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We examined Henslow’s Sparrow (Centronyx henslowii) response to prescribed fire at 32 grasslands at Big Oaks National Wildlife Refuge in southeastern Indiana from 1999 to 2009. We burned grasslands in the spring between 1999 and 2007 and monitored Henslow’s Sparrows for up to 4 yr after treatment. We used linear mixed models to analyze our data. Henslow’s Sparrow counts were correlated with time since prescribed fire and grassland size. The estimated changes in mean Henslow’s Sparrow density relative to pre-burn densities were –0.19, 1.15, 0.74, and –0.68 birds ha –1 for 1 to 4 breeding seasons after a spring burn, respectively. We found that Henslow’s Sparrows preferred larger grasslands both during the first breeding season after prescribed fire, when vegetation was presumed to possess less litter and structural density, and during the fourth breeding season after fire, when vegetation was presumed to be a more ideal composition, but preferred smaller grasslands in the interim. Thus, grassland size shapes the magnitude of Henslow’s Sparrow population response to fire, with populations in smaller grasslands experiencing greater amplitude changes. Larger grasslands might provide more habitat diversity following prescribed fire, attenuating population change. On average, Henslow’s Sparrows responded positively to prescribed fire in a network of grasslands and cumulative net change in densities were highest three breeding seasons after a burn suggesting that maintaining this burn frequency would be beneficial to Henslow’s Sparrow abundance.

The behavior of fission gases in molten fuel salt reactors governs activity transport from the reactor and can also affect the performance of the reactor itself. The gas solubility can be described thermodynamically by Henry’s law. However, the coupling of the condensed and gas phases depends on the interfacial area, which is difficult to measure or even to estimate. Surfaces of materials in the reactor will include disperse phases in the salt and porosity within the structural materials, covering a range of compositions and sizes. These attributes can affect measurements of fundamental properties such as gas solubility. Methods to obtain gas solubility, surface tension, interfacial energies, and bubble gas transport are reviewed. Recent data from manometric experiments are interpreted based on xenon sorption onto salt-wetted quartz.

The need to predict acoustic propagation through marine sediments that contain gas bubbles has become increasingly important for civil engineering and climate studies. There are relatively few in situ acoustic wave propagation studies of muddy intertidal sediments, in which bubbles of biogenic gas (generally methane, a potent greenhouse gas) are commonly found. We used a single experimental rig to conduct two in situ intertidal acoustical experiments to improve understanding of acoustic remote sensing of gassy sediments, eventually including gas bubble size distributions. In the first experiment, we measured sediment sound speed and attenuation between four aligned hydrophones for a quasi-plane wave propagating along the array. The second experiment involved a focused insonified sediment volume created by two transducers emitting coincident sound beams at different frequencies that generated bubble-mediated acoustic signals at combination frequencies. The results from sediment core analyses, and comparison of in situ acoustic velocity and attenuation values with those of water-saturated sediments, together provide ample evidence for the presence of in situ gas bubbles in the insonified volumes of sediments. These datasets are suitable for linear and non-linear inversion studies that estimate in situ greenhouse gas bubble populations, needed for future acoustical remote sensing applications.

In recent years, human serum albumin (HSA) has been characterized as an ideal drug carrier in the cancer arena. Caveolin-1 (Cav-1) has been established as the principal structural protein of caveolae and, thus, critical for caveolae-mediated endocytosis. Cav-1 has been shown to be overexpressed in cancers of the lung and pancreas, among others. We found that Cav-1 expression plays a critical role in both HSA uptake and response to albumin-based chemotherapies. As such, developing a novel albumin-based chemotherapy that is more selective for tumors with high Cav-1 expression or high levels of caveolar-endocytosis could have significant implications in biomarker-directed therapy. Herein, we present the development of a novel and effective HSA-SN-38 conjugate (SSH20). We find that SSH20 uptake decreases significantly by immunofluorescence assays and western blotting after silencing of Cav-1 expression through RNA interference. Decreased drug sensitivity occurs in Cav-1-depleted cells using cytotoxicity assays. Importantly, we find significantly reduced sensitivity to SSH20 in Cav-1-silenced tumors compared to Cav-1-expressing tumors in vivo. Notably, we show that SSH20 is significantly more potent than irinotecan in vitro and in vivo. Together, we have developed a novel HSA-conjugated chemotherapy that is potent, effective, safe, and demonstrates improved efficacy in high Cav-1-expressing tumors., Graphical abstract, In this study, the authors have developed and established a novel albumin-SN-38 conjugate (SSH20) and tested it in pre-clinical models of pancreatic and lung cancer. The advantageous properties inherent to SN-38 conjugation to albumin and targeted delivery make SSH20 an attractive candidate for further preclinical and potential clinical study.

