Remote observations of the asteroid (1) Ceres from ground- and space-based telescopes have provided its approximate density and shape, leading to a range of models for the interior of Ceres, from ...homogeneous to fully differentiated. A previously missing parameter that can place a strong constraint on the interior of Ceres is its moment of inertia, which requires the measurement of its gravitational variation together with either precession rate or a validated assumption of hydrostatic equilibrium. However, Earth-based remote observations cannot measure gravity variations and the magnitude of the precession rate is too small to be detected. Here we report gravity and shape measurements of Ceres obtained from the Dawn spacecraft, showing that it is in hydrostatic equilibrium with its inferred normalized mean moment of inertia of 0.37. These data show that Ceres is a partially differentiated body, with a rocky core overlaid by a volatile-rich shell, as predicted in some studies. Furthermore, we show that the gravity signal is strongly suppressed compared to that predicted by the topographic variation. This indicates that Ceres is isostatically compensated, such that topographic highs are supported by displacement of a denser interior. In contrast to the asteroid (4) Vesta, this strong compensation points to the presence of a lower-viscosity layer at depth, probably reflecting a thermal rather than compositional gradient. To further investigate the interior structure, we assume a two-layer model for the interior of Ceres with a core density of 2,460-2,900 kilograms per cubic metre (that is, composed of CI and CM chondrites), which yields an outer-shell thickness of 70-190 kilometres. The density of this outer shell is 1,680-1,950 kilograms per cubic metre, indicating a mixture of volatiles and denser materials such as silicates and salts. Although the gravity and shape data confirm that the interior of Ceres evolved thermally, its partially differentiated interior indicates an evolution more complex than has been envisioned for mid-sized (less than 1,000 kilometres across) ice-rich rocky bodies.
It is shown that corannulene‐based strained π‐surfaces can be obtained through the use of mechanochemical Suzuki and Scholl reactions. Besides being solvent‐free, the mechanochemical synthesis is ...high‐yielding, fast, and scalable. Therefore, gram‐scale preparation can be carried out in a facile and sustainable manner. The synthesized nanographene structure carries positive (bowl‐like) and negative (saddle‐like) Gaussian curvatures and adopts an overall quasi‐monkey saddle‐type of geometry. In terms of properties, the non‐planar surface exhibits a high electron affinity that was measured by cyclic voltammetry, with electrolysis and in situ UV/vis spectroscopy experiments indicating that the one‐electron reduced state displays a long lifetime in solution. Overall, these results indicate the future potential of mechanochemistry in accessing synthetically challenging and functional curved π‐systems.
Mechanochemistry is demonstrated to be an effective and sustainable synthetic tool in the preparation of curved π‐materials with high electron affinity and a highly reversible nature of the electron‐transfer process.
Thermochemical models have predicted that Ceres, is to some extent, differentiated and should have an icy crust with few or no impact craters. We present observations by the Dawn spacecraft that ...reveal a heavily cratered surface, a heterogeneous crater distribution, and an apparent absence of large craters. The morphology of some impact craters is consistent with ice in the subsurface, which might have favored relaxation, yet large unrelaxed craters are also present. Numerous craters exhibit polygonal shapes, terraces, flowlike features, slumping, smooth deposits, and bright spots. Crater morphology and simple-to-complex crater transition diameters indicate that the crust of Ceres is neither purely icy nor rocky. By dating a smooth region associated with the Kerwan crater, we determined absolute model ages (AMAs) of 550 million and 720 million years, depending on the applied chronology model.
