RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP-GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. ...Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. However, despite more than three decades of intense effort, no anti-RAS therapies have reached clinical application. Contributing to this failure has been an underestimation of the complexities of RAS. First, there is now appreciation that the four human RAS proteins are not functionally identical. Second, with >130 different missense mutations found in cancer, there is an emerging view that there are mutation-specific consequences on RAS structure, biochemistry and biology, and mutation-selective therapeutic strategies are needed. In this Cell Science at a Glance article and accompanying poster, we provide a snapshot of the differences between RAS isoforms and mutations, as well as the current status of anti-RAS drug-discovery efforts.
We have compiled a new and complete catalog of the main properties of the 1509 pulsars for which published information currently exists. The catalog includes all spin-powered pulsars, as well as ...anomalous X-ray pulsars and soft gamma-ray repeaters showing coherent pulsed emission, but excludes accretion-powered systems. References are given for all data listed. We have also developed a new World Wide Web interface for accessing and displaying either tabular or plotted data with the option of selecting pulsars to be displayed via logical conditions on parameter expressions. The Web interface has an 'expert' mode giving access to a wider range of parameters and allowing the use of custom databases. For users with locally installed software and database on Unix or Linux systems, the catalog may be accessed from a command-line interface. C-language functions to access specified parameters are also available. The catalog is updated from time to time to include new information.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to ...our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.
Contemporary pulsar-timing experiments have reached a sensitivity level where systematic errors introduced by existing analysis procedures are limiting the achievable science. We have developed ...tempo2, a new pulsar-timing package that contains propagation and other relevant effects implemented at the 1-ns level of precision (a factor of ∼100 more precise than previously obtainable). In contrast with earlier timing packages, tempo2 is compliant with the general relativistic framework of the IAU 1991 and 2000 resolutions and hence uses the International Celestial Reference System, Barycentric Coordinate Time and up-to-date precession, nutation and polar motion models. tempo2 provides a generic and extensible set of tools to aid in the analysis and visualization of pulsar-timing data. We provide an overview of the timing model, its accuracy and differences relative to earlier work. We also present a new scheme for predictive use of the timing model that removes existing processing artefacts by properly modelling the frequency dependence of pulse phase.
We provide an analysis of timing irregularities observed for 366 pulsars. Observations were obtained using the 76-m Lovell radio telescope at the Jodrell Bank Observatory over the past 36 years. ...These data sets have allowed us to carry out the first large-scale analysis of pulsar timing noise over time-scales of >10 yr, with multiple observing frequencies and for a large sample of pulsars. Our sample includes both normal and recycled pulsars. The timing residuals for the pulsars with the smallest characteristic ages are shown to be dominated by the recovery from glitch events, whereas the timing irregularities seen for older pulsars are quasi-periodic. We emphasize that previous models that explained timing residuals as a low-frequency noise process are not consistent with observation.
Continued timing observations of the double pulsar PSR J0737–3039A/B, which consists of two active radio pulsars (A and B) that orbit each other with a period of 2.45 h in a mildly eccentric ...(e=0.088) binary system, have led to large improvements in the measurement of relativistic effects in this system. With a 16-yr data span, the results enable precision tests of theories of gravity for strongly self-gravitating bodies and also reveal new relativistic effects that have been expected but are now observed for the first time. These include effects of light propagation in strong gravitational fields which are currently not testable by any other method. In particular, we observe the effects of retardation and aberrational light bending that allow determination of the spin direction of the pulsar. In total, we detect seven post-Keplerian parameters in this system, more than for any other known binary pulsar. For some of these effects, the measurement precision is now so high that for the first time we have to take higher-order contributions into account. These include the contribution of the A pulsar’s effective mass loss (due to spin-down) to the observed orbital period decay, a relativistic deformation of the orbit, and the effects of the equation of state of superdense matter on the observed post-Keplerian parameters via relativistic spin-orbit coupling. We discuss the implications of our findings, including those for the moment of inertia of neutron stars, and present the currently most precise test of general relativity’s quadrupolar description of gravitational waves, validating the prediction of general relativity at a level of 1.3×10^{-4} with 95% confidence. We demonstrate the utility of the double pulsar for tests of alternative theories of gravity by focusing on two specific examples and also discuss some implications of the observations for studies of the interstellar medium and models for the formation of the double pulsar system. Finally, we provide context to other types of related experiments and prospects for the future.
Semiconductor nanowires have been the subject of intensive research investment over the past few decades. Their physical properties afford them applications in a vast network of active ...microelectronic research fields, including logic device scaling in very large scale integrated circuits, sensor devices, and energy harvesting. A range of routes to semiconductor nanowire production have opened up as a result of advances in nanowire fabrication techniques over the last number of decades. These nanowire fabrication routes can usually be categorized into one of two paradigms, bottom-up or top-down. Microelectronic systems typically rely on integrated device platforms, where each device and component thereof can be individually addressed. This requirement for precise addressability places significant demands on the mode of fabrication, specifically with regard to device definition, placement and density, which have typically been strengths of top-down fabrication processes. However, in recent years, advances in bottom-up fabrication processes have opened up the possibility of a synergy between bottom-up and top-down processes to achieve the benefits of both. This review article highlights the important considerations required for the continued advancement of semiconductor nanowire fabrication with a focus on the application of semiconductor nanowire fabrication for next-generation field-effect transistor devices.
tempo2 is a new software package for the analysis of pulsar pulse times of arrival. In this paper, we describe in detail the timing model used by tempo2, and discuss limitations on the attainable ...precision. In addition to the intrinsic slow-down behaviour of the pulsar, tempo2 accounts for the effects of a binary orbital motion, the secular motion of the pulsar or binary system, interstellar, Solar system and ionospheric dispersion, observatory motion (including Earth rotation, precession, nutation, polar motion and orbital motion), tropospheric propagation delay, and gravitational time-dilation due to binary companions and Solar system bodies. We believe that the timing model is accurate in its description of predictable systematic timing effects to better than 1 ns, except in the case of relativistic binary systems where further theoretical development is needed. The largest remaining sources of potential error are measurement error, interstellar scattering, Solar system ephemeris errors, atomic clock instability and gravitational waves.
Gravitational waves are expected to be radiated by supermassive black hole binaries formed during galaxy mergers. A stochastic superposition of gravitational waves from all such binary systems would ...modulate the arrival times of pulses from radio pulsars. Using observations of millisecond pulsars obtained with the Parkes radio telescope, we constrained the characteristic amplitude of this background, Ac,yr, to be <1.0 × 10–15 with 95% confidence. This limit excludes predicted ranges for Ac,yr from current models with 91 to 99.7% probability. We conclude that binary evolution is either stalled or dramatically accelerated by galactic-center environments and that higher-cadence and shorter-wavelength observations would be more sensitive to gravitational waves.
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