Molten chloride salts are being given strong consideration for use in heat transfer and storage in concentrating solar power (CSP) systems as well as in some nuclear reactor applications. Containment of the molten salt, particularly at the highest temperatures, is a major material concern and has received considerable study. Another material issue is the pumps that will be required to move the molten salt along with the bearing materials that will be required to have sufficient corrosion resistance as well as wear resistance in the high temperature salt. A pair of coordinated studies in our laboratory has addressed the corrosion, and the wear issues of candidate bearing materials including the selection of candidate materials as well as their performance in a molten sodium chloride-potassium chloride-magnesium chloride salt environment. This article addresses the selection of candidate materials and their chemical compatibility with the molten salt. The studies have identified material pairs that have suitable properties for use as bearings that would be immersed in molten chloride salt.

One engineering challenge for the next-generation concentrating solar power (CSP) is to identify appropriate heat transfer and thermal energy storage media. A chloride salt mixture (20 wt % NaCl + 40 wt % MgCl₂ + 40 wt % KCl) in a molten phase is proposed as a potential fluid for carrying the heat as well as lubricating the CSP pump bearings. Due to the hygroscopic nature of MgCl₂, the presence of magnesium oxide (MgO) particles is inevitable. In order to understand the impact of MgO particles, this study investigated the tribological behavior of the molten chloride salt mixture containing MgO of various particle sizes and concentrations. Tests were conducted at 750 °C in a dry Ar environment using a zirconia ball sliding against a Haynes 244 alloy disc lubricated by the molten salt. There was a clear trend of the increased friction coefficient and wear loss for a larger particle size and/or a higher concentration of MgO. Distinct wear mechanisms were identified for the ceramic ball and alloy disc. Results provide fundamental insights for this new research avenue of molten salt lubrication for CSP.

In recent years, the emergence of targeted covalent inhibitors which bind to the G12C mutant of KRAS have offered a solution to this previously intractable target. Inhibitors of KRASG12C tend to be structurally complex, displaying features such as atropisomerism, chiral centres and a reactive covalent warhead. Such molecules result in lengthy and challenging syntheses, and as a consequence critical decisions need to be made at the design level to maximise the chances of success. Here we take a retrospective look into how computational chemistry can help guide and prioritise medicinal chemistry efforts in the context of a series of conformationally restricted tetracyclic quinolines.

Molten chloride salts (including MgCl2, KCl, NaCl, and ZnCl2) are being considered for heat transfer media for renewable (solar) and nuclear power generators, as fuel carrier for nuclear reactors, and as thermal energy storage media. Impurities such as oxygen, hydroxides, moisture, and sulfur are known to negatively influence the corrosion of materials in contact with the salt (e.g., structural metals). Commercially available chloride salts come with a range of impurities. Before using the chloride salts at high temperature, it is desirable to remove the impurities to increase the performance of the salt and reduce corrosion. In this study, we tested the use of thionyl chloride vaporized into a stream of argon to react with oxygenated impurities in a mixture of MgCl2-KCl-NaCl, removing them as HCl and SO2. The reagent was bubbled through the salt when both above and below the melting point. The reaction was followed using thermocouple data from the salt and by Fourier transform infrared (FTIR) spectroscopy on the exhaust of the reactor. The reaction kinetics were followed by comparing the peaks from SO2 product to SOCl2 reagent in the FTIR spectra. The purity of the salt was assessed at the end of the purification process by x-ray diffraction and inductively coupled plasma analysis. Although the process was effective in removing the oxygen content of the mixture, ternary compounds were formed in the process, including KNiCl3 and KMgCl3. The nickel in KNiCl3 came from the reaction between the salt and the nickel vessel. Thus, these experiments suggest that improvements to the process must be made before using SOCl2 vapors for the purification of chloride salts.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.

