Bioisosteric discovery of NPA101.3, a second generation RET/VEGFR2 inhibitor optimized for single-agent polypharmacology

RET receptor tyrosine kinase is a driver oncogene in human cancer. We recently identified the clinical drug candidate Pz-1, which targets RET and VEGFR2. A key in vivo metabolite of Pz-1 is its less active demethylated pyrazole analogue. Using bioisosteric substitution methods, here, we report the identification of NPA101.3, lacking the structural liability for demethylation. NPA101.3 showed selective inhibitory profile and an inhibitory concentration 50 (IC50) of <0.001 μM for both RET and VEGFR2. NPA101.3 inhibited phosphorylation of all tested RET oncoproteins as well as VEGFR2 and proliferation of cells transformed by RET. Oral administration of NPA101.3 (10 mg/kg/day) completely prevented formation of tumours induced by RET/C634Y-transformed cells, while it decreased, but did not abrogate, formation of tumours induced by a control oncogene (HRAS/G12V). The balanced synchronous inhibition of both RET and VEGFR2, as well the resistance to demethylation, renders NPA101.3 a potential clinical candidate for RET-driven cancers

Euclid preparation. XXXII. Evaluating the weak lensing cluster mass biases using the Three Hundred Project hydrodynamical simulations

The photometric catalogue of galaxy clusters extracted from ESA Euclid data is expected to be very competitive for cosmological studies. Using state-of-the-art hydrodynamical simulations, we present systematic analyses simulating the expected weak lensing profiles from clusters in a variety of dynamic states and at wide range of redshifts. In order to derive cluster masses, we use a model consistent with the implementation within the Euclid Consortium of the dedicated processing function and find that, when jointly modelling mass and the concentration parameter of the Navarro-Frenk-White halo profile, the weak lensing masses tend to be, on average, biased low by 5-10% with respect to the true mass, up to z=0.5. Using a fixed value for the concentration $c_{200} = 3$, the mass bias is diminished below 5%, up to z=0.7, along with its relative uncertainty. Simulating the weak lensing signal by projecting along the directions of the axes of the moment of inertia tensor ellipsoid, we find that orientation matters: when clusters are oriented along the major axis, the lensing signal is boosted, and the recovered weak lensing mass is correspondingly overestimated. Typically, the weak lensing mass bias of individual clusters is modulated by the weak lensing signal-to-noise ratio, related to the redshift evolution of the number of galaxies used for weak lensing measurements: the negative mass bias tends to be larger toward higher redshifts. However, when we use a fixed value of the concentration parameter, the redshift evolution trend is reduced. These results provide a solid basis for the weak-lensing mass calibration required by the cosmological application of future cluster surveys from Euclid and Rubin

Euclid preparation. XXXII. Evaluating the weak lensing cluster mass biases using the Three Hundred Project hydrodynamical simulations

The photometric catalogue of galaxy clusters extracted from ESA Euclid data is expected to be very competitive for cosmological studies. Using state-of-the-art hydrodynamical simulations, we present systematic analyses simulating the expected weak lensing profiles from clusters in a variety of dynamic states and at wide range of redshifts. In order to derive cluster masses, we use a model consistent with the implementation within the Euclid Consortium of the dedicated processing function and find that, when jointly modelling mass and the concentration parameter of the Navarro-Frenk-White halo profile, the weak lensing masses tend to be, on average, biased low by 5-10% with respect to the true mass, up to z=0.5. Using a fixed value for the concentration $c_{200} = 3$, the mass bias is diminished below 5%, up to z=0.7, along with its relative uncertainty. Simulating the weak lensing signal by projecting along the directions of the axes of the moment of inertia tensor ellipsoid, we find that orientation matters: when clusters are oriented along the major axis, the lensing signal is boosted, and the recovered weak lensing mass is correspondingly overestimated. Typically, the weak lensing mass bias of individual clusters is modulated by the weak lensing signal-to-noise ratio, related to the redshift evolution of the number of galaxies used for weak lensing measurements: the negative mass bias tends to be larger toward higher redshifts. However, when we use a fixed value of the concentration parameter, the redshift evolution trend is reduced. These results provide a solid basis for the weak-lensing mass calibration required by the cosmological application of future cluster surveys from Euclid and Rubin

The first and second data releases of the Kilo-Degree Survey

Context. The Kilo-Degree Survey (KiDS) is an optical wide-field imaging survey carried out with the VLT Survey Telescope and the OmegaCAM camera. KiDS will image 1500 square degrees in four filters (ugri), and together with its near-infrared counterpart VIKING will produce deep photometry in nine bands. Designed for weak lensing shape and photometric redshift measurements, its core science driver is mapping the large-scale matter distribution in the Universe back to a redshift of ~0.5. Secondary science cases include galaxy evolution, Milky Way structure, and the detection of high-redshift clusters and quasars. Aims. KiDS is an ESO Public Survey and dedicated to serving the astronomical community with high-quality data products derived from the survey data. Public data releases, the first two of which are presented here, are crucial for enabling independent confirmation of the survey’s scientific value. The achieved data quality and initial scientific utilization are reviewed in order to validate the survey data. Methods. A dedicated pipeline and data management system based on ASTRO-WISE, combined with newly developed masking and source classification tools, is used for the production of the data products described here. Science projects based on these data products and preliminary results are outlined. Results. For 148 survey tiles (≈160 sq.deg.) stacked ugri images have been released, accompanied by weight maps, masks, source lists, and a multi-band source catalogue. Limiting magnitudes are typically 24.3, 25.1, 24.9, 23.8 (5σ in a 2′′ aperture) in ugri, respectively, and the typical r-band PSF size is less than 0.7′′. The photometry prior to global homogenization is stable at the ~2% (4%) level in gri (u) with some outliers due to non-photometric conditions, while the astrometry shows a typical 2D rms of 0.03′′. Early scientific results include the detection of nine high-z QSOs, fifteen candidate strong gravitational lenses, high-quality photometric redshifts and structural parameters for hundreds of thousands of galaxies

