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

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

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

The ALMA-ALPINE [CII] survey: Kennicutt-Schmidt relation in four massive main-sequence galaxies at <i>z</i> ∼ 4.5

Aims. The Kennicutt-Schmidt (KS) relation between the gas and the star formation rate (SFR) surface density (Σ$_{gas}$ − Σ$_{SFR}$) is essential to understand star formation processes in galaxies. To date, it has been measured up to z ∼ 2.5 in main-sequence galaxies. In this Letter our aim is to put constraints at z ∼ 4.5 using a sample of four massive main-sequence galaxies observed by ALMA at high resolution. Methods. We obtained ∼0.3″-resolution [CII] and continuum maps of our objects, which we then converted into gas and obscured SFR surface density maps. In addition, we produced unobscured SFR surface density maps by convolving Hubble ancillary data in the rest-frame UV. We then derived the average Σ$_{SFR}$ in various Σ$_{gas}$ bins, and estimated the uncertainties using a Monte Carlo sampling. Results. Our galaxy sample follows the KS relation measured in main-sequence galaxies at lower redshift, and is slightly lower than the predictions from simulations. Our data points probe the high end both in terms of Σ$_{gas}$ and Σ$_{SFR}$, and gas depletion timescales (285–843 Myr) remain similar to z ∼ 2 objects. However, three of our objects are clearly morphologically disturbed, and we could have expected shorter gas depletion timescales (≲100 Myr) similar to merger-driven starbursts at lower redshifts. This suggests that the mechanisms triggering starbursts at high redshift may be different than in the low- and intermediate-z Universe

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

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ 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

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

The Impact of a Dedicated Research Education Month for Anesthesiology Residents

An educational intervention was implemented at the University of Michigan starting in 2008, in which anesthesiology interns complete a dedicated month-long didactic rotation in evidence-based medicine (EBM) and research methodology. We sought to assess its utility. Scores on a validated EBM test before and after the rotation were compared and assessed for significance of improvement. A survey was also given to gauge satisfaction with the quality of the rotation and self-reported improvement in understanding of EBM topics. Fourteen consecutive interns completed the research rotation during the study period. One hundred percent completed both the pre- and postrotation test. The mean pretest score was 7.78 ± 2.46 (median = 7.5, 0–15 scale, and interquartile range 7.0–10.0) and the mean posttest score was 10.00 ± 2.35 (median = 9.5, interquartile range 8.0–12.3), which represented a statistically significant increase (P=0.011, Wilcoxon signed-rank test). All fourteen of the residents “agreed” or “strongly agreed” that they would recommend the course to future interns and that the course increased their ability to critically review the literature. Our findings demonstrate that this can be an effective means of improving understanding of EBM topics and anesthesiology research

The ALMA-ALPINE [CII] survey: Kennicutt-Schmidt relation in four massive main-sequence galaxies at z~4.5

The Kennicutt-Schmidt (KS) relation between the gas and the star formation rate (SFR) surface density ($\Sigma_{\rm gas}$-$\Sigma_{\rm SFR}$) is essential to understand star formation processes in galaxies. So far, it has been measured up to z~2.5 in main-sequence galaxies. In this letter, we aim to put constraints at z~4.5 using a sample of four massive main-sequence galaxies observed by ALMA at high resolution. We obtained ~0.3"-resolution [CII] and continuum maps of our objects, which we then converted into gas and obscured SFR surface density maps. In addition, we produced unobscured SFR surface density maps by convolving Hubble ancillary data in the rest-frame UV. We then derived the average $\Sigma_{\rm SFR}$ in various $\Sigma_{\rm gas}$ bins, and estimated the uncertainties using a Monte Carlo sampling. Our galaxy sample follows the KS relation measured in main-sequence galaxies at lower redshift and is slightly lower than predictions from simulations. Our data points probe the high end both in terms of $\Sigma_{\rm gas}$ and $\Sigma_{\rm gas}$, and gas depletion timescales (285-843 Myr) remain similar to z~2 objects. However, three of our objects are clearly morphologically disturbed, and we could have expected shorter gas depletion timescales (~100 Myr) similar to merger-driven starbursts at lower redshifts. This suggests that the mechanisms triggering starbursts at high redshift may be different than in the low- and intermediate-z Universe.Comment: 9 pages, 7 figures, 2 tables, accepted by A&A (letter

Cold streams in early massive hot haloes as the main mode of galaxy formation

The massive galaxies in the young universe, ten billion years ago, formed stars at surprising intensities. Although this is commonly attributed to violent mergers, the properties of many of these galaxies are incompatible with such events, showing gas-rich, clumpy, extended rotating disks not dominated by spheroids (Genzel et al. 2006, 2008). Cosmological simulations and clustering theory are used to explore how these galaxies acquired their gas. Here we report that they are stream-fed galaxies, formed from steady, narrow, cold gas streams that penetrate the shock-heated media of massive dark matter haloes (Dekel & Birnboim 2006; Keres et al. 2005). A comparison with the observed abundance of star-forming galaxies implies that most of the input gas must rapidly convert to stars. One-third of the stream mass is in gas clumps leading to mergers of mass ratio greater than 1:10, and the rest is in smoother flows. With a merger duy cycle of 0.1, three-quarters of the galaxies forming stars at a given rate are fed by smooth streams. The rarer, submillimetre galaxies that form stars even more intensely are largely merger-induced starbursts. Unlike destructive mergers, the streams are likely to keep the rotating disk configuration intact, although turbulent and broken into giant star-forming clumps that merge into a central spheroid (Noguchi 1999; Genzel et al. 2008, Elmegreen, Bournaud & Elmegreen 2008, Dekel, Sari & Ceverino 2009). This stream-driven scenario for the formation of disks and spheroids is an alternative to the merger picture.Comment: Improved version, 25 pages, 13 figures, Letter to Nature with Supplementary Informatio