Tumorigenesis is a multistep process involving co-operation between several deregulated oncoproteins. In this study, we unravel previously unrecognized interactions and crosstalk between Pim kinases ...and the Notch signaling pathway, with implications for both breast and prostate cancer. We identify Notch1 and Notch3, but not Notch2, as novel Pim substrates and demonstrate that for Notch1, the serine residue 2152 is phosphorylated by all three Pim family kinases. This target site is located in the second nuclear localization sequence (NLS) of the Notch1 intracellular domain (N1ICD), and is shown to be important for both nuclear localization and transcriptional activity of N1ICD. Phosphorylation-dependent stimulation of Notch1 signaling promotes migration of prostate cancer cells, balances glucose metabolism in breast cancer cells, and supports in vivo growth of both types of cancer cells on chick embryo chorioallantoic membranes. Furthermore, Pim-induced growth of orthotopic prostate xenografts in mice is associated with enhanced nuclear Notch1 activity. Finally, simultaneous inhibition of Pim and Notch abrogates the cellular responses more efficiently than individual treatments, opening up new vistas for combinatorial cancer therapy.
Abstract
WASP-18 hosts a massive, very close-in Jupiter-like planet. Despite its young age (<1 Gyr), the star presents an anomalously low stellar activity level: the measured
activity parameter lies ...slightly below the basal level; there is no significant time-variability in the
value; there is no detection of the star in the X-rays. We present results of far-UV observations of WASP-18 obtained with COS on board of
Hubble Space Telescope
aimed at explaining this anomaly. From the star’s spectral energy distribution, we infer the extinction (
≈ 0.01 mag) and then the interstellar medium (ISM) column density for a number of ions, concluding that ISM absorption is not the origin of the anomaly. We measure the flux of the four stellar emission features detected in the COS spectrum (C
ii
, C
iii
, C
iv
, Si
iv
). Comparing the C
ii
/C
iv
flux ratio measured for WASP-18 with that derived from spectra of nearby stars with known age, we see that the far-UV spectrum of WASP-18 resembles that of old (>5 Gyr), inactive stars, in stark contrast with its young age. We conclude that WASP-18 has an intrinsically low activity level, possibly caused by star–planet tidal interaction, as suggested by previous studies. Re-scaling the solar irradiance reference spectrum to match the flux of the Si
iv
line, yields an XUV integrated flux at the planet orbit of 10.2 erg s
−1
cm
−2
. We employ the rescaled XUV solar fluxes to models of the planetary upper atmosphere, deriving an extremely low thermal mass-loss rate of 10
−20
M
J
Gyr
−1
. For such high-mass planets, thermal escape is not energy limited, but driven by Jeans escape.
Context.
Exoplanetary upper atmospheres are low density environments where radiative processes can compete with collisional ones and introduce non-local thermodynamic equilibrium (NLTE) effects into ...transmission spectra.
Aims.
We develop a NLTE radiative transfer framework capable of modelling exoplanetary transmission spectra over a wide range of planetary properties.
Methods.
We adapted the NLTE spectral synthesis code Cloudy to produce an atmospheric structure and atomic transmission spectrum in both NLTE and local thermodynamic equilibrium (LTE) for the hot Jupiter HD 209458b, given a published
T
–
P
profile and assuming solar metallicity. Selected spectral features, including H
α
, Na
I
D, He
I
λ
10 830, Fe
I
and
II
ultra-violet (UV) bands, and C, O, and Si UV lines, are compared with literature observations and models where available. The strength of NLTE effects are measured for individual spectral lines to identify which features are most strongly affected.
Results.
The developed modelling framework that computes NLTE synthetic spectra reproduces literature results for the He
I
λ
10 830 triplet, the Na
I
D lines, and the forest of Fe
I
lines in the optical. Individual spectral lines in the NLTE spectrum exhibit up to 40% stronger absorption relative to the LTE spectrum.