A comparison of methods to assess the antimicrobial activity of nanoparticle combinations on bacterial cells

Copyright: © 2018 Bankier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BACKGROUND: Bacterial cell quantification after exposure to antimicrobial compounds varies widely throughout industry and healthcare. Numerous methods are employed to quantify these antimicrobial effects. With increasing demand for new preventative methods for disease control, we aimed to compare and assess common analytical methods used to determine antimicrobial effects of novel nanoparticle combinations on two different pathogens. METHODS: Plate counts of total viable cells, flow cytometry (LIVE/DEAD BacLight viability assay) and qPCR (viability qPCR) were used to assess the antimicrobial activity of engineered nanoparticle combinations (NPCs) on Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria at different concentrations (0.05, 0.10 and 0.25 w/v%). Results were analysed using linear models to assess the effectiveness of different treatments. RESULTS: Strong antimicrobial effects of the three NPCs (AMNP0-2) on both pathogens could be quantified using the plate count method and flow cytometry. The plate count method showed a high log reduction (>8-log) for bacteria exposed to high NPC concentrations. We found similar antimicrobial results using the flow cytometry live/dead assay. Viability qPCR analysis of antimicrobial activity could not be quantified due to interference of NPCs with qPCR amplification. CONCLUSION: Flow cytometry was determined to be the best method to measure antimicrobial activity of the novel NPCs due to high-throughput, rapid and quantifiable results.Peer reviewe

Euclid: Discovering pair-instability supernovae with the Deep Survey

Pair-instability supernovae are theorized supernovae that have not yet been observationally confirmed. They are predicted to exist in low-metallicity environments. Because overall metallicity becomes lower at higher redshifts, deep near-infrared transient surveys probing high-redshift supernovae are suitable to discover pair-instability supernovae. The Euclid satellite, which is planned to be launched in 2023, has a near-infrared wide-field instrument that is suitable for a high-redshift supernova survey. Although no dedicated supernova survey is currently planned during the Euclid's 6 year primary mission, the Euclid Deep Survey is planned to make regular observations of three Euclid Deep Fields (40 deg2 in total) spanning six years. While the observations of the Euclid Deep Fields are not frequent, we show that the predicted long duration of pair-instability supernovae would allow us to search for high-redshift pair-instability supernovae with the Euclid Deep Survey. Based on the current observational plan of the Euclid mission, we conduct survey simulations in order to estimate the expected numbers of pair-instability supernova discoveries. We find that up to several hundred pair-instability supernovae at z < ~ 3.5 can be discovered by the Euclid Deep Survey. We also show that pair-instability supernova candidates can be efficiently identified by their duration and color that can be determined with the current Euclid Deep Survey plan. We conclude that the Euclid mission can lead to the first confident discovery of pair-instability supernovae if their event rates are as high as those predicted by recent theoretical studies. We also update the expected numbers of superluminous supernova discoveries in the Euclid Deep Survey based on the latest observational plan.Comment: 12 pages, 13 figures, 2 tables, submitted to Astronomy & Astrophysic

Euclid preparation: XXX. Performance assessment of the NISP red grism through spectroscopic simulations for the wide and deep surveys

This work focusses on the pilot run of a simulation campaign aimed at investigating the spectroscopic capabilities of the Euclid Near-Infrared Spectrometer and Photometer (NISP), in terms of continuum and emission line detection in the context of galaxy evolutionary studies. To this purpose, we constructed, emulated, and analysed the spectra of 4992 star-forming galaxies at 0:3 ≥ z ≥ 2:5 using the NISP pixel-level simulator. We built the spectral library starting from public multi-wavelength galaxy catalogues, with value-added information on spectral energy distribution (SED) fitting results, and stellar population templates from Bruzual & Charlot (2003, MNRAS, 344, 1000). Rest-frame optical and near-IR nebular emission lines were included using empirical and theoretical relations. Dust attenuation was treated using the Calzetti extinction law accounting for the differential attenuation in line-emitting regions with respect to the stellar continuum. The NISP simulator was configured including instrumental and astrophysical sources of noise such as the dark current, read-out noise, zodiacal background, and out-of-field stray light. In this preliminary study, we avoided contamination due to the overlap of the slitless spectra. For this purpose, we located the galaxies on a grid and simulated only the first order spectra.We inferred the 3.5δ NISP red grism spectroscopic detection limit of the continuum measured in the H band for star-forming galaxies with a median disk half-light radius of 0: 004 at magnitude H = 19:5 = 0:2ABmag for the Euclid Wide Survey and at H = 20:8 = 0:6ABmag for the Euclid Deep Survey. We found a very good agreement with the red grism emission line detection limit requirement for the Wide and Deep surveys. We characterised the effect of the galaxy shape on the detection capability of the red grism and highlighted the degradation of the quality of the extracted spectra as the disk size increased. In particular, we found that the extracted emission line signal-to-noise ratio (S/N) drops by 45% when the disk size ranges from 0: 0025 to 100. These trends lead to a correlation between the emission line S/N and the stellar mass of the galaxy and we demonstrate the effect in a stacking analysis unveiling emission lines otherwise too faint to detect