucial component of restenosis after coronary angioplasty. We have hypothesized that enhanced generation of platelet-derived thromboxane (TX)A
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in response to ...vascular damage plays a critical role in neointimal hyperplasia and that antiplatelet agents may mitigate it. In cocultures of human platelets and coronary artery smooth muscle cells (CASMC), we found that platelets induced morphologic changes and enhanced the migration of CASMC. The exposure of platelets to Aspirin an inhibitor of cyclooxygenase (COX)-1 reduced the generation of TXA
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and prevented the morphological and functional changes induced by platelets in CASMC. Platelet-derived TXA
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induced COX-2 and enhanced prostaglandin (PG)E
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biosynthesis in CASMC, a known mechanism promoting neointimal hyperplasia. COX-2 induction was prevented by different antiplatelet agents, i.e., Aspirin, the TP antagonist SQ29,548, or Revacept (a dimeric soluble GPVI-Fc fusion protein). The administration of the novel antiplatelet agent Revacept to C57BL/6 mice, beginning three days before femoral artery denudation, and continuing up to seven days after injury, prevented the increase of the systemic biosynthesis di TXA
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and reduced femoral artery intima-to-media area and the levels of markers of cell proliferation and macrophage infiltration. Revacept might serve as a therapeutic agent for percutaneous coronary angioplasty and stent implantation.
Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) after sensing viral/bacterial RNA or DNA by toll-like receptor (TLR) 7 or TLR9, respectively. However, aberrant pDCs activation ...can cause adverse effects on the host and contributes to the pathogenesis of type I IFN-related autoimmune diseases. Here, we show that heparin interacts with the human pDCs-specific blood dendritic cell antigen 2 (BDCA-2) but not with related lectins such as DCIR or dectin-2. Importantly, BDCA-2-heparin interaction depends on heparin sulfation and receptor glycosylation and results in inhibition of TLR9-driven type I IFN production in primary human pDCs and the pDC-like cell line CAL-1. This inhibition is mediated by unfractionated and low-molecular-weight heparin, as well as endogenous heparin from plasma, suggesting that the local blood environment controls the production of IFN-α in pDCs. Additionally, we identified an activation-dependent soluble form of BDCA-2 (solBDCA-2) in human plasma that functions as heparin antagonist and thereby increases TLR9-driven IFN-α production in pDCs. Of importance, solBDCA-2 levels in the serum were increased in patients with scrub typhus (an acute infectious disease caused by
) compared to healthy control subjects and correlated with anti-dsDNA antibodies titers. In contrast, solBDCA-2 levels in plasma from patients with bullous pemphigoid or psoriasis were reduced. In summary, this work identifies a regulatory network consisting of heparin, membrane-bound and solBDCA-2 modulating TLR9-driven IFN-α production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs-related autoimmune diseases.
We have recently developed a retargeting system for lentiviral vectors (LVs) that relies on the pseudotyping of LVs with engineered measles virus (MV) glycoproteins (hemagglutinin (H) and fusion ...protein (F)). Specificity is provided through display of a single-chain antibody (scFv) as targeting domain by fusion to the MV-H protein. As an alternative to scFv, designed ankyrin repeat proteins (DARPins) can be selected to become high-affinity binders to any kind of target molecule. In this study six HER2/neu-specific DARPins exhibiting different affinities and binding to different HER2/neu epitopes were applied as targeting domains. All H-DARPin fusion proteins were efficiently expressed on the cell surface. Upon coexpression with F, syncytia formation was observed in HER2/neu positive cells only and correlated directly with the HER2/neu receptor density. All H-DARPin proteins incorporated into LVs, albeit at different levels. The vectors only transduced HER2/neu-positive cells, while HER2/neu-negative cells remained untransduced. Highest titers were observed with one particular DARPin binding to the membrane distal domain of HER2/neu with medium affinity. When applied in vivo systemically, HER2/neu-targeted LVs showed exclusive gene expression in HER2/neu positive tumor tissue, while vesicular stomatitis virus-glycoprotein (VSV-G) pseudotyped vectors mainly transduced cells in spleen and liver. Thus, DARPins are a promising alternative to scFvs for retargeting of LVs.
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