Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Mutant Prourokinase with Adjunctive C1-Inhibitor Is an Effective and Safer Alternative to tPA in Rat Stroke

A single-site mutant (M5) of native urokinase plasminogen activator (prouPA) induces effective thrombolysis in dogs with venous or arterial thrombosis with a reduction in bleeding complications compared to tPA. This effect, related to inhibition of two-chain M5 (tcM5) by plasma C1-inhibitor (C1I), thereby preventing non-specific plasmin generation, was augmented by the addition of exogenous C1I to plasma in vitro. In the present study, tPA, M5 or placebo +/− C1I were administered in two rat stroke models. In Part-I, permanent MCA occlusion was used to evaluate intracranial hemorrhage (ICH) by the thrombolytic regimens. In Part II, thromboembolic occlusion was used with thrombolysis administered 2 h later. Infarct and edema volumes, and ICH were determined at 24 h, and neuroscore pre (2 h) and post (24 h) treatment. In Part I, fatal ICH occurred in 57% of tPA and 75% of M5 rats. Adjunctive C1I reduced this to 25% and 17% respectively. Similarly, semiquantitation of ICH by neuropathological examination showed significantly less ICH in rats given adjunctive C1I compared with tPA or M5 alone. In Part-II, tPA, M5, and M5+C1I induced comparable ischemic volume reductions (>55%) compared with the saline or C1I controls, indicating the three treatments had a similar fibrinolytic effect. ICH was seen in 40% of tPA and 50% of M5 rats, with 1 death in the latter. Only 17% of the M5+C1I rats showed ICH, and the bleeding score in this group was significantly less than that in either the tPA or M5 group. The M5+C1I group had the best Benefit Index, calculated by dividing percent brain salvaged by the ICH visual score in each group. In conclusion, adjunctive C1I inhibited bleeding by M5, induced significant neuroscore improvement and had the best Benefit Index. The C1I did not compromise fibrinolysis by M5 in contrast with tPA, consistent with previous in vitro findings

Architecture and performance of the KM3NeT front-end firmware

The KM3NeT infrastructure consists of two deep-sea neutrino telescopes being deployed in the Mediterranean Sea. The telescopes will detect extraterrestrial and atmospheric neutrinos by means of the incident photons induced by the passage of relativistic charged particles through the seawater as a consequence of a neutrino interaction. The telescopes are configured in a three-dimensional grid of digital optical modules, each hosting 31 photomultipliers. The photomultiplier signals produced by the incident Cherenkov photons are converted into digital information consisting of the integrated pulse duration and the time at which it surpasses a chosen threshold. The digitization is done by means of time to digital converters (TDCs) embedded in the field programmable gate array of the central logic board. Subsequently, a state machine formats the acquired data for its transmission to shore. We present the architecture and performance of the front-end firmware consisting of the TDCs and the state machine

VDES J2325−5229 a z = 2.7 gravitationally lensed quasar discovered using morphology-independent supervised machine learning

We present the discovery and preliminary characterization of a gravitationally lensed quasar with a source redshift zs = 2.74 and image separation of 2.9 arcsec lensed by a foreground zl = 0.40 elliptical galaxy. Since optical observations of gravitationally lensed quasars showthe lens system as a superposition of multiple point sources and a foreground lensing galaxy, we have developed a morphology-independent multi-wavelength approach to the photometric selection of lensed quasar candidates based on Gaussian Mixture Models (GMM) supervised machine learning. Using this technique and gi multicolour photometric observations from the Dark Energy Survey (DES), near-IR JK photometry from the VISTA Hemisphere Survey (VHS) and WISE mid-IR photometry, we have identified a candidate system with two catalogue components with iAB = 18.61 and iAB = 20.44 comprising an elliptical galaxy and two blue point sources. Spectroscopic follow-up with NTT and the use of an archival AAT spectrum show that the point sources can be identified as a lensed quasar with an emission line redshift of z = 2.739 ± 0.003 and a foreground early-type galaxy with z = 0.400 ± 0.002.We model the system as a single isothermal ellipsoid and find the Einstein radius θE ∼ 1.47 arcsec, enclosed mass Menc ∼ 4 × 1011 M and a time delay of ∼52 d. The relatively wide separation, month scale time delay duration and high redshift make this an ideal system for constraining the expansion rate beyond a redshift of 1