Background: Optimal patient selection for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) is unestablished. Molecular profiling may select patients at high risk for locoregional recurrence (LRR) who would benefit from radiation. Methods: We included resectable pancreatic cancer (R-PDAC) patients, divided into training and validation cohorts, treated among three institutions with surgery and adjuvant chemotherapy, and borderline resectable or locally advanced pancreatic cancer (BR/LA-PDAC) patients treated with chemotherapy with or without radiation at the primary study institution. We isolated RNA from R-PDAC surgical specimens. Using NanoString, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training cohort, miR-181b/d and miR-575, which were used to generate a risk score (RS). We evaluated the association of the median-dichotomized RS with recurrence and overall survival (OS). Results: We identified 183 R-PDAC and 77 BR/LA-PDAC patients with median follow up of 37 months treated between 2001 and 2014. On multivariable analysis of the R-PDAC training cohort (n = 90), RS was associated with worse LRR (HR = 1.34, 95%CI 1.27–11.38, p = 0.017) and OS (HR = 2.89, 95%CI 1.10–4.76, p = 0.027). In the R-PDAC validation cohort, RS was associated with worse LRR (HR = 2.39, 95%CI 1.03–5.54, p = 0.042), but not OS (p = 0.087). For BR/LA-PDAC, RS was associated with worse LRR (HR = 2.71, 95%CI 1.14–6.48, p = 0.025), DR (HR = 1.93, 95%CI 1.10–3.38, p = 0.022), and OS (HR = 1.97, 95%CI 1.17–3.34, p = 0.011). Additionally, after stratifying by RS and receipt of radiation in BR/LA-PDAC patients, high RS patients who did not receive radiation had worse LRR (p = 0.018), DR (p = 0.006), and OS (p &lt, 0.001) compared to patients with either low RS or patients who received radiation, irrespective of RS. Conclusions: RS predicted worse LRR and OS in R-PDAC and worse LRR, DR, and OS in BR/LA-PDAC. This may select patients who would benefit from radiation and should be validated prospectively.

In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.

The three-dimensional conformations adopted by a free ligand in solution impact bioactivity and physicochemical properties. Solution 1D NMR spectra inherently contain information on ligand conformational flexibility and three-dimensional shape, as well as the propensity of the free ligand to fully preorganize into the bioactive conformation. Herein we discuss some key learnings, distilled from our experience developing potent and selective synthetic macrocyclic inhibitors, including Mcl-1 clinical candidate AZD5991. Case studies have been selected from recent oncology research projects, demonstrating how 1D NMR conformational signatures can complement X-ray protein-ligand structural information to guide medicinal chemistry optimization. Learning to extract free ligand conformational information from routinely available 1D NMR signatures has proven to be fast enough to guide medicinal chemistry decisions within design cycles for compound optimization.

