Capillarity in pressure infiltration: improvements in characterization of high-temperature systems

In the pressure infiltration of metal matrix composites, molten metal is injected under external pressure into a porous preform of the reinforcing material. Equilibrium capillary parameters characterizing wetting for this process are summarized in plots of metal saturation versus applied pressure, also known as drainage curves. Such curves can be measured in our laboratory during a single experiment with an infiltration apparatus designed to track the rate of metal penetration into porous preforms under conditions characteristic of metal matrix composite processing (temperatures in excess of 1000°C and pressures in the order of 10MPa). For such measurements to be valid, infiltration of the preform with molten metal must be mechanically quasi-static, i.e., the metal must flow at a rate sufficiently low for the metal pressure to be essentially uniform across the preform at all times. We examine this requirement quantitatively, using a finite-difference model that simulates the unsaturated unidirectional ingress of molten metal into a ceramic particle preform of finite width. We furthermore present improvements in the experimental apparatus developed in our laboratory to measure the entire drainage curve in a single experiment. We compare numerical results with new experimental data for the copper/alumina system to show (i) that pressurization rates sufficiently low for quasi-static infiltration can be produced with this apparatus, and (ii) that taking the relative permeability equal to the saturation yields better agreement with experiment than does the expression originally proposed by Brooks and Core

Antiplasmodial Activity of Nitroaromatic Compounds : Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase

With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against the malaria parasite Plasmodium falciparum, we examined the single-electron reduction by P. falciparum ferredoxin:NADP+ oxidoreductase (PfFNR) of a series of nitrofurans and nitrobenzenes (n = 23), and their ability to inhibit P. falciparum glutathione reductase (PfGR). The reactivity of nitroaromatics in PfFNR-catalyzed reactions increased with their single-electron reduction midpoint potential (E17). Nitroaromatic compounds acted as non- or uncompetitive inhibitors towards PfGR with respect to NADPH and glutathione substrates. Using multiparameter regression analysis, we found that the in vitro activity of these compounds against P. falciparum strain FcB1 increased with their E17 values, octanol/water distribution coefficients at pH 7.0 (log D), and their activity as PfGR inhibitors. Our data demonstrate that both factors, the ease of reductive activation and the inhibition of PfGR, are important in the antiplasmodial in vitro activity of nitroaromatics. To the best of our knowledge, this is the first quantitative demonstration of this kind of relationship. No correlation between antiplasmodial activity and ability to inhibit human erythrocyte GR was detected in tested nitroaromatics. Our data suggest that the efficacy of prooxidant antiparasitic agents may be achieved through their combined action, namely inhibition of antioxidant NADPH:disulfide reductases, and the rapid reduction by single-electron transferring dehydrogenases-electrontransferases

Induction of Proinflammatory Multiple Sclerosis-Associated Retrovirus Envelope Protein by Human Herpesvirus-6A and CD46 Receptor Engagement

The aberrant expression of human endogenous retrovirus (HERV) elements of the HERV-W family has been associated with different diseases, including multiple sclerosis (MS). In particular, the expression of the envelope protein (Env) from the multiple sclerosis-associated retrovirus (MSRV), a member of HERV-W family and known for its potent proinflammatory activity, is repeatedly detected in the brain lesions and blood of MS patients. Furthermore, human herpesvirus 6 (HHV-6) infection has long been suspected to play a role in the pathogenesis of MS and neuroinflammation. We show here that both HHV-6A and stimulation of its receptor, transmembrane glycoprotein CD46, induce the expression of MSRV-Env. The engagement of extracellular domains SCR3 and SCR4 of CD46-Cyt1 isoform was required for MSRV-env transactivation, limiting thus the MSRV-Env induction to the CD46 ligands binding these domains, including C3b component of complement, specific monoclonal antibodies, and both infectious and UV-inactivated HHV-6A, but neither HHV-6B nor measles virus vaccine strain. Induction of MSRV-Env required CD46 Cyt-1 singling and was abolished by the inhibitors of protein kinase C. Finally, both membrane-expressed and secreted MSRV-Env trigger TLR4 signaling, displaying thus a proinflammatory potential, characteristic for this viral protein. These data expand the specter of HHV-6A effects in the modulation of the immune response and support the hypothesis that cross-talks between exogenous and endogenous viruses may contribute to inflammatory diseases and participate in neuroinflammation. Furthermore, they reveal a new function of CD46, known as an inhibitor of complement activation and receptor for several pathogens, in transactivation of HERV env genes, which may play an important role in the pathogenesis of inflammatory diseases