An r -process enhanced star in the dwarf galaxy Tucana III

Chemically peculiar stars in dwarf galaxies provide a window for exploring the birth environment of stars with varying chemical enrichment. We present a chemical abundance analysis of the brightest star in the newly discovered ultra-faint dwarf galaxy candidate Tucana III. Because it is particularly bright for a star in an ultra-faint Milky Way (MW) satellite, we are able to measure the abundance of 28 elements, including 13 neutron-capture species. This star, DES J235532.66−593114.9 (DES J235532), shows a mild enhancement in neutron-capture elements associated with the r-process and can be classified as an r-I star. DES J235532 is the first r-I star to be discovered in an ultra-faint satellite, and Tuc III is the second extremely low-luminosity system found to contain rprocess enriched material, after Reticulum II. Comparison of the abundance pattern of DES J235532 with r-I and r-II stars found in other dwarf galaxies and in the MW halo suggests a common astrophysical origin for the neutron-capture elements seen in all r-process enhanced stars. We explore both internal and external scenarios for the r-process enrichment of Tuc III and show that with abundance patterns for additional stars, it should be possible to distinguish between them

The Dark Energy Survey : more than dark energy – an overview

This overview paper describes the legacy prospect and discovery potential of the Dark Energy Survey (DES) beyond cosmological studies, illustrating it with examples from the DES early data. DES is using a wide-field camera (DECam) on the 4 m Blanco Telescope in Chile to image 5000 sq deg of the sky in five filters (grizY). By its completion, the survey is expected to have generated a catalogue of 300 million galaxies with photometric redshifts and 100 million stars. In addition, a time-domain survey search over 27 sq deg is expected to yield a sample of thousands of Type Ia supernovae and other transients. The main goals of DES are to characterize dark energy and dark matter, and to test alternative models of gravity; these goals will be pursued by studying large-scale structure, cluster counts, weak gravitational lensing and Type Ia supernovae. However, DES also provides a rich data set which allows us to study many other aspects of astrophysics. In this paper, we focus on additional science with DES, emphasizing areas where the survey makes a difference with respect to other current surveys. The paper illustrates, using early data (from ‘Science Verification’, and from the first, second and third seasons of observations), what DES can tell us about the Solar system, the Milky Way, galaxy evolution, quasars and other topics. In addition, we show that if the cosmological model is assumed to be +cold dark matter, then important astrophysics can be deduced from the primary DES probes. Highlights from DES early data include the discovery of 34 trans-Neptunian objects, 17 dwarf satellites of the Milky Way, one published z > 6 quasar (and more confirmed) and two published superluminous supernovae (and more confirmed)

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins

Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, nonkinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here, we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically relevant ROS1 RTK fusion oncoproteins. SDC4-ROS1 and SLC34A2-ROS1 fusion oncoproteins resided on endosomes and activated the MAPK pathway. CD74-ROS1 variants that localized instead to the endoplasmic reticulum (ER) showed compromised activation of MAPK. Forced relocalization of CD74-ROS1 from the ER to endosomes restored MAPK signaling. ROS1 fusion oncoproteins that better activate MAPK formed more aggressive tumors. Thus, differential subcellular localization controlled by the N-terminal fusion partner regulates the oncogenic mechanisms and output of certain RTK fusion oncoproteins. SIGNIFICANCE: ROS1 fusion oncoproteins exhibit differential activation of MAPK signaling according to subcellular localization, with ROS1 fusions localized to endosomes, the strongest activators of MAPK signaling

The LMC geometry and outer stellar populations from early DES data

The Dark Energy Camera has captured a large set of images as part of Science Verification (SV) for the Dark Energy Survey (DES). The SV footprint covers a large portion of the outer LargeMagellanic Cloud (LMC), providing photometry 1.5 mag fainter than the main sequence turn-off of the oldest LMC stellar population.We derive geometrical and structural parameters for various stellar populations in the LMC disc. For the distribution of all LMC stars, we find an inclination of i = −38. ◦ 14 ± 0. ◦ 08 (near side in the north) and a position angle for the line of nodes of θ0 = 129. ◦ 51 ± 0. ◦ 17. We find that stars younger than ∼4 Gyr are more centrally concentrated than older stars. Fitting a projected exponential disc shows that the scale radius of the old populations is R>4 Gyr = 1.41 ± 0.01 kpc, while the younger population has R<4 Gyr = 0.72 ± 0.01 kpc. However, the spatial distribution of the younger population deviates significantly from the projected exponential disc model. The distribution of old stars suggests a large truncation radius of Rt = 13.5 ± 0.8 kpc. If this truncation is dominated by the tidal field of the Galaxy, we find that the LMC is 24+9 −6 times less massive than the encircled Galactic mass. By measuring the Red Clump peak magnitude and comparing with the best-fitting LMC disc model, we find that the LMC disc is warped and thicker in the outer regions north of the LMC centre. Our findings may either be interpreted as a warped and flared disc in the LMC outskirts, or as evidence of a spheroidal halo component