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Introduction HGF/c-MET signaling is a significant driver of glioblastoma (GBM) growth and disease progression. Unfortunately, c-MET targeted therapies have been found to be largely ineffective suggesting additional redundant mechanisms of c-MET activation. Methods Utilizing RNA-sequencing (RNA-seq) and ribosome profiling analyses of circular RNAs, circ-HGF (hsa_circ_0080914) was identified as markedly upregulated in primary GBM and found to potentially encode an HGF protein variant (C-HGF) 119 amino acids in length. This candidate HGF variant was characterized and evaluated for its ability to mediate c-MET activation and regulate PDX GBM cell growth, motility and invasive potential in vitro and tumor burden in intracranial xenografts in mice. Results An internal ribosome entry site (IRES) was identified within the circ-HGF RNA which mediated translation of the cross-junctional ORF encoding C-HGF and was observed to be highly expressed in GBM relative to normal brain tissue. C-HGF was also found to be secreted from GBM cells and concentrated cell culture supernatants or recombinant C-HGF activated known signaling cascades downstream of c-MET. C-HGF was shown to interact directly with the c-MET receptor resulting in its autophosphorylation and activation in PDX GBM lines. Knockdown of C-HGF resulted in suppression of c-MET signaling and marked inhibition of cell growth, motility and invasiveness, whereas overexpression of C-HGF displayed the opposite effects. Additionally, modulation of C-HGF expression regulated tumor growth in intracranial xenografted PDX GBM models. Conclusions These results reveal an alternative mechanism of c-MET activation via a circular RNA encoded HGF protein variant which is relevant in GBM biology. Targeting C-HGF may offer a promising approach for GBM clinical management.

Heat shock proteins (HSPs), especially Hsp70 (HSPA1), have been associated with cellular protection from various cellular stresses including heat, hypoxia-ischemia, neurodegeneration, toxins, and trauma. Endogenous HSPs are often synthesized in direct response to these stresses but in many situations are inadequate in protecting cells. The present study addresses the transduction of Hsp70 into cells providing protection from acute oxidative stress by H2O2. The recombinant Fv-Hsp70 protein and two mutant Fv-Hsp70 proteins minus the ATPase domain and minus the ATPase and terminal lid domains were tested at 0.5 and 1.0 μM concentrations after two different concentrations of H2O2 treatment. All three recombinant proteins protected SH-SY5Y cells from acute H2O2 toxicity. This data indicated that the protein binding domain was responsible for cellular protection. In addition, experiments pretreating cells with inhibitors of antioxidant proteins catalase and gamma-glutamylcysteine synthase (GGCS) before H2O2 resulted in cell death despite treatment with Fv-Hsp70, implying that both enzymes were protected from acute oxidative stress after treatment with Fv-Hsp70. This study demonstrates that Fv-Hsp70 is protective in our experiments primarily by the protein-binding domain. The Hsp70 terminal lid domain was also not necessary for protection.

Heat shock proteins (HSPs), especially Hsp70 (HSPA1), have been associated with cellular protection from various cellular stresses including heat, hypoxia-ischemia, neurodegeneration, toxins, and trauma. Endogenous HSPs are often synthesized in direct response to these stresses but in many situations are inadequate in protecting cells. The present study addresses the transduction of Hsp70 into cells providing protection from acute oxidative stress by H2O2. The recombinant Fv-Hsp70 protein and two mutant Fv-Hsp70 proteins minus the ATPase domain, and minus the ATPase and terminal lid domains were tested at 0.5 and 1.0 uM concentrations after two different concentrations of H2O2treatment. All three recombinant proteins protected SH-SY5Y cells from acute H2O2toxicity. This data indicated that the protein binding domain was responsible for cellular protection. In addition, experiments pretreating cells with inhibitors of antioxidant proteins catalase and gamma-glutamylcysteine synthase (GGCS) before H2O2resulted in cell death despite treatment with Fv-Hsp70, implying that both enzymes were protected from acute oxidative stress after treatment with Fv-Hsp70. This study demonstrates that Fv-Hsp70 is protective in our experiments primarily by the protein-binding domain. The Hsp70 terminal lid domain was also not necessary for protection. Cellular protection was protective via the antioxidant proteins catalase and GGCS.