Use of atomic layer deposition (ALD) in microelectromechanical systems (MEMS) has increased as ALD enables conformal growth on 3-dimensional structures at relatively low temperatures. For MEMS device ...design and fabrication, the understanding of stress and mechanical properties such as elastic modulus, hardness and adhesion of thin film is crucial. In this work a comprehensive characterization of the stress, elastic modulus, hardness and adhesion of ALD aluminum oxide (Al2O3) films grown at 110–300°C from trimethylaluminum and water is presented. Film stress was analyzed by wafer curvature measurements, elastic modulus by nanoindentation and surface-acoustic wave measurements, hardness by nanoindentation and adhesion by microscratch test and scanning nanowear. The films were also analyzed by ellipsometry, optical reflectometry, X-ray reflectivity and time-of-flight elastic recoil detection for refractive index, thickness, density and impurities. The ALD Al2O3 films were under tensile stress in the scale of hundreds of MPa. The magnitude of the stress decreased strongly with increasing ALD temperature. The stress was stable during storage in air. Elastic modulus and hardness of ALD Al2O3 saturated to a fairly constant value for growth at 150 to 300°C, while ALD at 110°C gave softer films with lower modulus. ALD Al2O3 films adhered strongly on cleaned silicon with SiOx termination.
•The residual stress of Al2O3 was tensile and stable during the storage in air.•Elastic modulus of Al2O3 saturated to at 170GPa for films grown at 150 to 300°C.•At 110°C Al2O3 films were softer with high residual hydrogen and lower density.•The Al2O3 adhered strongly on the SiOx-terminated silicon.
The results of a 3 + 1 sterile neutrino search using eight years of data from the IceCube Neutrino Observatory are presented. A total of 305 735 muon neutrino events are analyzed in reconstructed ...energy-zenith space to test for signatures of a matter-enhanced oscillation that would occur given a sterile neutrino state with a mass-squared differences between 0.01 and 100 eV2. The best-fit point is found to be at sin2(2θ24) = 0.10 and Δm412 = 4.5 eV2, which is consistent with the no sterile neutrino hypothesis with a p value of 8.0%.
We study the response of the outer Van Allen radiation belt during an intense magnetic storm on 15–22 February 2014. Four interplanetary coronal mass ejections (ICMEs) arrived at Earth, of which the ...three last ones were interacting. Using data from the Van Allen Probes, we report the first detailed investigation of electron fluxes from source (tens of kiloelectron volts) to core (megaelectron volts) energies and possible loss and acceleration mechanisms as a response to substructures (shock, sheath and ejecta, and regions of shock‐compressed ejecta) in multiple interacting ICMEs. After an initial enhancement induced by a shock compression of the magnetosphere, core fluxes strongly depleted and stayed low for 4 days. This sustained depletion can be related to a sequence of ICME substructures and their conditions that influenced the Earth's magnetosphere. In particular, the main depletions occurred during a high‐dynamic pressure sheath and shock‐compressed southward ejecta fields. These structures compressed/eroded the magnetopause close to geostationary orbit and induced intense and diverse wave activity in the inner magnetosphere (ULF Pc5, electromagnetic ion cyclotron, and hiss) facilitating both effective magnetopause shadowing and precipitation losses. Seed and source electrons in turn experienced stronger variations throughout the studied interval. The core fluxes recovered during the last ICME that made a glancing blow to Earth. This period was characterized by a concurrent lack of losses and sustained acceleration by chorus and Pc5 waves. Our study highlights that the seemingly complex behavior of the outer belt during interacting ICMEs can be understood by the knowledge of electron dynamics during different substructures.
Key Points
Detailed response of the outer belt to substructures in a complex solar wind driver is investigated
Most substructures in the interacting ICMEs here deplete the core radiation belt population but inject source electrons
Core electrons were enhanced during sustained chorus and Pc5 activity and lack of losses
A search for high-energy neutrinos interacting within the IceCube detector between 2010 and 2012 provided the first evidence for a high-energy neutrino flux of extraterrestrial origin. Results from ...an analysis using the same methods with a third year (2012-2013) of data from the complete IceCube detector are consistent with the previously reported astrophysical flux in the 100 TeV-PeV range at the level of 10(-8) GeV cm-2 s-1 sr-1 per flavor and reject a purely atmospheric explanation for the combined three-year data at 5.7σ. The data are consistent with expectations for equal fluxes of all three neutrino flavors and with isotropic arrival directions, suggesting either numerous or spatially extended sources. The three-year data set, with a live time of 988 days, contains a total of 37 neutrino candidate events with deposited energies ranging from 30 to 2000 TeV. The 2000-TeV event is the highest-energy neutrino interaction ever observed.