PURPOSE/OBJECTIVE(S) SMAD4 (DPC4) is a transcription factor that mediates TGF-beta signal transduction and is mutationally in-activated in about one-third of pancreatic cancer (PC). Studies have suggested that SMAD4 loss is associated with a higher rate of distant metastasis (DM), but other studies have refuted this claim. An assessment of SMAD4 expression was performed in NRG/RTOG 9704, a prospective phase III trial comparing different post-operative chemotherapy regimens combined with 5-fluorouracil-based chemoradiation for resectable PC. It was hypothesized that higher SMAD4 expression is associated with lower incidence of DM and better disease-free and overall survival (DFS & OS). MATERIALS/METHODS An automated quantitative immunofluorescence SMAD4 analysis was performed in pan-cytokeratin positive tumor cells on a tissue microarray with samples from NRG/RTOG 9704, using a microscope and image analysis software. Total cellular SMAD4 was analyzed as a categorical variable dichotomized by the median. DFS & OS were estimated with the Kaplan-Meier method & groupings compared with the log-rank test. Local-regional recurrence (LRR) & DM were estimated by the cumulative incidence method & groupings compared with Gray's test. Univariate & multivariable Cox proportional hazards (OS & DFS) or Fine-Gray (DM & LRR) regression models were used to evaluate associations between SMAD4 & outcomes. SMAD4 was included in all models; stepwise selection identified significant variables among treatment, age, gender, race, CA19-9, tumor location & diameter, nodes, & surgical margin status. RESULTS Of 451 eligible patients on NRG/RTOG 9704, tissue from 141 patients was analyzable. There were no significant differences in baseline characteristics/outcomes for patients with & without tissue. There were no statistically significant differences in baseline characteristics between the low & high SMAD4 groupings. High SMAD4 expression was associated with better DFS & OS compared to low SMAD4, with a 32% risk reduction (RRed) of DFS failure [HR (95% CI): 0.68 (0.48, 0.97); P = 0.03] & a 31% RRed of death [HR (95% CI): 0.69 (0.48, 0.99); P = 0.04]. This difference in DFS appeared to be due to a lower incidence of DM in tumors with high SMAD4, with a 31% RRed of failing distantly [HR (95% CI): 0.69 (0.48, 0.99), P = 0.048]. No differences were detected in LRR. After adjusting for CA19-9 on multivariable analysis, high SMAD4 remained associated with better DFS with a 34% RRed of failing [HR (95% CI): 0.66 (0.46, 0.96), P = 0.03]. Tumors with high SMAD4 showed a trend of being associated with less DM [HR (95% CI): 0.68 (0.46, 1.004), P = 0.052], after adjusting for age & surgical margin status. CONCLUSION Tumor expression of SMAD4 is significantly associated with better clinical outcome, specifically lower DM and higher DFS and OS, in tumor samples from a large, phase III randomized trial of resectable pancreatic cancer.

Purpose/objective(s) Laboratory experiments show that activation of β-catenin signaling promotes pancreatic cancer (PC) growth, but studies addressing its prognostic value in patients (pts) are scarce and with conflicting results. This question has been examined using samples from a large prospective clinical trial. Materials/methods NRG/RTOG 9704 was a phase III trial which compared 5-fluorouracil - to gemcitabine-based chemotherapy in pts after pancreatectomy. All pts received 5-fluorouracil -based chemoradiotherapy. Quantitative immunofluorescence analysis for β-catenin was performed on a tissue microarray developed from these pts. β-catenin and its active form (total, nuclear, and cytoplasmic) were assayed in pan-cytokeratin positive tumor cells. Assay performers were blinded to all clinical outcomes. Scores were dichotomized at their median. OS and DFS were estimated univariately with the Kaplan-Meier method and groups compared using the log-rank test. Cox proportional hazards models were used to identify the impact of expression on OS and DFS. The following variables were included in the models: β-catenin, treatment, age, gender, race, CA19-9, tumor location, nodal involvement, tumor diameter, and surgical margin status. Results Of 451 eligible pts, 141 samples were analyzable. There were no significant differences in baseline characteristics/outcomes for pts with and without tissue. For cytoplasmic β-catenin univariately, levels ≥ median were associated with better OS [HR (95% CI): 0.65 (0.45, 0.93); P = 0.02] and DFS [HR (95% CI): 0.70 (0.49, 0.99); P = 0.04]. On multivariable analysis, levels ≥ median were associated with better OS [HR (95% CI): 0.63 (0.43, 0.92), P = 0.02], after adjusting for CA19-9, age, and race, with a 37% risk reduction of death. There was a trend towards better DFS for pts with levels ≥ median [HR (95% CI): 0.70 (0.48, 1.01), P = 0.054], after adjusting for CA19-9. For cytoplasmic active β-catenin univariately, levels ≥ median were associated with better OS [HR (95% CI): 0.65 (0.45, 0.94); P = 0.02], that remained significant on multivariable analysis [HR (95% CI): 0.64 (0.44, 0.94); P = 0.02]. There were no associations with efficacy for nuclear or total β-catenin, nor in its active form. Conclusion In this high-quality database from a prospective phase III clinical trial, cytoplasmic β-catenin and cytoplasmic active β-catenin are statistically significantly associated with OS and DFS and with OS, respectively, independent of other known prognostic factors. In agreement with one previous publication, high levels of cytoplasmic β-catenin, which is transcriptionally silent, were associated with a reduced risk of death. The significant magnitude of these effects makes them clinically relevant, warranting further investigation. This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 (NCORP), U24CA196067 (NRG Specimen Bank) from the National Cancer Institute (NCI).