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)
. Targeted therapies are approved for ...patients with 'classical' mutations and a small number of other mutations
. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown
. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
Cochlear implant users hear pitch evoked by stimulation rate, but discrimination diminishes for rates above 300 Hz. This upper limit on rate pitch is surprising given the remarkable and specialized ...ability of the auditory nerve to respond synchronously to stimulation rates at least as high as 3 kHz and arguably as high as 10 kHz. Sensitivity to stimulation rate as a pitch cue varies widely across cochlear implant users and can be improved with training. The present study examines individual differences and perceptual learning of stimulation rate as a cue for pitch ranking. Adult cochlear implant users participated in electrode psychophysics that involved testing once per week for three weeks. Stimulation pulse rate discrimination was measured in bipolar and monopolar configurations for apical and basal electrodes. Base stimulation rates between 100 and 800 Hz were examined. Individual differences were quantified using psychophysically derived metrics of spatial tuning and temporal integration. This study examined distribution of measures across subjects, predictive power of psychophysically derived metrics of spatial tuning and temporal integration, and the effect of training on rate discrimination thresholds. Psychophysical metrics of spatial tuning and temporal integration were not predictive of stimulation rate discrimination, but discrimination thresholds improved at lower frequencies with training. Since most clinical devices do not use variable stimulation rates, it is unknown to what extent recipients may learn to use stimulation rate cues if provided in a clear and consistent manner.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The imminent threat of viral epidemics and pandemics dictates a need for therapeutic approaches that target viral pathology irrespective of the infecting strain. Reactive oxygen species are ancient ...processes that protect plants, fungi and animals against invading pathogens including bacteria. However, in mammals reactive oxygen species production paradoxically promotes virus pathogenicity by mechanisms not yet defined. Here we identify that the primary enzymatic source of reactive oxygen species, NOX2 oxidase, is activated by single stranded RNA and DNA viruses in endocytic compartments resulting in endosomal hydrogen peroxide generation, which suppresses antiviral and humoral signaling networks via modification of a unique, highly conserved cysteine residue (Cys98) on Toll-like receptor-7. Accordingly, targeted inhibition of endosomal reactive oxygen species production abrogates influenza A virus pathogenicity. We conclude that endosomal reactive oxygen species promote fundamental molecular mechanisms of viral pathogenicity, and the specific targeting of this pathogenic process with endosomal-targeted reactive oxygen species inhibitors has implications for the treatment of viral disease.Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.
Nitrous oxide (N
O), like carbon dioxide, is a long-lived greenhouse gas that accumulates in the atmosphere. Over the past 150 years, increasing atmospheric N
O concentrations have contributed to ...stratospheric ozone depletion
and climate change
, with the current rate of increase estimated at 2 per cent per decade. Existing national inventories do not provide a full picture of N
O emissions, owing to their omission of natural sources and limitations in methodology for attributing anthropogenic sources. Here we present a global N
O inventory that incorporates both natural and anthropogenic sources and accounts for the interaction between nitrogen additions and the biochemical processes that control N
O emissions. We use bottom-up (inventory, statistical extrapolation of flux measurements, process-based land and ocean modelling) and top-down (atmospheric inversion) approaches to provide a comprehensive quantification of global N
O sources and sinks resulting from 21 natural and human sectors between 1980 and 2016. Global N
O emissions were 17.0 (minimum-maximum estimates: 12.2-23.5) teragrams of nitrogen per year (bottom-up) and 16.9 (15.9-17.7) teragrams of nitrogen per year (top-down) between 2007 and 2016. Global human-induced emissions, which are dominated by nitrogen additions to croplands, increased by 30% over the past four decades to 7.3 (4.2-11.4) teragrams of nitrogen per year. This increase was mainly responsible for the growth in the atmospheric burden. Our findings point to growing N
O emissions in emerging economies-particularly Brazil, China and India. Analysis of process-based model estimates reveals an emerging N
O-climate feedback resulting from interactions between nitrogen additions and climate change. The recent growth in N
O emissions exceeds some of the highest projected emission scenarios
, underscoring the urgency to mitigate N
O emissions.
Extreme-ultraviolet images of Comet Lovejoy (C/2011 W3) from the Atmospheric Imaging Assembly show striations related to the magnetic field structure in both open and closed magnetic regions. The ...brightness contrast implies coronal density contrasts of at least a factor of six between neighboring flux tubes over scales of a few thousand kilometers. These density structures imply variations in the Alfven speed on a similar scale. They will drastically affect the propagation and dissipation of Alfven waves, and that should be taken into account in models of coronal heating and solar wind acceleration. In each striation, the cometary emission moves along the magnetic field and broadens with time. The speed and the rate of broadening are related to the parallel and perpendicular components of the velocities of the cometary neutrals when they become ionized. We use a magnetohydrodynamic model of the coronal magnetic field and the theory of pickup ions to compare the measurements with theoretical predictions, in particular with the energy lost to Alfven waves as the cometary ions isotropize.