We report a quasidifferential upper limit on the extremely-high-energy (EHE) neutrino flux above 5×106 GeV based on an analysis of nine years of IceCube data. The astrophysical neutrino flux ...measured by IceCube extends to PeV energies, and it is a background flux when searching for an independent signal flux at higher energies, such as the cosmogenic neutrino signal. We have developed a new method to place robust limits on the EHE neutrino flux in the presence of an astrophysical background, whose spectrum has yet to be understood with high precision at PeV energies. A distinct event with a deposited energy above 106 GeV was found in the new two-year sample, in addition to the one event previously found in the seven-year EHE neutrino search. These two events represent a neutrino flux that is incompatible with predictions for a cosmogenic neutrino flux and are considered to be an astrophysical background in the current study. The obtained limit is the most stringent to date in the energy range between 5×106 and 2×1010 GeV. This result constrains neutrino models predicting a three-flavor neutrino flux of Eν2ϕνe+νμ+ντ≃2×10−8 GeV/cm2 sec sr at 109 GeV. A significant part of the parameter space for EHE neutrino production scenarios assuming a proton-dominated composition of ultra-high-energy cosmic rays is disfavored independently of uncertain models of the extragalactic background light which previous IceCube constraints partially relied on.
The status of psychosocial stress at work as a risk factor for type 2 diabetes is unclear because existing evidence is based on small studies and is subject to confounding by lifestyle factors, such ...as obesity and physical inactivity. This collaborative study examined whether stress at work, defined as "job strain," is associated with incident type 2 diabetes independent of lifestyle factors.
We extracted individual-level data for 124,808 diabetes-free adults from 13 European cohort studies participating in the IPD-Work Consortium. We measured job strain with baseline questionnaires. Incident type 2 diabetes at follow-up was ascertained using national health registers, clinical screening, and self-reports. We analyzed data for each study using Cox regression and pooled the study-specific estimates in fixed-effect meta-analyses.
There were 3,703 cases of incident diabetes during a mean follow-up of 10.3 years. After adjustment for age, sex, and socioeconomic status (SES), the hazard ratio (HR) for job strain compared with no job strain was 1.15 (95% CI 1.06-1.25) with no difference between men and women (1.19 1.06-1.34 and 1.13 1.00-1.28, respectively). In stratified analyses, job strain was associated with an increased risk of diabetes among those with healthy and unhealthy lifestyle habits. In a multivariable model adjusted for age, sex, SES, and lifestyle habits, the HR was 1.11 (1.00-1.23).
Findings from a large pan-European dataset suggest that job strain is a risk factor for type 2 diabetes in men and women independent of lifestyle factors.
Venus, unlike Earth, is an extremely dry planet although both began with similar masses, distances from the Sun, and presumably water inventories. The high deuterium-to-hydrogen ratio in the venusian ...atmosphere relative to Earth's also indicates that the atmosphere has undergone significantly different evolution over the age of the Solar System. Present-day thermal escape is low for all atmospheric species. However, hydrogen can escape by means of collisions with hot atoms from ionospheric photochemistry, and although the bulk of O and O2 are gravitationally bound, heavy ions have been observed to escape through interaction with the solar wind. Nevertheless, their relative rates of escape, spatial distribution, and composition could not be determined from these previous measurements. Here we report Venus Express measurements showing that the dominant escaping ions are O+, He+ and H+. The escaping ions leave Venus through the plasma sheet (a central portion of the plasma wake) and in a boundary layer of the induced magnetosphere. The escape rate ratios are Q(H+)/Q(O+) = 1.9; Q(He+)/Q(O+) = 0.07. The first of these implies that the escape of H+ and O+, together with the estimated escape of neutral hydrogen and oxygen, currently takes place near the stoichometric ratio corresponding to water.
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