In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.

ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.

Salt impurities directly affect degradation of structural materials in molten salt environments, so impurity quantification and analysis of salts is important for the deployment of next generation molten salt nuclear reactors. Despite the importance of moisture and other oxygen containing impurities, reliable methods of measuring these impurities are not well qualified or commonly used. Herein, we present two methods for analysis of oxygen content and one method for analysis of hydrogen content in fluoride salts demonstrated on two batches of LiF-NaF-KF (FLiNaK) salt with differing purity levels. The intentional addition of varying amounts of oxygen and hydrogen to the FLiNaK salt as internal standards produced a linear response using a commercial combustion analysis instrument, and measured amounts were consistent with the standards. These results indicate the technique is a valid method for measuring oxygen and hydrogen content in fluoride salts. Corrosion studies of 316H in FLiNaK revealed 5 times more mass loss in the salt containing more impurities including hydrogen and transition metals.

Molten salts are considered as candidate heat transfer fluids and thermal energy storage media for next generation concentrating solar power (CSP). A molten salt circulates inside the piping and heat exchanger and also functions as a lubricant for the sleeve bearings of the CSP pump. Wear- and corrosion-resistant high-temperature bearing materials are critical for the pump efficiency and durability. This study evaluated the tribological performance of candidate bearing materials in lubrication of a molten chloride salt mixture (20% NaCl + 40% MgCl2 + 40% KCl) at 750 °C in an inert argon gas (a simulative CSP pump environment). Six ceramic-alloy pairs were tested, zirconia and silicon nitride against Haynes 244, Hastelloy C276, and Tribaloy T900 alloy, and ranked by the friction coefficient and wear loss. Characterization of worn surfaces suggested the wear mechanism as a combination of abrasion, adhesion, and tribocorrosion. Results from this study provide fundamental insight for the development and selection of bearing materials for molten salt powered CSP pumps.

In the United States, approximately 2500 casks are loaded with commercial spent nuclear fuel (SNF) that has transitioned from wet storage (spent fuel pools) to dry storage. The number of loaded dry...

Engineering demonstration reactors are nuclear reactors built to establish proof of concept for technology options that have never been built. Examples of engineering demonstration reactors include Peach Bottom 1 for high temperature gas-cooled reactors and the Experimental Breeder Reactor-II for sodium-cooled fast reactors. Engineering demonstrations have historically played a vital role in advancing the technology readiness level of reactor concepts. This paper details a preconceptual design for a fluoride salt-cooled engineering demonstration reactor. The fluoride salt-cooled high-temperature reactor (FHR) demonstration reactor (DR) is a concept for a salt-cooled reactor with 100 megawatts of thermal output. It would use tristructural-isotropic (TRISO) particle fuel in compacts within prismatic graphite blocks. FLiBe (2 7LiF-BeF2) is the reference primary coolant. The FHR DR is designed to be small, simple, and affordable. Development of the FHR DR is an intermediate step to enable near-term commercial FHRs. The design philosophy of the FHR DR was focused on safety, near-term deployment, and flexibility. Lower risk technologies are purposely included in the initial FHR DR design to ensure that the reactor can be built, licensed, and operated as an engineering demonstration with minimal risk and cost. These technologies include TRISO particle fuel, replaceable core structures, and consistent structural material selection for core structures and the primary and intermediate loops, and tube-and-shell primary-to-intermediate heat exchangers. Important capabilities to be demonstrated by building and operating the FHR DR include: • core design methodologies, • heat exchanger performance (including passive decay heat removal), • pump performance, • reactivity control, • salt chemistry control to maximize plant life, • salt procurement, handling, maintenance and ultimate disposal, and • tritium management. Non-nuclear separate and integral test efforts (e.g., heated salt loops or loops using simulant fluids) are necessary to develop the technologies that will be demonstrated in the FHR DR.