Cytoplasmic DNA triggers a cGAS-mediated signaling cascade that promotes an innate immune response and is potentially actionable in cancer immunotherapy. Here we show that a cytoplasmic-localizing lupus anti-DNA autoantibody activates cGAS and facilitates an immune-mediated prolongation of survival in orthotopic models of glioblastoma (GBM). Mechanistically, cellular penetration and blood-brain barrier crossing by the anti-DNA autoantibody is linked to nucleoside transport. Pulldown, knockdown, signaling, and cytotoxicity assays demonstrate autoantibody association with and activation of cGAS. In orthotopic GBM models, the autoantibody localizes to brain tumor, increases tumor CD8+ T cell content, and prolongs survival in immunocompetent but not immunodeficient mice. This work introduces the new concept of a cGAS-activating anti-DNA autoantibody, which impacts theories on mechanisms of autoimmunity and has translational applications in cancer immunotherapy.

The Hippo and mTOR signaling cascades are major regulators of cell growth and division. Aberrant regulation of these pathways has been demonstrated to contribute to gliomagenesis and result in enhanced glioblastoma proliferation and invasive characteristics. Several crosstalk mechanisms have been described between these two pathways, although a complete picture of these signaling interactions is lacking and is required for effective therapeutic targeting. Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity. We show that mTORC2 activity enhances YAP transcriptional activity and the induction of YAP-dependent target gene expression while its ablation via genetic or pharmacological means has the opposite affects on YAP function. mTORC2 interacts with YAP via Sin1 and mutational analysis of serine 436 demonstrates that this phosphorylation event affects several properties of YAP leading to enhanced transactivation potential. Moreover, YAP serine 436 mutants display altered glioblastoma growth, migratory capacity and invasiveness both in vitro and in xenograft experiments. We further demonstrate that mTORC2 is able to regulate a Hippo pathway resistant allele of YAP suggesting that mTORC2 can regulate YAP independent of Hippo signaling. Correlative associations between the expression of these components in GBM patient samples also supported the presence of this signaling relationship. These results advance a direct mTORC2/YAP signaling axis driving GBM growth, motility and invasiveness.

Ξ− atomic X-ray spectroscopy is one of the most useful methods for investigation of the Ξ–nucleus strong interaction. Since the X-ray energy is shifted and/or broadened due to the Ξ–nucleus strong interaction compared to those calculated from electromagnetic interaction alone, the measurement of the energy shift, ΔE, and the width, Γ, give us information on the Ξ–nucleus potential. A serious problem in the measurement is the significant background derived from in-flight Ξ− decay. A novel method of identifying stopped Ξ− events using the nuclear emulsion was developed to realize the first Ξ− atomic X-ray spectroscopy experiment as the J-PARC E07 experiment, which also aimed at searching for ΛΛ and Ξ− hypernuclei in the emulsion. The X-rays emitted from Ξ− Br and Ξ− Ag atoms were measured using germanium detectors. No clear peaks were observed in the obtained spectra. However, we succeeded in reducing the background to 1/170 by this method employing coincidence measurements using nuclear emulsion and X-ray detectors.

The β-delayed one- and two-neutron emission probabilities (P_{1n} and P_{2n}) of 20 neutron-rich nuclei with N≥82 have been measured at the RIBF facility of the RIKEN Nishina Center. P_{1n} of ^{130,131}Ag, ^{133,134}Cd, ^{135,136}In, and ^{138,139}Sn were determined for the first time, and stringent upper limits were placed on P_{2n} for nearly all cases. β-delayed two-neutron emission (β2n) was unambiguously identified in ^{133}Cd and ^{135,136}In, and their P_{2n} were measured. Weak β2n was also detected from ^{137,138}Sn. Our results highlight the effect of the N=82 and Z=50 shell closures on β-delayed neutron emission probability and provide stringent benchmarks for newly developed macroscopic-microscopic and self-consistent global models with the inclusion of a statistical treatment of neutron and γ emission. The impact of our measurements on r-process nucleosynthesis was studied in a neutron star merger scenario. Our P_{1n} and P_{2n} have a direct impact on the odd-even staggering of the final abundance, improving the agreement between calculated and observed Solar System abundances. The odd isotope fraction of Ba in r-process-enhanced (r-II) stars is also better reproduced using our new data.

