1,810 research outputs found

    Discrimination of Potent Inhibitors of Toxoplasma gondii Enoyl-Acyl Carrier Protein Reductase by a Thermal Shift Assay

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    Many microbial pathogens rely on a type II fatty acid synthesis (FASII) pathway that is distinct from the type I pathway found in humans. Enoyl-acyl carrier protein reductase (ENR) is an essential FASII pathway enzyme and the target of a number of antimicrobial drug discovery efforts. The biocide triclosan is established as a potent inhibitor of ENR and has been the starting point for medicinal chemistry studies. We evaluated a series of triclosan analogues for their ability to inhibit the growth of Toxoplasma gondii, a pervasive human pathogen, and its ENR enzyme (TgENR). Several compounds that inhibited TgENR at low nanomolar concentrations were identified but could not be further differentiated because of the limited dynamic range of the TgENR activity assay. Thus, we adapted a thermal shift assay (TSA) to directly measure the dissociation constant (Kd) of the most potent inhibitors identified in this study as well as inhibitors from previous studies. Furthermore, the TSA allowed us to determine the mode of action of these compounds in the presence of the reduced nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide (NAD+) cofactor. We found that all of the inhibitors bind to a TgENR–NAD+ complex but that they differed in their dependence on NAD+ concentration. Ultimately, we were able to identify compounds that bind to the TgENR–NAD+ complex in the low femtomolar range. This shows how TSA data combined with enzyme inhibition, parasite growth inhibition data, and ADMET predictions allow for better discrimination between potent ENR inhibitors for the future development of medicine

    Aluminium content of spanish infant formula

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    Aluminium toxicity has been relatively well documented in infants with impaired renal function and premature neonates. The aims of this study were to analyse the concentration of aluminium in the majority of infant formulae sold commercially in Spain, to determine the influence of aluminium content in the tap water in reconstituted powder formulae and to estimate the theoretical toxic aluminium intake in comparison with the PTWI, and lastly, to discuss the possible interactions of certain essential trace elements added to formulation with aluminium according to type or main protein based infant formula. A total of 82 different infant formulae from 9 different manufacturers were studied. Sample digestion was simulated in a closed acid-decomposition microwave system. Aluminium concentration was determined by atomic absorption spectrophotometry with graphite furnace. In general, the infant formulae studied provide an aluminium level higher than that found in human milk, especially in the case of soya, preterm or hydrolysed casein-based formulae. Standard formulae provide lower aluminium intakes amounting to about 4 % PTWI. Specialised and preterm formulae result in moderate intake (11 – 12 % and 8 – 10 % PTWI, respectively). Soya formulae contribute the highest intake (15 % PTWI). Aluminium exposure from drinking water used for powder formula reconstitution is not considered a clear potential risk. In accordance with the present state of knowledge about aluminium toxicity, it seems prudent to call for continued efforts to standardise routine quality control and reduce aluminium levels in infant formula as well as to keep the aluminium concentration under 300 g l-1 for all infant formulae, most specifically those formulae for premature and low birth neonates

    Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

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    This paper presents measurements of the W+→Ό+ÎœW^+ \rightarrow \mu^+\nu and W−→Ό−ΜW^- \rightarrow \mu^-\nu cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

    Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector