Hedgehog signaling is aberrantly activated in glioma, medulloblastoma, basal cell carcinoma, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, breast cancer, and other tumors. ...Hedgehog signals activate GLI family members via Smoothened. RTK signaling potentiates GLI activity through PI3K-AKT-mediated GSK3 inactivation or RAS-STIL1-mediated SUFU inactivation, while GPCR signaling to Gs represses GLI activity through adenylate cyclase-mediated PKA activation. GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin. Hedgehog signals are fine-tuned based on positive feedback loop via GLI1 and negative feedback loop via PTCH1, PTCH2, and HHIP1. Excessive positive feedback or collapsed negative feedback of Hedgehog signaling due to epigenetic or genetic alterations leads to carcinogenesis. Hedgehog signals induce cellular proliferation through upregulation of N-Myc, Cyclin D/E, and FOXM1. Hedgehog signals directly upregulate JAG2, indirectly upregulate mesenchymal BMP4 via FOXF1 or FOXL1, and also upregulate WNT2B and WNT5A. Hedgehog signals induce stem cell markers BMI1, LGR5, CD44 and CD133 based on cross-talk with WNT and/or other signals. Hedgehog signals upregulate BCL2 and CFLAR to promote cellular survival, SNAI1 (Snail), SNAI2 (Slug), ZEB1, ZEB2 (SIP1), TWIST2, and FOXC2 to promote epithelial-to-mesenchymal transition, and PTHLH (PTHrP) to promote osteolytic bone metastasis. KAAD-cyclopamine, Mu-SSKYQ-cyclopamine, IPI-269609, SANT1, SANT2, CUR61414 and HhAntag are small-molecule inhibitors targeted to Smoothened, GANT58, GANT61 to GLI1 and GLI2, and Robot-nikinin to SHH. Hedgehog signaling inhibitors should be used in combination with RTK inhibitors, GPCR modulators, and/or irradiation for cancer therapy.
Chorus emissions composed of coherent whistler mode waves are responsible for pitch angle scattering of energetic electrons. This scattering is closely related to energetic electron precipitation ...into the atmosphere, contributing to pulsating auroras. Conventionally, energetic electrons are considered to satisfy the cyclotron resonance condition over the energy range of a few to tens of kiloelectron volts and are scattered toward the loss cone by waves. However, previous simulation studies indicate that low pitch angle electrons tend to be scattered away from the loss cone by coherent whistler mode waves. We examine the mechanism of anomalous trapping at low pitch angles, deriving a particle equation with low pitch angle assumptions. An additional term that is conventionally neglected represents the Lorentz force caused by the wave magnetic field and the parallel particle velocity. Therefore, due to the large v‖×Bw Lorentz force, low pitch angle electrons satisfying the cyclotron resonant condition are scattered away from the loss cone and effectively trapped by waves. We perform test particle simulations in a one‐dimensional dipole magnetic field with a whistler mode wave model and reproduce the anomalous trapping of electrons. The simulation results show that the majority of electrons at high and moderate pitch angles are scattered toward low pitch angle regions while low pitch angle electrons are strongly scattered toward high pitch angle regions. Consequently, a coherent chorus element produces a bump in the electron pitch angle distribution.
Key Points
Coherent whistler mode waves cause anomalous trapping of electrons at low pitch angles
Test particle simulations demonstrate the theoretically predicted motion of electrons
The relation between wave intensity and electron flux near the loss cone is not proportional
International development of reduced activation ferritic-martensitic (RAFM) steels has focused on 9 wt percentage Cr, which primarily contain M23C6 (M = Cr-rich) and small amounts of MX (M = Ta/V, ...X = C/N) precipitates, not adequate to maintain strength and creep resistance above ∼500 °C. To enable applications at higher temperatures for better thermal efficiency of fusion reactors, computational alloy thermodynamics coupled with strength modeling have been employed to explore a new generation RAFM steels. The new alloys are designed to significantly increase the amount of MX nanoprecipitates, which are manufacturable through standard and scalable industrial steelmaking methods. Preliminary experimental results of the developed new alloys demonstrated noticeably increased amount of MX, favoring significantly improved strength, creep resistance, and Charpy impact toughness as compared to current RAFM steels. The strength and creep resistance were comparable or approaching to the lower bound of, but impact toughness was noticeably superior to 9–20Cr oxide dispersion-strengthened ferritic alloys.
To collect data for fusion applications and understand the basic properties of tungsten, single-crystal tungsten was neutron irradiated in the mixed-spectrum High Flux Isotope Reactor at the Oak ...Ridge National Laboratory at temperatures of 90–830 °C to fast fluences of 0.01–9 × 1025 n/m2 (E > 0.1 MeV). For tensile tests at room temperature of the irradiated material in both orientations, and tensile orientation, initially there was strengthening that peaked at 0.02 dpa and was followed by progressive modulus of toughness reduction, approaching zero at higher doses. For all irradiation temperatures, in elevated temperature tensile tests there was a distinct transition from ductile-to-brittle behavior between 0.1 and 0.4 dpa, accompanied by an increase in indentation hardness. The ductile-to-brittle transition with increasing dose was particularly critical because it presented as a total loss in elongation and modulus of toughness. The critical transition dose was well below the dose (∼1 dpa) where irradiation-induced precipitates are visible in the TEM. The extent of Vickers microhardness increase was significant at higher doses and did not depend on irradiation temperature or crystal orientation, reaching 12.9 GPa after 2.8 dpa. The significant mechanical property degradation above 0.1 dpa is believed to have been caused by the accumulation of irradiation-induced clusters and eventually precipitates of the transmutation elements Re and Os.
