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The most abundant neutral constituent in the exospheric region (i.e., beyond = 500 km altitude) is the atomic hydrogen (H); however, its density distributions predicted by physics-based models have been challenged by satellite-based observations of its far ultraviolet emissions. This discrepancy may impact magnetospheric ions' densities and velocities since numerous chemistry and ion-neutral coupling interactions rely sensitively on the underlying neutral hydrogen population. The Polar Wind Outflow Model a first-principled model for relevant ion species in the high-latitude ionosphere, is employed to investigate the role of neutral H on the ionospheric outflow. Specifically, variability in the outflow of ionospheric H+, He+, N+, and O+ as a response to systematic enhancement and depletion of H number densities were simulated. The altitudedependent ion density and energy partition profiles vary with neutral H density, solar activities, and ion species. These findings suggest that the exosphere plays a crucial role in controlling the production and loss of ions through ionospheric chemistry, as well as the energy contributions by altering ionneutral-electron collisions and the ambipolar electric field to the high-latitude ionospheric outflow. As a result, the escape rates of the ionospheric outflow are directly associated with exospheric distributions. This work potentially helps understand the dominant mechanisms of atmospheric escape, particularly during a hydrogen-rich early Earth's and exoplanet's atmosphere, which is known to play a significant role in understanding the evolution of Earth's atmosphere. [ABSTRACT FROM AUTHOR]

The oncogenic fusion protein EWS::FLI1 is an attractive therapeutic target in Ewing sarcoma (ES). Mithramycin A (MithA) is a potent and specific inhibitor of EWS::FLI1 that can selectively radiosensitize ES cells through transcriptional inhibition of DNA double-strand break (DSB) repair. Here, we evaluate temporal changes in cell cycle progression and apoptosis in ES cells treated with MithA and/or ionizing radiation (RTx), testing the hypothesis that combining MithA with ionizing radiation would synergistically impair cell cycle progression and enhance apoptotic elimination to a greater extent than either agent alone. Four EWS::FLI1+ ES cell lines TC-71, RD-ES, SK-ES-1, and A673, and one EWS::ERG cell line (CHLA-25) were exposed to 10nM MithA or vehicle and followed 24 h later by exposure to 2 Gy x-radiation or sham irradiation. Reactive oxygen species (ROS) activity was evaluated by cytometric assay, and assay of antioxidant gene expression by RT-qPCR. Cell cycle changes were evaluated by flow cytometry of nuclei stained with propidium iodide. Apoptosis was assessed by cytometric assessment of Caspase-3/7 activity and by immunoblotting of PARP-1 cleavage. Radiosensitization was evaluated by clonogenic survival assay. Proliferation (EdU) and apoptosis (TUNEL) were evaluated in SK-ES-1 xenograft tumors following pretreatment with 1 mg/kg MithA, followed 24 h later by a single 4 Gy fraction of x-radiation. MithA-treated cells showed reduced levels of ROS, and were associated with increased expression of antioxidant genes SOD1, SOD2, and CAT. It nonetheless induced persistent G0/G1 arrest and a progressive increase of the sub-G1 fraction, suggesting apoptotic degeneration. In vitro assays of Caspase-3/7 activity and immunoblotting of Caspase-3/7 dependent cleavage of PARP-1 indicated that apoptosis began as early as 24 h after MithA exposure, reducing clonogenic survival. Tumors from xenograft mice treated with either radiation alone, or in combination with MithA showed a significant reduction of tumor cell proliferation, while apoptosis was significantly increased in the group receiving the combination of MithA and RTx. Taken together, our data show that the anti-proliferative and cytotoxic effects of MithA are the prominent components of radiosensitization of EWS::FLI1+ ES, rather than the result of acutely enhanced ROS levels. [ABSTRACT FROM AUTHOR]

Purpose: The oncogenic EWS:Fli1 fusion protein is a key transcriptional mediator of Ewing sarcoma initiation, progression, and therapeutic resistance. Mithramycin A (MithA) is a potent and specific inhibitor of transcription mediated by the EWS:Fli1. We tested the hypothesis that pretreatment with MithA could selectively radiosensitize EWS:Fli1+ tumor cells by altering the transcriptional response to radiation injury.Methods and Materials: A panel of 4 EWS:Fli1+ and 3 EWS:Fli1- Ewing sarcoma cell lines and 1 nontumor cell line were subjected to MithA dose-response viability assays to determine the relative potency of MithA in cells possessing or lacking the EWS:Fli1 fusion. Radiosensitization by MithA was evaluated by clonogenic survival assays in vitro and in a murine xenograft model. DNA damage was evaluated by comet assay and γ-H2Ax flow cytometry. Immunoblotting, flow cytometry, and reverse-transcription, polymerase chain reaction were used to evaluate DNA damage-induced signaling and repair processes and apoptosis.Results: We found that MithA alone could potently and selectively inhibit the growth of EWS:Fli1+ tumor cells, but not cells lacking this fusion. Pretreatment with MithA for 24 hours before irradiation significantly reduced clonogenic survival in vitro and delayed tumor regrowth in vivo, prolonging survival of EWS:Fli1+ tumor-bearing mice. Although MithA did not increase the level of DNA double-strand breaks, mechanistic studies revealed that MithA pretreatment selectively inhibited DNA double-strand break repair through downregulation of EWS:Fli1-mediated transcription, leading to tumor cell death by apoptosis.Conclusions: Our data indicate that MithA is an effective radiosensitizer of EWS:Fli1+ tumors and may achieve better local control at lower doses of radiation. [ABSTRACT FROM AUTHOR]