Recent Duplication and Functional Divergence in Parasitic Nematode Levamisole-Sensitive Acetylcholine Receptors

Helminth parasites rely on fast-synaptic transmission in their neuromusculature to experience the outside world and respond to it. Acetylcholine plays a pivotal role in this and its receptors are targeted by a wide variety of both natural and synthetic compounds used in human health and for the control of parasitic disease. The model, Caenorhabditis elegans is characterized by a large number of acetylcholine receptor subunit genes, a feature shared across the nematodes. This dynamic family is characterized by both gene duplication and loss between species. The pentameric levamisole-sensitive acetylcholine receptor has been characterized from C. elegans, comprised of five different subunits. More recently, cognate receptors have been reconstituted from multiple parasitic nematodes that are found to vary in subunit composition. In order to understand the implications of receptor composition change and the origins of potentially novel drug targets, we investigated a specific example of subunit duplication based on analysis of genome data for 25 species from the 50 helminth genome initiative. We found multiple independent duplications of the unc-29, acetylcholine receptor subunit, where codon substitution rate analysis identified positive, directional selection acting on amino acid positions associated with subunit assembly. Characterization of four gene copies from a model parasitic nematode, Haemonchus contortus, demonstrated that each copy has acquired unique functional characteristics based on phenotype rescue of transgenic C. elegans and electrophysiology of receptors reconstituted in Xenopus oocytes. We found evidence that a specific incompatibility has evolved for two subunits co-expressed in muscle. We demonstrated that functional divergence of acetylcholine receptors, driven by directional selection, can occur more rapidly than previously thought and may be mediated by alteration of receptor assembly. This phenomenon is common among the clade V parasitic nematodes and this work provides a foundation for understanding the broader context of changing anthelmintic drug targets across the parasitic nematodes

Clinical trials in children: Equity, quality and relevance

This thesis investigates the equity, quality and relevance of clinical trials in children to inform better evidence-based child healthcare and outcomes worldwide. A comprehensive review of the literature revealed that despite current initiatives to encourage more trials in children, there is still a paucity of safety and efficacy data of many medicines prescribed in this population. An analysis of trials registered in children showed that disease burden was moderately correlated to trials and this scarcity was particularly prevalent in low-and middle-income countries. We explored the contributory factors to this inequity by conducting a systematic review of stakeholders’ views of trials in children in low-and middle-income countries. In the study evaluating the completeness of protocols of trials in children submitted to ethics committees, we found that protocols are generally comprehensive, but many key domains in trial design and conduct are not reported. Key-informant trial stakeholders who were interviewed proposed strategies to improve trials such as addressing the unique needs of children, embedding trials as part of routine clinical care and streamlining regulatory approvals. Increasing international collaboration, establishing sustainable centralised trials infrastructure, and aligning research to child health priorities were proposed to encourage more high-quality trials that address global child healthcare needs

Correction: Thioredoxin Glutathione Reductase from Schistosoma mansoni: An Essential Parasite Enzyme and a Key Drug Target

Correction: Thioredoxin Glutathione Reductase from Schistosoma mansoni: An Essential Parasite Enzyme and a Key Drug Targe

Thioredoxin Glutathione Reductase from Schistosoma mansoni: An Essential Parasite Enzyme and a Key Drug Target

Using both genetic and biochemical approaches, David Williams and colleagues show that the parasite thioredoxin glutathione reductase meets all the major criteria to be a key target for antischistosomal chemotherapy