The Joint Projects under the Japan-USA Fusion Cooperation Program started in 1981 and has continued for more than 40 years. In the Joint Projects, although a wide range of fusion materials and ...engineering issues were covered, neutron radiation effects on fusion reactor materials have always been the major research emphases, and the neutron irradiation facilities in the US were jointly used by Japanese and US researchers. Japanese test facilities including neutron and charged particle irradiation facilities were complementarily used.
The initial focus of the Joint Projects was on fundamental fusion neutron radiation effects and irradiation correlation. Systematic comparison of fission and fusion radiation effects in comparable damage levels and the effects of transmutation-induced helium were investigated. The collaboration was then focused on the effect of dynamic irradiation effects in variable conditions. In addition to the relatively fundamental studies, the Joint Projects contributed largely to development of candidate materials such as RAFM steels, vanadium alloys, SiC/SiC composites, and tungsten alloys, through a mechanism-oriented approach. The Joint Projects also covered issues specific to materials application to fusion blankets and plasma-facing components, including neutron radiation effects such as tritium retention and permeation of neutron-irradiated plasma-facing materials. Various irradiation technologies were developed and applied to the irradiation experiments, including those for in-situ testing.
Considering that high energy neutron sources, such as A-FNS and IFMIF-DONES, now have high viability, the research supporting the neutron source programs is essential. The knowledge obtained through the Joint Projects is valuable and should be advanced for this purpose. To this end, it is of urgent necessity to launch an international scientific program accumulating knowledge of fusion neutron radiation effects, including their fundamental aspects.
Intense lower band chorus waves are ubiquitous in the inner magnetosphere. Their properties have been modeled by various codes and investigated using measurements of many spacecraft missions. This ...study aims to compare simulated and observed properties of chorus waves. We present detailed comparisons between results from four different codes of nonlinear chorus wave generation and statistical observations from satellites, focusing on the fine structure of such chorus waves. We show that simulations performed with these different codes well reproduce the observed wave packet characteristics, although in somewhat complementary parameter domains as concerns wave packets sizes, amplitudes, and frequency sweep rates. In particular, simulations generate both the frequently observed short wave packets with high positive and negative frequency sweep rates, and the more rare long and intense packets with mainly rising tones. Moreover, simulations reproduce quantitatively both the increase of the size of the observed chorus wave packets with their peak amplitude, and the fast decrease of their frequency sweep rate as their size increases. This confirms the reliability of the main existing codes for accurately modeling chorus wave generation, although we find that initial conditions should be carefully selected to reproduce a given parameter range.
Key Points
Four different codes of chorus wave nonlinear generation well reproduce the observed wave packet characteristics
The simulations recover complementary domains of observed wave packets sizes, amplitudes, and frequency sweep rates
The simulations reproduce the observed short wave packets with high positive and negative frequency sweep rates
The stability of MX-type precipitates is critical to retain mechanical properties of both reduced activation ferritic–martensitic (RAFM) and conventional FM steels at elevated temperatures above ...∼500°C. The stability of TaC, TaN and VN nanoprecipitates under thermal aging (600 and 700°C), creep (600°C) and ion irradiation (Fe ion, 500°C) conditions was systematically studied in this work. The statistical particle evolution in density and size was characterized using transmission electron microscopy. Nanoprecipitate stability under the studied conditions manifested differently through either dissolution, reprecipitation, growth or fragmentation, with TaC exhibiting the greatest stability followed by VN and TaN in sequence. Nanoprecipitate evolution phenomena and mechanisms and the apparent disagreement of this interpretation with published literature on the subject are discussed. These findings not only help understanding the degradation mechanisms of RAFM and conventional FM steels at elevated temperatures and under stress and irradiation, but should also prove beneficial to the development of advanced RAFM steels.
The silicon carbide fiber-reinforced silicon carbide matrix (SiC/SiC) composite system for fusion applications has seen a continual evolution from development a fundamental understanding of the ...material system and its behavior in a hostile irradiation environment to the current effort which is directed at a broad-based program of technology maturation program. In essence, over the past few decades this material system has steadily moved from a laboratory curiosity to an engineering material, both for fusion structural applications and other high performance application such as aerospace. This paper outlines the recent international scientific and technological achievements towards the development of SiC/SiC composite material technologies for fusion application and discusses future research directions. It also reviews the materials system in the larger context of progress to maturity as an engineering material for both the larger nuclear community and broader engineering applications.
Raman spectra from polycrystalline beta-silicon carbide (SiC) were collected following neutron irradiation at 380–1180°C to 0.011–1.87 displacement per atom. The longitudinal optical (LO) peak ...shifted to a lower frequency and broadened as a result of the irradiation. The changes observed in the LO phonon line shape and position in neutron-irradiated SiC are explained by a combination of changes in the lattice constant and Young's modulus, and the phonon confinement effect. The phonon confinement model reasonably estimates the defect-defect distance in the irradiated SiC, which is consistent with results from previous experimental studies and simulations.
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Castable nanostructured alloys (CNAs) are being developed as a new generation of reduced-activation ferritic-martensitic (RAFM) steels to overcome certain limitations of the current RAFM steels, such ...as their narrow operating temperature range and associated low strength at high temperatures. Six CNAs were developed and examined, exhibiting noticeably increased yield strength, tensile strength and creep resistance as compared to the current RAFM steels, which are comparable to ODS-Eurofer (0.3% Y2O3) at 650 °C. The enhanced strength of CNAs is also associated with a beneficial increase in Charpy impact upper-shelf energies, up to ∼2.5 times that of the current RAFM steels, with comparable ductile-brittle transition temperatures. A broad analysis of microstructure, alloy chemistry and grain size analyses clearly support the mechanisms that explain the mechanical property improvements of these CNAs, providing essential insight for further development of advanced RAFM steels to meet the challenges of future fusion reactors.
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