INTRODUCTION: Recent studies have suggested that dysregulated Hippo pathway signaling may contribute to glioblastoma proliferation and invasive characteristics. The downstream effector of the pathway, the Yes-associated protein (YAP) oncoprotein, has emerged as a promising target in glioblastoma multiforme (GBM). METHODS: Utilizing a high-throughput yeast two-hybrid based screen, a small molecule was identified which inhibits the association of the co-transcriptional activator YAP1 and the TEA domain family member 1 (TEAD1) transcription factor protein–protein interaction interface. This candidate inhibitor, NSC682769, a novel benzazepine compound, was evaluated for its ability to affect Hippo/YAP axis signaling and potential anti-glioblastoma properties. RESULTS: NSC682769 potently blocked association of YAP and TEAD in vitro and in GBM cells treated with submicromolar concentrations. Moreover, inhibitor-coupled bead pull down and surface plasmon resonance analyses demonstrate that NSC682769 binds to YAP. NSC682769 treatment of GBM lines and patient derived cells resulted in downregulation of YAP expression levels resulting in curtailed YAP-TEAD transcriptional activity. In GBM cell models, NSC682769 inhibited proliferation, colony formation, migration, invasiveness and enhanced apoptosis. In tumor xenograft and genetically engineered mouse models, NSC682769 exhibited marked anti-tumor responses and resulted in increased overall survival and displayed significant blood-brain barrier penetration. CONCLUSIONS: These results demonstrate that blockade of YAP-TEAD association is a viable therapeutic strategy for glioblastoma. On the basis of these favorable preclinical studies further clinical studies are warranted.

We investigate the impacts of neutrino cooling mechanism inside the neutron star (NS) core on the light curves of type-I X-ray bursts and X-ray superbursts. From several observations of NS thermal evolution, physical processes of fast neutrino cooling, such as the direct Urca (DU) process, are indicated. They significantly decrease the surface temperature of NSs, though the cooling effect could be suppressed by nucleon superfluidity. In the present study, focusing on the DU process and nucleon superfluidity, we investigate the effects of NS cooling on the X-ray bursts using a general-relativistic stellar-evolution code. We find that the DU process leads find the longer recurrence time and the higher peak luminosity, which could be obstructed by the neutrons superfluidity. We also apply our burst models to the comparison with {\it Clocked burster} GS 1826$-$24, and to the recurrence time of superburst triggered by carbon ignition. These effects are significant within a certain range of binary parameters and uncertainty of the NS equation of state., Comment: 12 pages, 8 figures, 3 Tables

INTRODUCTION: Clinical trials directed at mechanistic target of rapamycin (mTOR) inhibition have yielded disappointing results in glioblastoma (GBM). A major mechanism of resistance involves the activation of a salvage pathway stimulating internal ribosome entry site (IRES)-mediated protein synthesis. PRMT5 activity has been implicated in the enhancement of IRES activity. METHODS: We analyzed the expression and activity of PRMT5 in response to mTOR inhibition in GBM cell lines and short-term patient cultures. To determine whether PRMT5 conferred resistance we used genetic and pharmacological approaches to ablate PRMT5 activity and assessed the effects on in vitro and in vivo sensitivity. Mutational analyses of the requisite IRES-trans-acting factor (ITAF), hnRNP A1 determined whether PRMT5-mediated methylation was necessary for ITAF RNA binding and IRES activity. RESULTS: PRMT5 activity is stimulated in response to mTOR inhibitors. Knockdown or treatment with a PRMT5 inhibitor blocked IRES activity and sensitizes GBM cells. Ectopic expression of non-methylatable hnRNP A1 mutants demonstrated that methylation of either arginine residues 218 or 225 was sufficient to maintain IRES binding and hnRNP A1-dependent cyclin D1 or c-MYC IRES activity, however a double R218K/R225K mutant was unable to do so. The PRMT5 inhibitor EPZ015666 displayed synergistic anti-GBM effects in vitro and in a xenograft mouse model in combination with PP242. CONCLUSIONS: These results demonstrate that PRMT5 activity is stimulated upon mTOR inhibition in GBM. Our data further support a signaling cascade in which PRMT5-mediated methylation of hnRNP A1 promotes IRES RNA binding and activation of IRES-mediated protein synthesis and resultant mTOR inhibitor resistance.

