A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.

With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.We also thank the Bill and Melinda Gates Foundation and the EU FP7 MM4TB Grant n°260872, the ERC-STG INTRACELLTB Grant n°260901, the Agence Nationale de la Recherche (ANR-10-EQPX-04-01), the Feder (12001407 (D-AL) Equipex Imaginex BioMed) and the Région Nord Pas de Calais, France, for providing funding to support this work.This is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C5OB02630

Charged multifluids in general relativity

The exact 1+3 covariant dynamical fluid equations for a multi-component plasma, together with Maxwell's equations are presented in such a way as to make them suitable for a gauge-invariant analysis of linear density and velocity perturbations of the Friedmann-Robertson-Walker model. In the case where the matter is described by a two component plasma where thermal effects are neglected, a mode representing high-frequency plasma oscillations is found in addition to the standard growing and decaying gravitational instability picture. Further applications of these equations are also discussed.Comment: 14 pages (example added), to appear in Class. Quantum Gra

The nature of the short wavelength excitations in vitreous silica: X-Rays Brillouin scattering study

The dynamical structure factor (S(Q,E)) of vitreous silica has been measured by Inelastic X-ray Scattering varying the exchanged wavevector (Q) at fixed exchanged energy (E) - an experimental procedure that, contrary to the usual one at constant Q, provides spectra with much better identified inelastic features. This allows the first direct evidence of Brillouin peaks in the S(Q,E) of SiO_2 at energies above the Boson Peak (BP) energy, a finding that excludes the possibility that the BP marks the transition from propagating to localised dynamics in glasses.Comment: 4 pages, 3 Postscript figures. To appear in Physical Review Letter

Human NK Cells Differ More in Their KIR2DL1-Dependent Thresholds for HLA-Cw6-Mediated Inhibition than in Their Maximal Killing Capacity

In this study we have addressed the question of how activation and inhibition of human NK cells is regulated by the expression level of MHC class I protein on target cells. Using target cell transfectants sorted to stably express different levels of the MHC class I protein HLA-Cw6, we show that induction of degranulation and that of IFN-γ secretion are not correlated. In contrast, the inhibition of these two processes by MHC class-I occurs at the same level of class I MHC protein. Primary human NK cell clones were found to differ in the amount of target MHC class I protein required for their inhibition, rather than in their maximum killing capacity. Importantly, we show that KIR2DL1 expression determines the thresholds (in terms of MHC I protein levels) required for NK cell inhibition, while the expression of other receptors such as LIR1 is less important. Furthermore, using mathematical models to explore the dynamics of target cell killing, we found that the observed delay in target cell killing is exhibited by a model in which NK cells require some activation or priming, such that each cell can lyse a target cell only after being activated by a first encounter with the same or a different target cell, but not by models which lack this feature

Gut bacteria at 6 months of age are associated with immune cell status in 1-year-old children

publishedVersio

Visually estimated ejection fraction by two dimensional and triplane echocardiography is closely correlated with quantitative ejection fraction by real-time three dimensional echocardiography

<p>Abstract</p> <p>Background</p> <p>Visual assessment of left ventricular ejection fraction (LVEF) is often used in clinical routine despite general recommendations to use quantitative biplane Simpsons (BPS) measurements. Even thou quantitative methods are well validated and from many reasons preferable, the feasibility of visual assessment (eyeballing) is superior. There is to date only sparse data comparing visual EF assessment in comparison to quantitative methods available. The aim of this study was to compare visual EF assessment by two-dimensional echocardiography (2DE) and triplane echocardiography (TPE) using quantitative real-time three-dimensional echocardiography (RT3DE) as the reference method.</p> <p>Methods</p> <p>Thirty patients were enrolled in the study. Eyeballing EF was assessed using apical 4-and 2 chamber views and TP mode by two experienced readers blinded to all clinical data. The measurements were compared to quantitative RT3DE.</p> <p>Results</p> <p>There were an excellent correlation between eyeballing EF by 2D and TP vs 3DE (r = 0.91 and 0.95 respectively) without any significant bias (-0.5 ± 3.7% and -0.2 ± 2.9% respectively). Intraobserver variability was 3.8% for eyeballing 2DE, 3.2% for eyeballing TP and 2.3% for quantitative 3D-EF. Interobserver variability was 7.5% for eyeballing 2D and 8.4% for eyeballing TP.</p> <p>Conclusion</p> <p>Visual estimation of LVEF both using 2D and TP by an experienced reader correlates well with quantitative EF determined by RT3DE. There is an apparent trend towards a smaller variability using TP in comparison to 2D, this was however not statistically significant.</p

Positioning aquatic animals with acoustic transmitters

Geolocating aquatic animals with acoustic tags has been ongoing for decades, relying on the detection of acoustic signals at multiple receivers with known positions to calculate a 2D or 3D position, and ultimately recreate the path of an aquatic animal from detections at fixed stations.This method of underwater geolocation is evolving with new software and hardware options available to help investigators design studies and calculate positions using solvers based predominantly on time-difference-of-arrival and time-of-arrival.We provide an overview of the considerations necessary to implement positioning in aquatic acoustic telemetry studies, including how to design arrays of receivers, test performance, synchronize receiver clocks and calculate positions from the detection data. We additionally present some common positioning algorithms, including both the free open-source solvers and the 'black-box' methods provided by some manufacturers for calculating positions.This paper is the first to provide a comprehensive overview of methods and considerations for designing and implementing better positioning studies that will support users, and encourage further knowledge advances in aquatic systems