Bathyraja multispinis, Multispine Skate

The Multispine Skate (Bathyraja multispinis) is a medium-sized (to 126 cm total length) skate that occurs in the Southeast Pacific Ocean from Coquimbo, Chile to Cape Horn and in the Southwest Atlantic Ocean from Santa Catarina, Brazil to Tierra del Fuego and the Falkland Islands (Malvinas) and is demersal on the continental and insular shelves and slopes at depths of 70-740 m. It is captured in demersal trawl and longline fisheries that operate throughout its range and there is little refuge at depth; it is likely to be retained for sale for human consumption in the Southwest Atlantic, but is discarded dead in the Southeast Pacific. Across its range, skates are typically not recorded or managed at the species level, and there are no estimates of population size. In Argentina, there are no species-specific data, but rays in general declined in catch-per-unit-effort (CPUE) in the 1990s and early 2000s. In the Falkland Islands (Malvinas) target skate fishery, this species showed an either stable or increasing trend in CPUE over the time-series from 1994 to 2013. Overall, due to the level of inadequately managed fisheries it is exposed to, general declines of skates in some parts of its range, and its lack of refuge at depth, balanced with the increase in CPUE in the Falkland Islands (Malvinas), it is suspected that this skate has undergone a population reduction of 20-29% over the past three generations (45 years). Therefore, the Multispine Skate is assessed as Near Threatened, nearly meeting the threshold for Vulnerable A2bd.Fil: Pollom, R.. University Fraser Simon; CanadáFil: Dulvy, N. K.. University Fraser Simon; CanadáFil: Acuña, E.. Universidad Católica del Norte; ChileFil: Bustamante, C.. Universidad de Antofagasta; ChileFil: Charvet, P.. Universidade Federal do Paraná; BrasilFil: Chiaramonte, Gustavo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia". Estación Hidrobiológica de Puerto Quequén (sede Quequén); ArgentinaFil: Cuevas, J. M.. Wildlife Conservation Society; Estados UnidosFil: Herman, K.. Georgia Aquarium; Estados UnidosFil: Paesch, L.. Dirección Nacional de Recursos Acuáticos; UruguayFil: Pompert, J.. No especifíca;Fil: Velez Zuazo, X.. Smithsonian Conservation Biology Institute; Estados Unido

Bathyraja brachyurops, Broadnose Skate

The Broadnose Skate (Bathyraja brachyurops) is a medium-sized (to 125 cm total length) skate that occurs in the Southeast Pacific and Southwest Atlantic Oceans from Biobío, Chile, south around Cape Horn and north to Rio Grande do Sul, Brazil, including the Falkland Islands (Malvinas). It is demersal on the inner continental shelf and upper slope at depths of 28?604 m. This skate is taken as bycatch in inadequately-managed demersal trawl and longline fisheries throughout most of its range. In the Argentina-Uruguay Common Fishing Zone, it is taken as bycatch but recorded with all other coastal skates. Species-specific catch time-series for Argentinian fisheries are unavailable, but overall skate landings were minimal prior to 1994 before rising rapidly and reaching a peak in 2007 and then dropping again until 2017. It is one of the main species captured in the Falkland Islands (Malvinas) multispecies target skate fishery, where the catch-per-unit-effort time-series suggests its relative abundance increased over the period 1994?2013. In Chile, it is a retained bycatch of the commercial longline fishery targeting Yellownose Skate, and in trawl fisheries targeting Chilean Hake and crustaceans. Overall, due to the level of fishing pressure that this skate is exposed to throughout much of its geographic range, its limited refuge at depth, its continued common presence in fisheries catches, and its moderately productive life history that allows it to withstand some fishing pressure, combined with an increasing trend in the Falkland Islands (Malvinas) and declines in skates in general elsewhere in its range, it is suspected that a population reduction of 20-29% has occurred over the past three generations (42 years). Therefore, the Broadnose Skate is assessed as Near Threatened, nearly meeting the threshold under criterion A2bd.Fil: Pollom, R.. University Fraser Simon; CanadáFil: Dulvy, N. K.. University Fraser Simon; CanadáFil: Acuña, E.. Universidad Católica del Norte; ChileFil: Bustamante, C.. Universidad de Antofagasta; ChileFil: Charvet, P.. Universidade Federal do Paraná; BrasilFil: Chiaramonte, Gustavo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia". Estación Hidrobiológica de Puerto Quequén (sede Quequén); ArgentinaFil: Cuevas, J. M.. Wildlife Conservation Society; Estados UnidosFil: Herman, K.. Georgia Aquarium; Estados UnidosFil: Paesch, L.. Dirección Nacional de Recursos Acuáticos; UruguayFil: Pompert, J.. No especifíca;Fil: Velez Zuazo, X.. No especifíca

Dynamical effects in multifragmentation at intermediate energies

The fragmentation of the quasi-projectile is studied with the INDRA multidetector for different colliding systems and incident energies in the Fermi energy range. Different experimental observations show that a large part of the fragmentation is not compatible with the statistical fragmentation of a fully equilibrated nucleus. The study of internal correlations is a powerful tool, especially to evidence entrance channel effects. These effects have to be included in the theoretical descriptions of nuclear multifragmentation.Comment: 13 pages, 26 figures, submitted to Physical Review