164 research outputs found
Residual stress of as-deposited and rolled Wire + Arc Additive Manufacturing Ti–6Al–4V components
Wire + arc additive manufacturing components contain significant residual stresses, which manifest in distortion. High-pressure rolling was applied to each layer of a linear Ti–6Al–4V wire + arc additive manufacturing component in between deposition passes. In rolled specimens, out-of-plane distortion was more than halved; a change in the deposits' geometry due to plastic deformation was observed and process repeatability was increased. The Contour method of residual stresses measurements showed that although the specimens still exhibited tensile stresses (up to 500 MPa), their magnitude was reduced by 60%, particularly at the interface between deposit and substrate. The results were validated with neutron diffraction measurements, which were in good agreement away from the baseplate
Achieving Sustainable Phosphorus Use in Food Systems through Circularisation
Publication history: Accepted - 28 May 2018; Published - 30 May 2018.The notion of a phosphorus (P) circular economy provides the philosophy, framework,
and opportunity to enable food production systems to become more efficient, sustainable,
and resilient to a future P scarcity or sudden price shock. Whilst P recovery and recycling are central
strategies for closing the P cycle, additional gains in environmental performance of food systems
can be obtained by further minimising the amounts of P (a) introduced into the food system by
lowering system P demand and (b) lost from the system by utilising legacy P stores in the landscape.
This minimisation is an important cascading component of circularisation because it reduces the
amounts of P circulating in the system, the amounts of P required to be recycled/recovered and
the storage of unused P in the landscape, whilst maintaining agricultural output. The potential
for circularisation and minimisation depends on regional differences in these P flow dynamics.
We consider incremental and transformative management interventions towards P minimisation
within circular economies, and how these might be tempered by the need to deliver a range of
ecosystem services. These interventions move away from current production philosophies based on
risk-averse, insurance-based farming, and current consumption patterns which have little regard
for their environmental impact. We argue that a greater focus on P minimisation and circularisation
should catalyse different actors and sectors in the food chain to embrace P sustainability and should
empower future research needs to provide the confidence for them to do so without sacrificing future
regional food security.This paper was produced as part of the RePhoKUs project (The role of phosphorus in the
sustainability and resilience of the UK food system) funded by BBSRC, ESRC, NERC, and the Scottish Government
under the UK Global Food Security research programme (Grant No. BB/R005842/1)
OGA Inhibition By GlcNAc-Selenazoline
The title compound, which differs from the powerful O-GlcNAcase (OGA) inhibitor GlcNAc-thiazoline only at the chalcogen atom (Se for S), is a much weaker inhibitor in a direct OGA assay. In human cells, however, the selenazoline shows comparable ability to induce hyper-O-GlcNAc-ylation, and the two show similar reduction of insulin-stimulated translocation of glucose transporter 4 in differentiated 3T3 adipocytes. (C) 2010 Elsevier Ltd. All rights reserved
Molecules incorporating a benzothiazole core scaffold inhibit the N-myristoyltransferase of Plasmodium falciparum.
Recombinant N-myristoyltransferase of Plasmodium falciparum (termed PfNMT) has been used in the development of a SPA (scintillation proximity assay) suitable for automation and high-throughput screening of inhibitors against this enzyme. The ability to use the SPA has been facilitated by development of an expression and purification system which yields considerably improved quantities of soluble active recombinant PfNMT compared with previous studies. Specifically, yields of pure protein have been increased from 12 microg x l(-1) to >400 microg x l(-1) by use of a synthetic gene with codon usage optimized for expression in an Escherichia coli host. Preliminary small-scale 'piggyback' inhibitor studies using the SPA have identified a family of related molecules containing a core benzothiazole scaffold with IC50 values 80% at a concentration of 10 microM
Molecular determinants of binding to the Plasmodium subtilisin-like protease 1.
PfSUB1, a subtilisin-like protease of the human malaria parasite Plasmodium falciparum, is known to play important roles during the life cycle of the parasite and has emerged as a promising antimalarial drug target. In order to provide a detailed understanding of the origin of binding determinants of PfSUB1 substrates, we performed molecular dynamics simulations in combination with MM-GBSA free energy calculations using a homology model of PfSUB1 in complex with different substrate peptides. Key interactions, as well as residues that potentially make a major contribution to the binding free energy, are identified at the prime and nonprime side of the scissile bond and comprise peptide residues P4 to P2'. This finding stresses the requirement for peptide substrates to interact with both prime and nonprime side residues of the PfSUB1 binding site. Analyzing the energetic contributions of individual amino acids within the peptide-PfSUB1 complexes indicated that van der Waals interactions and the nonpolar part of solvation energy dictate the binding strength of the peptides and that the most favorable interactions are formed by peptide residues P4 and P1. Hot spot residues identified in PfSUB1 are dispersed over the entire binding site, but clustered areas of hot spots also exist and suggest that either the S4-S2 or the S1-S2' binding site should be exploited in efforts to design small molecule inhibitors. The results are discussed with respect to which binding determinants are specific to PfSUB1 and, therefore, might allow binding selectivity to be obtained
Prediction of storm transfers and annual loads with data-based mechanistic models using high-frequency data
Excess nutrients in surface waters, such as phosphorus (P) from agriculture, result in poor water quality, with adverse effects on ecological health and costs for remediation. However, understanding and prediction of P transfers in catchments have been limited by inadequate data and over-parameterised models with high uncertainty. We show that, with high temporal resolution data, we are able to identify simple dynamic models that capture the P load dynamics in three contrasting agricultural catchments in the UK. For a flashy catchment, a linear, second-order (two pathways) model for discharge gave high simulation efficiencies for short-term storm sequences and was useful in highlighting uncertainties in out-of-bank flows. A model with nonlinear rainfall input was appropriate for predicting seasonal or annual cumulative P loads where antecedent conditions affected the catchment response. For second-order models, the time constant for the fast pathway varied between 2 and 15 h for all three catchments and for both discharge and P, confirming that high temporal resolution data are necessary to capture the dynamic responses in small catchments (10–50 km2/. The models led to a better understanding of the dominant nutrient transfer modes, which will be helpful in determining phosphorus transfers following changes in precipitation patterns in the future
Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.
BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/principal findingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.ConclusionGiven the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans
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