Type I X-ray bursts are thermonuclear explosions on the neutron star (NS) surface caused by mass accretion from a companion star. Observations of X-ray bursts provide valuable information on X-ray binary systems, e.g., binary parameters, the chemical composition of accreted matter, and the nuclear equation of state (EOS) of NSs. There have been several theoretical studies to constrain the physics of X-ray bursters. However, they have mainly focused on the burning layers above the solid crust of the NS, which brings up issues of the treatment of NS gravitation and internal energy. In this study, focusing on the microphysics inside NSs, we calculate a series of X-ray bursts using a general-relativistic stellar-evolution code with several NS EOSs. We compare the X-ray-burst models with the burst parameters of a clocked burster associated with GS 1826-24. We find a monotonic correlation between the NS radius and the light-curve profile. A larger radius shows a higher recurrence time and a large peak luminosity. In contrast, the dependence of light curves on the NS mass becomes more complicated, where the neutrino cooling suppresses the efficiency of nuclear ignition. We also constrain the EOS and mass of GS 1826-24, i.e., stiffer EOSs, corresponding to larger NS radii, are not preferred due to too-high peak luminosity. The EOS and the cooling and heating of NSs are important to discuss the theoretical and observational properties of X-ray bursts., 19 pages, 16 figures, 3 tables, updated to match published version (ApJ)

We have performed the first direct measurement of the 83Rb(p,g) radiative capture reaction cross section in inverse kinematics using a radioactive beam of 83Rb at incident energies of 2.4 and 2.7 A MeV. The measured cross section at an effective relative kinetic energy of Ecm = 2.393 MeV, which lies within the relevant energy window for core collapse supernovae, is smaller than the prediction of statistical model calculations. This leads to the abundance of 84Sr produced in the astrophysical p process being higher than previously calculated. Moreover, the discrepancy of the present data with theoretical predictions indicates that further experimental investigation of p-process reactions involving unstable projectiles is clearly warranted., 6 pages, 4 figures, published in Physical Review Letters

Mosquitoes have developed specialized oviposition strategies that allow them to develop in a wide variety of aquatic habitats. Environmentally cued hatching traits may also play an important role in the successful colonization of some larval habitats, but this subject has remained largely unexplored in Culicidae. Aedes atropalpus (Coquillett) is an autogenous rock pool specialist that may maintain unique adaptations for oviposition and egg hatching. We investigated the egg-laying strategies of Ae. atropalpus exposed to standard (non-diapausing) rearing conditions and diapause-inducing conditions and tested the impact of physical agitation on egg hatch rates by exposing floating and submerged eggs to physical agitation treatments. The results of the oviposition experiment indicate that Ae. atropalpus females primarily lay non-diapausing eggs directly onto the water surface and lay diapausing eggs directly on solid surfaces. The egg-hatching experiment demonstrated that physical agitation significantly increases Ae. atropalpus hatch rates. Floating and submerged eggs responded similarly to the agitation treatment. These data suggest that oviposition behaviors based on both egg diapause status and environmentally-cued hatching strategies may be important adaptations for Ae. atropalpus in riverine rock pools.

The $\nu p$ process appears in proton-rich, hot matter which is expanding in a neutrino wind and may be realised in explosive environments such as core-collapse supernovae or in outflows from accretion disks. The impact of uncertainties in nuclear reaction cross sections on the finally produced abundances has been studied by applying Monte Carlo variation of all astrophysical reaction rates in a large reaction network. As the detailed astrophysical conditions of the $\nu p$ process still are unknown, a parameter study was performed, with 23 trajectories covering a large range of entropies and $Y_\mathrm{e}$. The resulting abundance uncertainties are given for each trajectory. The $\nu p$ process has been speculated to contribute to the light $p$ nuclides but it was not possible so far to reproduce the solar isotope ratios. It is found that it is possible to reproduce the solar $^{92}$Mo/$^{94}$Mo abundance ratio within nuclear uncertainties, even within a single trajectory. The solar values of the abundances in the Kr-Sr region relative to the Mo region, however, cannot be achieved within a single trajectory. They may still be obtained from a weighted superposition of different trajectories, though, depending on the actual conditions in the production site. For a stronger constraint of the required conditions, it would be necessary to reduce the uncertainties in the 3$\alpha$ and $^{56}$Ni(n,p)$^{56}$Co rates at temperatures $T>3$ GK., Comment: 6 pages, 1 figure, 2 tables; to appear in JPS Conference Proceedings (OMEG15, 2019); summarizes and expands on arXiv:1907.13129 with an additional discussion of isotopic ratios of p-nuclides; v2: typos fixed