The escape of heavy ions from the Earth atmosphere is a consequence of energization and transport mechanisms, including photoionization, electron precipitation, ion‐electron‐neutral chemistry, and collisions. Numerous studies considered the outflow of O+ ions only, but ignored the observational record of outflowing N+. In spite of 12% mass difference, N+ and O+ ions have different ionization potentials, ionospheric chemistry, and scale heights. We expanded the Polar Wind Outflow Model (PWOM) to include N+ and key molecular ions in the polar wind. We refer to this model expansion as the Seven Ion Polar Wind Outflow Model (7iPWOM), which involves expanded schemes for suprathermal electron production and ion‐electron‐neutral chemistry and collisions. Numerical experiments, designed to probe the influence of season, as well as that of solar conditions, suggest that N+ is a significant ion species in the polar ionosphere and its presence largely improves the polar wind solution, as compared to observations. Plain Language Summary: Nitrogen is the most abundant element in the Earth's atmosphere. Around 78% N2 and 21% O2 form the air we breathe and expand into high‐altitude atmosphere, the thermosphere, and eventually the ionosphere. The neutral molecules in the ionosphere are ionized by solar radiation, and some of them break up into atoms, and others become charged particles. The ionospheric ions with sufficient energy can flow out into space, and the abundances of these outflowing ionospheric ions highly impact the near‐Earth plasma properties. Studies focused on outflowing O+ ions have been conducted for several years. However, the contribution of N+ ions to the outflow solution is still largely unknown due to the instrumental limitations. This letter addresses the transport and energization of ionospheric N+ ions based on theoretical predictions, and examines the role of N+ ions to the collision and chemistry in the topside ionosphere. This study shows that N+ ions are important components in the high‐altitude polar ionosphere and their abundances can be affected by the sunlight and seasonal variations. Key Points: We developed a seven‐ion polar wind model (7iPWOM), which solves for the outflowing N+ ionsN+ ions are the second most abundant ionospheric species, up to 1,200 kmThe presence of N+ ions improves the overall polar wind solution, when compared with observations [ABSTRACT FROM AUTHOR]

The article focuses on the importance of an instructional partnership between librarians and faculty in improving learning abilities of the student as well as exposing them to East Asian languages. It presents two examples of how faculty members can help student in understanding East Asian language through partnering with librarians which includes requiring student to use East Asian language in research and assignments. It cites that faculty can require student to use library resources in East Asia languages in their research paper and to work with East Asian librarian in locating the materials. It relates that faculty can also ask student to use East Asian materials for language learning assignments. It discusses how the two strategies can be implemented in the instructional system.

Purpose: The oncogenic EWS:Fli1 fusion protein is a key transcriptional mediator of Ewing sarcoma initiation, progression, and therapeutic resistance. Mithramycin A (MithA) is a potent and specific inhibitor of transcription mediated by the EWS:Fli1. We tested the hypothesis that pretreatment with MithA could selectively radiosensitize EWS:Fli1 + tumor cells by altering the transcriptional response to radiation injury., Methods and Materials: A panel of 4 EWS:Fli1 + and 3 EWS:Fli1 - Ewing sarcoma cell lines and 1 nontumor cell line were subjected to MithA dose-response viability assays to determine the relative potency of MithA in cells possessing or lacking the EWS:Fli1 fusion. Radiosensitization by MithA was evaluated by clonogenic survival assays in vitro and in a murine xenograft model. DNA damage was evaluated by comet assay and γ-H2Ax flow cytometry. Immunoblotting, flow cytometry, and reverse-transcription, polymerase chain reaction were used to evaluate DNA damage-induced signaling and repair processes and apoptosis., Results: We found that MithA alone could potently and selectively inhibit the growth of EWS:Fli1 + tumor cells, but not cells lacking this fusion. Pretreatment with MithA for 24 hours before irradiation significantly reduced clonogenic survival in vitro and delayed tumor regrowth in vivo, prolonging survival of EWS:Fli1 + tumor-bearing mice. Although MithA did not increase the level of DNA double-strand breaks, mechanistic studies revealed that MithA pretreatment selectively inhibited DNA double-strand break repair through downregulation of EWS:Fli1-mediated transcription, leading to tumor cell death by apoptosis., Conclusions: Our data indicate that MithA is an effective radiosensitizer of EWS:Fli1 + tumors and may achieve better local control at lower doses of radiation., (Copyright © 2021 Elsevier Inc. All rights reserved.)