We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants ...yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.
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•ERBB2 mutations occur in at least 25 tumor types with varying patterns of mutations•Mutation-induced changes in drug-binding pocket volume dictate drug sensitivity•Poziotinib inhibits mutant HER2, yielding a 42% response rate in NSCLC patients•Combination of poziotinib with T-DM1 potentiates antitumor activity of both agents
Robichaux et al. show that ERBB2 mutation hotspots vary across human tumor types, which affect the volume of the HER2 TKI binding pocket and dictate drug sensitivity. Poziotinib is the most potent HER2 TKI among those tested. Moreover, poziotinib enhances T-DM1 efficacy by increasing the cell-surface HER2 level.
Ceres is the largest body in the asteroid belt with a radius of approximately 470 km. In part due to its large mass, Ceres more closely approaches hydrostatic equilibrium than major asteroids. ...Pre‐Dawn mission shape observations of Ceres revealed a shape consistent with a hydrostatic ellipsoid of revolution. The Dawn spacecraft Framing Camera has been imaging Ceres since March 2015, which has led to high‐resolution shape models of the dwarf planet, while the gravity field has been globally determined to a spherical harmonic degree 14 (equivalent to a spatial wavelength of 211 km) and locally to 18 (a wavelength of 164 km). We use these shape and gravity models to constrain Ceres' internal structure. We find a negative correlation and admittance between topography and gravity at degree 2 and order 2. Low admittances between spherical harmonic degrees 3 and 16 are well explained by Airy isostatic compensation mechanism. Different models of isostasy give crustal densities between 1,200 and 1,400 kg/m3 with our preferred model giving a crustal density of
1,287+70−87 kg/m3. The mantle density is constrained to be
2,434+5−8 kg/m3. We compute isostatic gravity anomaly and find evidence for mascon‐like structures in the two biggest basins. The topographic power spectrum of Ceres and its latitude dependence suggest that viscous relaxation occurred at the long wavelengths (>246 km). Our density constraints combined with finite element modeling of viscous relaxation suggests that the rheology and density of the shallow surface are most consistent with a rock, ice, salt and clathrate mixture.
Plain Language Summary
Ceres is the largest body in the asteroid belt. Unlike most of the objects in that region of the solar system, Ceres has a round shape due to its sufficient gravity. Little was known about Ceres before the Dawn mission. The measurements by the Dawn spacecraft allowed precise determination of Ceres' shape and gravity field. We use these two data sets to understand its internal structure. It was predicted in the past that Ceres topography would quickly viscously relax if Ceres had an icy crust. We find only a modest evidence of viscous relaxation, which implies that Ceres' crust is much stronger than water ice. We also find that Ceres topography is isostatically compensated. That is, much like with a floating iceberg, the weight of mountains is compensated by a displaced volume of the underlying mantle. Such a simple model explains most of Ceres' gravity anomalies. However, some gravity anomalies remain unaccounted for. For example, we find evidence for a mass concentration analogous to those in lunar maria in the two biggest impact basins. A strong negative anomaly is observed around Occator—the famous bright spot crater. A strong positive anomaly is centered at Ahuna Mons—a unique pyramid‐shaped mountain. The globally averaged crustal density that we find is rather low. Remarkably, Ceres crust is made out of a strong, rock‐like material that, however, has a density much lower than that of rocks. This implies that Ceres' crust contains a lot of salts and clathrates, which are strong and light materials.
Key Points
We use a two‐layer isostatic model to derive constraints on Ceres' internal structure
Deviation of topography power spectrum from a power law and more subdued topography at equator are indicative of limited viscous relaxation
Observed isostatic anomalies include mascon‐like structures in big impact basins and strong gravity anomalies at Occator and Ahuna Mons
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