To understand the changing nuclear and mechanical characteristics of spent nuclear fuel (SNF) or used nuclear fuel (UNF) and the different storage, transportation, and disposal systems at various stages within the waste management system, different types of analyses are required. These analyses require the use of assorted tools and numerous types of data. Using the appropriate modeling and simulation (M&S) parameters and selecting from the diversity of analytic tools to conduct SNF analyses can be a tedious, error-prone, and time-consuming undertaking for analysts and reviewers alike. A new, integrated data and analysis system was designed to simplify and automate performance of accurate, efficient evaluations for characterizing the input to the overall U.S. nuclear waste management system—the UNF-Storage, Transportation & Disposal Analysis Resource and Data System (UNF-ST&DARDS). A relational database has been assembled to provide a standard means by which UNF-ST&DARDS can succinctly store and re...

Loading requirements for dry cask storage of spent nuclear fuel are driven primarily by decay heat capacity limitations, which themselves are determined through recommended limits on peak cladding temperature within the cask. This study examines the relative sensitivity of peak material temperatures within the cask to parameters that influence both the stored fuel residual decay heat as well as heat removal mechanisms. These parameters include the detailed reactor operating history parameters (e.g., soluble boron concentrations and the presence of burnable poisons) as well as factors that influence heat removal, including non-dominant processes (such as conduction from the fuel basket to the canister and radiation within the canister) and ambient environmental conditions. By examining the factors that drive heat removal from the cask alongside well-understood factors that drive decay heat, it is therefore possible to make a contextual analysis of the most important parameters to evaluation of peak material temperatures within the cask. The goal of this analysis is to afford modelers the ability to develop best-estimate thermal models for vertical dry cask storage systems useful for material degradation studies. In contrast to more conservative bounding analyses used for safety and licensing studies (which are primarily intended to illustrate that recommended temperature limits are not exceeded), material degradation phenomena are frequently temperature-dependent, requiring best-estimate thermal models to properly evaluate. The canister-level parameters that have the greatest impact on peak fuel material temperatures drive convective heat transfer in the cask annulus (comprised of the region between the storage canister and the concrete overpack) and within the canister basket. These parameters include the ambient air temperature, the canister fill gas pressure, and the pressure drop between the annular region inlet and outlet. Other cask design parameters which would be expected to contribute substantially to the peak clad temperature were overall proved to be of marginal significance, including material properties such as the fuel basket thermal conductivity and emissivity, along with frictional flow losses from the spacer grid. Meanwhile, factors that drive conduction from the fuel basket region and material properties which drive radiative transport between the fuel and basket likewise exhibit low sensitivity for peak clad temperature estimates. Fuel irradiation history parameters that drive decay heat (such as the discharge burnup and average moderator density) nevertheless dominate peak clad temperature sensitivity. While the assembly power history significantly influences short-term decay heat post-discharge, it manifests minimal sensitivity for cooling times over 10 years and is thus of negligible importance for assemblies stored in wet storage for at least this time.

The repurposing of military lands is common in many parts of the world and presents a variety of conservation opportunities. This study examines land cover at Big Oaks National Wildlife Refuge, Indiana (U.S.A.) as it transitioned from military proving ground to wildlife refuge from 1985 to 2013. We use remote sensing, semi-structured interviews, and a review of planning and management documents to examine this transition. Limited change in land cover composition and distribution are detected, despite changes in use and management. This landscape similarity relates to similarities in land management practices, and the impact of landscape history on current management practices. The findings suggest that military use and conservation objectives at this site yield similar land covers and are not necessarily in contrast to each other. As military base closures continue, the potential to maintain and expand conservation opportunities on these lands will likely grow in importance.