Internal ribosome entry site (IRES)-mediated protein synthesis has been demonstrated to play an important role in resistance to mechanistic target of rapamycin (mTOR) targeted therapies. Previously, we have demonstrated that the IRES trans-acting factor (ITAF), hnRNP A1 is required to promote IRES activity and small molecule inhibitors which bind specifically to this ITAF and curtail IRES activity, leading to mTOR inhibitor sensitivity. Here we report the identification of riluzole (Rilutek&reg, ), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), via an in silico docking analysis of FDA-approved compounds, as an inhibitor of hnRNP A1. In a riluzole-bead coupled binding assay and in surface plasmon resonance imaging analyses, riluzole was found to directly bind to hnRNP A1 and inhibited IRES activity via effects on ITAF/RNA-binding. Riluzole also demonstrated synergistic anti-glioblastoma (GBM) affects with mTOR inhibitors in vitro and in GBM xenografts in mice. These data suggest that repurposing riluzole, used in conjunction with mTOR inhibitors, may serve as an effective therapeutic option in glioblastoma.

Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.

Ξ− atomic X-ray spectroscopy is one of the most useful methods for investigation of the Ξ-nucleus strong interaction. A serious problem in the measurement is the significant background coming from in-flight Ξ− decay. For the first Ξ− atomic X-ray spectroscopy experiment, a novel method of identifying stopped Ξ− events using nuclear emulsion was developed to reject background photons from in-flight Ξ− decay. We succeeded in reducing the background to 1/170 by this method employing coincidence measurements using the nuclear emulsion and X-ray detectors.

Invasive container mosquito species Aedes aegypti (L.) and Ae. albopictus (Skuse) frequently co-occur in nature where they are typically segregated spatially by distinctive macrohabitat preferences that may select for different oviposition strategies. In a standard cage environment, we compared oviposition site selection by individual gravid females of these species exposed to variable numbers of water-holding cups and the presence or absence of a rugose wettable container lining. Offered plastic cups with and without lining, both species laid a significantly higher percentage of eggs in cups with lining (95.3% for Ae. aegypti, 88.4% for Ae. albopictus), than in cups without (4.7% for Ae. aegypti, 11.6% for Ae. albopictus). Linear regressions of container availability versus the number of lined cups colonized were similar for Ae. aegypti and Ae. albopictus. Rates of oviposition on the water surface differed by species for both cup types, with Ae. albopictus laying a higher percentage of eggs on the water surface in cups without lining (28.1% for Ae. aegypti, 51.3% for Ae. albopictus), than in cups with (5.3% for Ae. aegypti, 2.5% for Ae. albopictus). The more varied oviposition strategies of Ae. albopictus are interpreted in the context of its broader macrohabitat use and inferior egg desiccation resistance.

Rapid displacements of resident Aedes aegypti by invasions of Aedes albopictus have been documented in the southeastern United States and Bermuda. Interspecific mating has been detected in nature between these species and proposed as a likely mechanism for these displacements by means of asymmetric reproductive interference, or satyrization. However, rapid displacements of A. aegypti have not been detected in most localities where these two invasive species are known to co-occur. Aedes albopictus invaded the United States and Brazil at approximately the same time, in the mid-1980s, but the origins of the invading strains are known to be different. Here we tested the hypothesis, in standardized cage environments, that A. albopictus males from Brazil are less capable of satyrizing A. aegypti females than A. albopictus males from the United States. Using strains of A. aegypti and A. albopictus from the United States of known susceptibility to and capacity for interspecific mating, we demonstrate that A. albopictus colonized from collections in the Brazilian cities of Rio de Janeiro and Manaus were relatively unsuccessful in inseminating virgin female A. aegypti from Key West Florida compared to A. albopictus from peninsular Florida. We suggest that the low satyrization potential of Brazilian A. albopictus males may contribute to the lack of documented competitive displacements of A. aegypti in that country.

