The Ras GTPases are frequently mutated in human cancer, and, although the Raf kinases are essential effectors of Ras signaling, the tumorigenic properties of specific Ras-Raf complexes are not well ...characterized. Here, we examine the ability of individual Ras and Raf proteins to interact in live cells using bioluminescence resonance energy transfer (BRET) technology. We find that C-Raf binds all mutant Ras proteins with high affinity, whereas B-Raf exhibits a striking preference for mutant K-Ras. This selectivity is mediated by the acidic, N-terminal segment of B-Raf and requires the K-Ras polybasic region for high-affinity binding. In addition, we find that C-Raf is critical for mutant H-Ras-driven signaling and that events stabilizing B-Raf/C-Raf dimerization, such as Raf inhibitor treatment or certain B-Raf mutations, can allow mutant H-Ras to engage B-Raf with increased affinity to promote tumorigenesis, thus revealing a previously unappreciated role for C-Raf in potentiating B-Raf function.
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•C-Raf binds all Ras proteins equivalently, but B-Raf exhibits selectivity for K-Ras•Raf N-terminal segments and Ras HVR sequences determine binding preferences•C-Raf is critical for downstream transmission of H-Ras-driven signaling•Events that increase B-Raf/C-Raf dimerization augment the B-Raf/H-Ras interaction
The Raf kinases bind to active Ras proteins and function to transmit signals that control cell growth and tumorigenesis. The study by Terrell et al. reveals distinct binding preferences between individual Ras and Raf family members and identifies events that can alter these interactions to upregulate Ras-driven cancer signaling.
Summary
Primary production in the Southern Ocean is dominated by diatom‐rich phytoplankton assemblages, whose individual physiological characteristics and community composition are strongly shaped by ...the environment, yet knowledge on how diatoms allocate cellular energy in response to ocean acidification (OA) is limited. Understanding such changes in allocation is integral to determining the nutritional quality of diatoms and the subsequent impacts on the trophic transfer of energy and nutrients.
Using synchrotron‐based Fourier transform infrared microspectroscopy, we analysed the macromolecular content of selected individual diatom taxa from a natural Antarctic phytoplankton community exposed to a gradient of fCO2 levels (288–1263 µatm).
Strong species‐specific differences in macromolecular partitioning were observed under OA. Large taxa showed preferential energy allocation towards proteins, while smaller taxa increased both lipid and protein stores at high fCO2.
If these changes are representative of future Antarctic diatom physiology, we may expect a shift away from lipid‐rich large diatoms towards a community dominated by smaller taxa, but with higher lipid and protein stores than their present‐day contemporaries, a response that could have cascading effects on food web dynamics in the Antarctic marine ecosystem.
Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO₂⁻) and Na2-EDTA ...(disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism Pseudomonas aeruginosa in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of P. aeruginosa with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.
The amount of ice present in clouds can affect cloud lifetime, precipitation and radiative properties. The formation of ice in clouds is facilitated by the presence of airborne ice-nucleating ...particles. Sea spray is one of the major global sources of atmospheric particles, but it is unclear to what extent these particles are capable of nucleating ice. Sea-spray aerosol contains large amounts of organic material that is ejected into the atmosphere during bubble bursting at the organically enriched sea-air interface or sea surface microlayer. Here we show that organic material in the sea surface microlayer nucleates ice under conditions relevant for mixed-phase cloud and high-altitude ice cloud formation. The ice-nucleating material is probably biogenic and less than approximately 0.2 micrometres in size. We find that exudates separated from cells of the marine diatom Thalassiosira pseudonana nucleate ice, and propose that organic material associated with phytoplankton cell exudates is a likely candidate for the observed ice-nucleating ability of the microlayer samples. Global model simulations of marine organic aerosol, in combination with our measurements, suggest that marine organic material may be an important source of ice-nucleating particles in remote marine environments such as the Southern Ocean, North Pacific Ocean and North Atlantic Ocean.
The Kilodegree Extremely Little Telescope (KELT) project has been conducting a photometric survey of transiting planets orbiting bright stars for over 10 years. The KELT images have a pixel scale of ...∼23″ pixel−1-very similar to that of NASA's Transiting Exoplanet Survey Satellite (TESS)-as well as a large point-spread function, and the KELT reduction pipeline uses a weighted photometric aperture with radius 3′. At this angular scale, multiple stars are typically blended in the photometric apertures. In order to identify false positives and confirm transiting exoplanets, we have assembled a follow-up network (KELT-FUN) to conduct imaging with spatial resolution, cadence, and photometric precision higher than the KELT telescopes, as well as spectroscopic observations of the candidate host stars. The KELT-FUN team has followed-up over 1600 planet candidates since 2011, resulting in more than 20 planet discoveries. Excluding ∼450 false alarms of non-astrophysical origin (i.e., instrumental noise or systematics), we present an all-sky catalog of the 1128 bright stars (6 < V < 13) that show transit-like features in the KELT light curves, but which were subsequently determined to be astrophysical false positives (FPs) after photometric and/or spectroscopic follow-up observations. The KELT-FUN team continues to pursue KELT and other planet candidates and will eventually follow up certain classes of TESS candidates. The KELT FP catalog will help minimize the duplication of follow-up observations by current and future transit surveys such as TESS.
