We present experimental results from the first systematic study of performance scaling with drive parameters for a magnetoinertial fusion concept. In magnetized liner inertial fusion experiments, the ...burn-averaged ion temperature doubles to 3.1 keV and the primary deuterium-deuterium neutron yield increases by more than an order of magnitude to 1.1 × 1013 (2 kJ deuterium-tritium equivalent) through a simultaneous increase in the applied magnetic field (from 10.4 to 15.9 T), laser preheat energy (from 0.46 to 1.2 kJ), and current coupling (from 16 to 20 MA). Individual parametric scans of the initial magnetic field and laser preheat energy show the expected trends, demonstrating the importance of magnetic insulation and the impact of the Nernst effect for this concept. A drive-current scan shows that present experiments operate close to the point where implosion stability is a limiting factor in performance, demonstrating the need to raise fuel pressure as drive current is increased. Simulations that capture these experimental trends indicate that another order of magnitude increase in yield on the Z facility is possible with additional increases of input parameters.
Most of the world's crops depend on pollinators, so declines in both managed and wild bees raise concerns about food security. However, the degree to which insect pollination is actually limiting ...current crop production is poorly understood, as is the role of wild species (as opposed to managed honeybees) in pollinating crops, particularly in intensive production areas. We established a nationwide study to assess the extent of pollinator limitation in seven crops at 131 locations situated across major crop-producing areas of the USA. We found that five out of seven crops showed evidence of pollinator limitation. Wild bees and honeybees provided comparable amounts of pollination for most crops, even in agriculturally intensive regions. We estimated the nationwide annual production value of wild pollinators to the seven crops we studied at over $1.5 billion; the value of wild bee pollination of all pollinator-dependent crops would be much greater. Our findings show that pollinator declines could translate directly into decreased yields or production for most of the crops studied, and that wild species contribute substantially to pollination of most study crops in major crop-producing regions.
We report the magneto-Rayleigh-Taylor instability (MRTI) plays an essential role in astrophysical systems and in magneto-inertial fusion, where it is known to be an important degradation mechanism of ...confinement and target performance. In this Letter, we show for the first time experimental evidence of mode mixing and the onset of an inverse-cascade process resulting from the nonlinear coupling of two discrete preseeded axial modes (400- and 550 - μm wavelengths) on an Al liner that is magnetically imploded using the 20-MA, 100-ns rise-time Z Machine at Sandia National Laboratories. Four radiographs captured the temporal evolution of the MRTI. We introduce a novel unfold technique to analyze the experimental radiographs and compare the results to simulations and to a weakly nonlinear model. We find good quantitative agreement with simulations using the radiation magnetohydrodynamics code hydra. Spectral analysis of the MRTI time evolution obtained from the simulations shows evidence of harmonic generation, mode coupling, and the onset of an inverse-cascade process. The experiments provide a benchmark for future work on the MRTI and motivate the development of new analytical theories to better understand this instability.
Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently ...demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited.
This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH.
We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months 95% confidence interval 3.6–10.8 months. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation.
RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.
•Resistance is a major challenge in RET fusion-positive lung cancer treated with RET tyrosine kinase inhibitors (TKIs).•RET mutations involving the solvent front residue G810 are a recurrent yet infrequent mechanism of resistance to RET TKIs.•The majority of resistance to selective RET inhibition is driven by RET-independent resistance, such as MET amplification.•RET TKIs with potency against RET solvent front mutations and combination strategies are needed to overcome resistance.