In boiling water reactors, the shroud dome, separators, and dryers above the core are made of approximately 100,000 kg of stainless steel. During a severe accident in which the coolant boils away and exothermic oxidation of zirconium occurs, gases (steam and hydrogen) are superheated in the core region and pass through the upper internals. In this scenario, the upper internals can also be heated by thermal radiation from the hot degrading core. Historically, models of the upper internals have been relatively simple in severe accident codes. The upper internals are typically modeled in MELCOR as two lumped volumes with simplified heat transfer characteristics and no structural integrity considerations, and with limited ability to oxidize, melt, and relocate. The potential for and the subsequent impact of the upper internals to heat up, oxidize, fail, and relocate during a severe accident was investigated. A higher fidelity representation of the shroud dome, steam separators, and steam driers was developed in MELCOR v1.8.6 by extending the core region upwards. The MELCOR modeling effort entailed adding 45 additional core cells and control volumes, 98 flow paths, and numerous control functions. The model accounts for the mechanical loading and structural integrity, oxidation, melting, flow area blockage, and relocation of the various components. Consistent with a previous study, the results indicate that the upper internals can reach high temperatures during a severe accident sufficient to lose their structural integrity and relocate. The additional 100 metric tons of stainless steel debris influences the subsequent in-vessel and ex-vessel accident progression.

Lower head failure and corium-concrete interaction were predicted to occur at Fukushima Daiichi Unit 1 (1F1) by several different system-level code analyses, including MELCOR v2.1 and MAAP5. Althou...

Lower head failure and corium-concrete interaction were predicted to occur at Fukushima Daiichi Unit 1 (1F1) by several different system-level code analyses, including MELCOR v2.1 and MAAP5. Althou...

In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline

The reactor accidents at Fukushima Daiichi have rekindled interest in light water reactor (LWR) severe accident phenomenology. Postevent analyses have identified several areas that may warrant addi...

Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.

We completed a novel assessment to determine the unquantified and uncredited safety margins (i.e., the difference between the licensing basis and as-loaded calculations) available in as-loaded spent nuclear fuel (SNF) casks. This assessment was performed as part of a broader effort to assess issues and uncertainties related to the continued safety of casks during extended storage and transportability following extended storage periods. Detailed analyses crediting the actual as-loaded cask inventory were performed for each of the casks at three decommissioned pressurized water reactor (PWR) sites to determine their characteristics relative to regulatory safety criteria for criticality, thermal, and shielding performance. These detailed analyses were performed in an automated fashion by employing a comprehensive and integrated data and analysis tool—Used Nuclear Fuel-Storage, Transportation & Disposal Analysis Resource and Data System (UNF-STD calculated decay heat margins ranged from 4 to almost 22 kW (as of 2014); and significant uncredited transportation dose rate margins were also observed. The results demonstrate that, at least for the casks analyzed here, significant uncredited safety margins are available that could potentially be used to compensate for SNF assembly and canister structural performance related uncertainties associatedmore » with long-term storage and subsequent transportation. The results also suggest that these inherent margins associated with how casks are loaded could support future changes in cask licensing to directly or indirectly credit the margins. Work continues to quantify the uncredited safety margins in the SNF casks loaded at other nuclear reactor sites.« less

Populations of Henslow’s Sparrows have declined dramatically in recent decades, coinciding with widespread loss of native grassland habitat. Prescribed burning is a primary tool for maintaining grassland patches, but its effects on nest survival of Henslow’s Sparrows remains largely unknown, especially in conjunction with other factors. We monitored 135 nests of Henslow’s Sparrows at Big Oaks National Wildlife Refuge in southern Indiana from 1998–2001 in an effort to understand factors influencing nest survival, including prescribed burning of habitat. We used a mixed-effects implementation of the logistic exposure model to predict daily nest survival in an information theoretic framework. We found that daily survival declined near the onset of hatching and increased with the height of standing dead vegetation, although this relationship was weak. We found only nominal support to suggest that time since burn influenced nest survival. Overall, nest age was the most important factor in estimating d...

B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of diffuse large B-cell lymphoma (DLBCL) cell lines, but neither BCL6 inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6 degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6 population. Analysis of subcellular fractions also showed incomplete BCL6 degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen with both BCL6 inhibitor and degrader. In summary, we have developed potent and selective BCL6 inhibitors and a BCL6 PROTAC that effectively degraded BCL6, but both modalities failed to induce a significant phenotypic response in DLBCL despite achieving cellular concentrations.

[Image: see text] We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound 21, a highly potent ATM inhibitor (ATM cell IC(50) 0.0028 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. In vivo, 21 in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound 21 was selected for preclinical evaluation alongside AZD0156.