We present the discovery of KELT-21b, a hot Jupiter transiting the V = 10.5 A8V star HD 332124. The planet has an orbital period of P = 3.6127647 0.0000033 days and a radius of . We set an upper ...limit on the planetary mass of at confidence. We confirmed the planetary nature of the transiting companion using this mass limit and Doppler tomographic observations to verify that the companion transits HD 332124. These data also demonstrate that the planetary orbit is well-aligned with the stellar spin, with a sky-projected spin-orbit misalignment of . The star has K, , , and km s−1, the highest projected rotation velocity of any star known to host a transiting hot Jupiter. The star also appears to be somewhat metal poor and -enhanced, with and /Fe = 0.145 0.053; these abundances are unusual, but not extraordinary, for a young star with thin-disk kinematics like KELT-21. High-resolution imaging observations revealed the presence of a pair of stellar companions to KELT-21, located at a separation of 1 2 and with a combined contrast of with respect to the primary. Although these companions are most likely physically associated with KELT-21, we cannot confirm this with our current data. If associated, the candidate companions KELT-21 B and C would each have masses of ∼0.12 , a projected mutual separation of ∼20 au, and a projected separation of ∼500 au from KELT-21. KELT-21b may be one of only a handful of known transiting planets in hierarchical triple stellar systems.
The death of massive stars, manifested as gamma-ray bursts and core-collapse supernovae, critically influence how the universe formed and evolves. Despite their fundamental importance, our ...understanding of these enigmatic objects is severely limited. We have performed a concept study of an Astrophysical Transient Observatory (ATO) that will rapidly facilitate an expansion of our understanding of these objects. ATO combines a very wide-field X-ray telescope, a near-infrared telescope, a multi-mode ultraviolet instrument, and a rapidly slewing spacecraft to realize two primary goals: (1) characterize the highest-redshift massive stars and their environments, and (2) constrain the poorly understood explosion mechanism of massive stars. The goals are met by observing the first massive stars to explode as gamma-ray bursts and to probe their environments, and by observing the shock breakout of core-collapse supernovae to measure the outer envelope parameters of massive stars. Additionally, ATO will observe the shock breakout of Type Ia supernovae and their shock interaction with a companion, electromagnetic counterparts to gravitational wave sources, kilonovae, tidal disruption events, cataclysmic variables, X-ray transients, flares from exoplanet host stars, and the escape of ionizing radiation from star-forming galaxies. A description of the ATO instruments, the mission simulation, and technology readiness level is provided.
Hematopoiesis in mammals undergoes a developmental shift in location from fetal liver to bone marrow accompanied by a gradual transition from highly proliferative to deeply quiescent stem cell ...populations. P2Y receptors are G-protein-coupled nucleotide receptors participating in vascular and immune responses to injury. We identified a P2Y-like receptor for UDP-conjugated sugars, GPR105 (P2Y14), with restricted expression on primitive cells in the hematopoietic lineage. Anti-GPR105 antibody selectively isolated a subset of hematopoietic cells within the fetal bone marrow, but not in the fetal liver, that was enriched for G0 cell cycle status and for in vitro stem-cell-like multipotential long-term culture capability. Conditioned media from bone marrow stroma induced receptor activation and chemotaxis that was sensitive to G alpha i and anti-receptor antibody inhibition. GPR105 is a G-protein-coupled receptor identifying a quiescent, primitive population of hematopoietic cells restricted to bone marrow. It mediates primitive cell responses to specific hematopoietic microenvironments and extends the known immune system functions of P2Y receptors to the stem cell level. These data suggest a new class of receptors participating in the regulation of the stem cell compartment.
RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S ...activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.
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•RAC1P29S activates PAK, AKT, and the SRF/MRTF transcription program in melanocytes•RAC1P29S induces a melanocytic to mesenchymal transition through SRF/MRTF and PAK•RAC1P29S cooperates with BRAF mutation or NF1 deletion to promote melanomagenesis•RAC1P29S induces resistance to BRAF inhibitors through SRF/MRTF
RAC1P29S is a common mutation in human cutaneous melanoma. Lionarons et al. show that RAC1P29S induces a melanocytic to mesenchymal switch via an SRF/MRTF-mediated gene expression program, cooperates with BRAF in melanomagenesis, and drives BRAF inhibitor resistance, which is reversed by SRF/MRTF inhibition.
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