It is common to conceptualize the water table as a subdued replica of surface topography, where groundwater recharges at, and flows from, topographic highs and flows to, and discharges at, ...topographic lows, in humid (i.e. wetter) environments. This concept is also regularly applied to peatland hydrology, where hydraulic gradients are shown to be towards the peatland. However, this may not be a realistic representation of hydrology for low-relief and sub-humid regions. While it is widely accepted that peatlands maintain internal water tables in drought conditions through a system of autogenic negative feedback loops, there is a general lack of knowledge concerning the controls on, and patterns of, forestland hydrologic process that drive the hydraulic gradients between wetlands and their adjacent forestlands in water-limited conditions in low-relief areas. This study identifies the hydrologic function (i.e. source or sink of water) of forested uplands and peatlands in the Boreal Plains region of Canada and demonstrates that during a mesic (non-drought) year most peatlands are, in fact, potential sources of groundwater to adjacent forestlands. Sixteen forestland-peatland pairs were selected to represent a spectrum of forested hummock and peatland morphometries, topographic positions, and geologic settings. Hydraulic gradients determined for each well pair during the ice-off season demonstrate that the dominant gradient under mesic climatic conditions is from peatlands to adjacent forestlands, opposite of the topographic gradient, and that the sink-source function of each land unit does not change seasonally. Water table depressions under each forested hummock indicate that boreal forestlands are not reliable sources of groundwater recharge, spatially or temporally, which supports previous research showing that peatlands are the primary water source for runoff; illustrating the need for alternative conceptualizations of catchment hydrology in water limited regions of the boreal. Social Media Summary. Forests are poor sources of water to boreal peatlands and landscapes due to water table depressions.
Magnetizing the fuel in inertial confinement fusion relaxes ignition requirements by reducing thermal conductivity and changing the physics of burn product confinement. Diagnosing the level of fuel ...magnetization during burn is critical to understanding target performance in magneto-inertial fusion (MIF) implosions. In pure deuterium fusion plasma, 1.01 MeV tritons are emitted during deuterium-deuterium fusion and can undergo secondary deuterium-tritium reactions before exiting the fuel. Increasing the fuel magnetization elongates the path lengths through the fuel of some of the tritons, enhancing their probability of reaction. Based on this feature, a method to diagnose fuel magnetization using the ratio of overall deuterium-tritium to deuterium-deuterium neutron yields is developed. Analysis of anisotropies in the secondary neutron energy spectra further constrain the measurement. Secondary reactions also are shown to provide an upper bound for the volumetric fuel-pusher mix in MIF. The analysis is applied to recent MIF experiments M. R. Gomez et al., Phys. Rev. Lett. 113, 155003 (2014) on the Z Pulsed Power Facility, indicating that significant magnetic confinement of charged burn products was achieved and suggesting a relatively low-mix environment. Both of these are essential features of future ignition-scale MIF designs.
Phenotypic heterogeneity exists within collectively invading packs of tumor cells, suggesting that cellular subtypes cooperate to drive invasion and metastasis. Here, we take a chemical biology ...approach to probe cell:cell cooperation within the collective invasion pack. These data reveal metabolic heterogeneity within invasive chains, in which leader cells preferentially utilize mitochondrial respiration and trailing follower cells rely on elevated glucose uptake. We define a pyruvate dehydrogenase (PDH) dependency in leader cells that can be therapeutically exploited with the mitochondria-targeting compound alexidine dihydrochloride. In contrast, follower cells highly express glucose transporter 1 (GLUT1), which sustains an elevated level of glucose uptake required to maintain proliferation. Co-targeting of both leader and follower cells with PDH and GLUT1 inhibitors, respectively, inhibits cell growth and collective invasion. Taken together, our work reveals metabolic heterogeneity within the lung cancer collective invasion pack and provides rationale for co-targeting PDH and GLUT1 to inhibit collective invasion.
The pace of discovery of potentially actionable pharmacogenetic variants has increased dramatically in recent years. However, the implementation of this new knowledge for individualized patient care ...has been slow. The Pharmacogenomics Research Network (PGRN) Translational Pharmacogenetics Program seeks to identify barriers and develop real‐world solutions to implementation of evidence‐based pharmacogenetic tests in diverse health‐care settings. Dissemination of the resulting toolbox of “implementation best practices” will prove useful to a broad audience.
Clinical Pharmacology & Therapeutics (2013); 94 2, 207–210. doi:10.1038/clpt.2013.59
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