Overexpression of Rictor has been demonstrated to result in increased mechanistic target of rapamycin C2 (mTORC2) nucleation and activity leading to tumor growth and increased invasive characteristics in glioblastoma multiforme (GBM). However, the mechanisms regulating Rictor expression in these tumors is not clearly understood. In this report, we demonstrate that Rictor is regulated at the level of mRNA translation via heat-shock transcription factor 1 (HSF1)-induced HuR activity. HuR is shown to directly bind the 3' untranslated region of the Rictor transcript and enhance translational efficiency. Moreover, we demonstrate that mTORC2/AKT signaling activates HSF1 resulting in a feed-forward cascade in which continued mTORC2 activity is able to drive Rictor expression. RNAi-mediated blockade of AKT, HSF1 or HuR is sufficient to downregulate Rictor and inhibit GBM growth and invasive characteristics in vitro and suppress xenograft growth in mice. Modulation of AKT or HSF1 activity via the ectopic expression of mutant alleles support the ability of AKT to activate HSF1 and demonstrate continued HSF1/HuR/Rictor signaling in the context of AKT knockdown. We further show that constitutive overexpression of HuR is able to maintain Rictor expression under conditions of AKT or HSF1 loss. The expression of these components is also examined in patient GBM samples and correlative associations between the relative expression of these factors support the presence of these signaling relationships in GBM. These data support a role for a feed-forward loop mechanism by which mTORC2 activity stimulates Rictor translational efficiency via an AKT/HSF1/HuR signaling cascade resulting in enhanced mTORC2 activity in these tumors.

The propagation of uncertainties in reaction cross sections and rates of neutron-, proton-, and alpha-induced reactions into the final isotopic abundances obtained in nucleosynthesis models is an important issue in studies of nucleosynthesis and Galactic Chemical Evolution. We developed a Monte Carlo method to allow large-scale postprocessing studies of the impact of nuclear uncertainties on nucleosynthesis. Temperature-dependent rate uncertainties combining realistic experimental and theoretical uncertainties are used. From detailed statistical analyses uncertainties in the final abundances are derived as probability density distributions. Furthermore, based on rate and abundance correlations an automated procedure identifies the most important reactions in complex flow patterns from superposition of many zones or tracers. The method so far was already applied to a number of nucleosynthesis processes. Here we focus on the production of p-nuclei in white dwarfs exploding as thermonuclear (type Ia) supernovae. We find generally small uncertainties in the final abundances despite of the dominance of theoretical nuclear uncertainties. A separate analysis of low- and high-density regions indicates that the total uncertainties are dominated by the high-density regions., 6 pages, 3 figures; invited talk at 13th Int. Conf. on Nucleus-Nucleus Collisions, Saitama, Japan, 2018. To be published in JPS Conf. Proceedinngs; summarizes results from arXiv:1807.11475; v2: updated reference and receipt date; as accepted for publication

Phosgene is classified as a chemical warfare agent, yet data on its short-duration high concentration toxicity in a nose-only exposure rat model is sparse and inconsistent. Hence, an exposure system for short term/high concentration exposure was developed and characterized. Herein, we report the median lethal concentration (LC(50)) for a 10-min nasal exposure of phosgene in a 24-h rat survival model. Male Wistar rats (Envigo) weighing 180-210 g on the day of exposure, were exposed to phosgene gas via nose-only inhalation using a system specifically designed to allow the simultaneous exposure and quantification of phosgene. After 24 h, the surviving rats were euthanized, the lung/body mass ratio determined, and lung tissues analyzed for histopathology. Increased terminal airway edema in the lungs located primarily at the alveoli (resulting in an increased lung/body mass ratio) coincided with the observed mortality. An LC(50) value of 129.2 mg/m(3) for a 10-min exposure was determined. Furthermore, in agreement with other highly toxic compounds, this study reveals a LC(50) concentration value supportive of a non-linear toxic load model, where the toxic load exponent is > 1 (n(e) = 1.17). Thus, in line with other chemical warfare agents, phosgene toxicity is predicted to be more severe with short-duration, high-concentration exposures than long-duration, low-concentration exposures. This model is anticipated to be refined and developed to screen novel therapeutics against relevant short-term high concentration phosgene exposures expected from a terrorist attack, battlefield deployment, or industrial accident.