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At least 577 records · Page 32

Medical and Scientific Evaluations aboard the KC-135. Microgravity-Compatible Flow Cytometer

A spaceflight-compatible flow cytometer would be useful for the diagnosis of astronaut illness during long duration spaceflight and for conducting in-flight research to evaluate the effects of microgravity on human physiology. Until recently, the primary limitations preventing the development of a spaceflight compatible flow cytometer have been largely mechanical. Standard commercially available flow cytometers are large, complex instruments that use high-energy lasers and require significant training to operate. Standard flow cytometers function by suspending the particles to be analyzed inside a sheath fluid for analysis. This requires the presence of several liters of sheath fluid for operation, and generates a corresponding amount of liquid hazardous waste. The particles are then passed through a flow cell which uses the fluid mechanical property of hydrodynamic focusing to place the cells in single-file (laminar flow) as they pass through a laser beam for scanning and evaluation. Many spaceflight experiments have demonstrated that fluid physics is dramatically altered in microgravity (MSF [Manned Space Flight] Fluid Physics Data Sheet-August 1997) and previous studies have shown that sheath-fluid based hydrodynamic focusing may also be altered during microgravity (Crucian et al, 2000). For these reasons it is likely that any spaceflight compatible design for a flow cytometer would abandon the sheath fluid requirement. The elimination of sheath fluid would remove both the problems of weight associated with large volumes of liquids as well as the large volume of liquid waste generated. It would also create the need for a method to create laminar particle flow distinct from the standard sheath-fluid based method. The spaceflight prototype instrument is based on a recently developed commercial flow cytometer possessing a novel flow cell design that creates single-particle laser scanning and evaluation without the need for sheath-fluid based hydrodynamic focusing. This instrument also possesses a number of design advances that make it conditionally microgravity compatible: it is highly miniaturized and lightweight, uses a low energy diode laser, has a small number of moving parts, does not use sheath fluid and does not generate significant liquid waste. Although possessing certain limitations, the commercial cytometer functions operationally like a standard bench top laboratory flow cytometer, aspirating liquid particle samples and generating histogram or dot-plot data in standard FCS file format. In its current configuration however, the cytometer is limited to three parameter/two-color capability (two color PMTs + forward scatter), does not allow compensation between colors, does not allow linear analysis and is operated by rather inflexible software with limited capabilities. This is due to the fact that the cytometer has been designed and marketed as an instrument specific to a few particular assays, not as a multipurpose cytometer.

Crucian, Brian↗

Effects of the Hydrophobic Block Length Ratio of Poly(vinylbenzyl N -methylpiperidinium carbonate)- b -polyethylene- b -poly(vinylbenzyl N -methylpiperidinium carbonate) Block Copolymers for Anion Exchange Membrane Electrolysis

Electrolysis of water to produce hydrogen from renewable electricity is an extremely attractive strategy to reduce energy dependence on fossil fuels. Development of membrane and ionomer materials that maintain high performance with long lifetimes is needed. We developed and investigated the performance and durability of a series of polyethylene-based ABA triblock copolymer anion exchange ionomer and membrane (AEI, AEM) materials for anion exchange membrane water electrolysis. Poly(vinylbenzyl N-methylpiperidinium carbonate)-b-polyethylene-b-poly(vinylbenzyl N-methylpiperidinium carbonate) was synthesized with different hydrophobic/hydrophilic block ratios (1.02:1, 2.58:1, and 4.46:1) resulting in a range of ion exchange capacities (1.1–1.8 meq g –1 ) and water swelling (23–154%) characteristics. All AEMs showed full anionic dissociation, as evidenced by linear Arrhenius correlations, and excellent carbonate conductivity of 8–94 mS cm –1 at 50 °C. Hydrophilic phase separation may offer superior chemical durability by only wetting the ion-conducting region of the polymer and avoiding attack at the nonwetted backbone. We evaluated the performance and durability of these AEMs as a function of hydrophobic polyethylene (PE) content. The AEM containing the least amount of PE displayed the highest performance of 1 A cm –2 at 2.3 V but degraded at 40 mV h –1 before catastrophically failing after <3 h at 0.5 A cm –2 . With greater PE-containing AEMs, the degradation rate was reduced by 3 orders of magnitude with only a 0.2 V increase in voltage. Constant current electrolysis for 50 h resulted in a voltage change of 0.3 mV h –1 in a single-cell water electrolyzer and 1 M potassium carbonate. In a 600 h test, the voltage change in the final 200 h was impressively low for an experimental film, 58 μV h –1 . Postmortem analysis indicated that the membrane did not thin and that water becomes more tightly hydrogen-bound in the polymer after electrolysis.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Automated segmentation of soft X-ray tomography: Native cellular structure with submicron resolution at high-throughput for whole-cell quantitative imaging in yeast

Soft X-ray tomography (SXT) is an invaluable tool for quantitatively analyzing cellular structures at suboptical isotropic resolution. However, it has traditionally depended on manual segmentation, limiting its scalability for large datasets. Here, we leverage a deep learning-based autosegmentation pipeline to segment and label cellular structures in hundreds of cells across three Saccharomyces cerevisiae strains. This task-based pipeline uses manual iterative refinement to improve segmentation accuracy for key structures, including the cell body, nucleus, vacuole, and lipid droplets, enabling high-throughput and precise phenotypic analysis. Using this approach, we quantitatively compared the three-dimensional (3D) whole-cell morphometric characteristics of wild-type, VPH1-GFP, and vac14 strains, uncovering detailed strain-specific cell and organelle size and shape variations. We show the utility of SXT data for precise 3D curvature analysis of entire organelles and cells and detection of fine morphological features using surface meshes. Our approach facilitates comparative analyses with high spatial precision and statistical throughput, uncovering subtle morphological features at the single-cell and population level. This workflow significantly enhances our ability to characterize cell anatomy and supports scalable studies on the mesoscale, with applications in investigating cellular architecture, organelle biology, and genetic research across diverse biological contexts.

Chen, Jianhua [Lawrence Berkeley National Laborato↗

Thermocrinis jamiesonii sp. nov., a thiosulfate-oxidizing, autotropic thermophile isolated from a geothermal spring

An obligately thermophilic, chemolithotrophic, microaerophilic bacterium, designated strain GBS1T, was isolated from the water column of Great Boiling Spring, Nevada, USA. Thiosulfate was required for growth. Although capable of autotrophy, growth of GBS1T was enhanced in the presence of acetate, peptone, or Casamino acids. Growth occurred at 70-85 °C with an optimum at 80 °C, at pH 6.5-7.75 with an optimum at pH 7.25, at 0.5-8% oxygen with an optimum at 1-2%, and at ≤200 mM sodium chloride. The doubling time under optimal growth conditions was 1.3 hrs, with a final cell density of 6.2±0.5 x 107 cells/mL. Non-motile, rod-shaped cells 1.4-2.4 x 0.4-0.6 µm occurred singly or in pairs. Major cellular fatty acids (>5% of total) were C20:1ω9c (44.8%), C18:0 (26.0%), C16:0 (9.9%) and C20:0 (5.4%). Phylogenetic analysis of the GBS1T 16S rRNA gene sequence indicated an affiliation with Thermocrinis ruber and other Thermocrinis spp., but comparisons of 16S rRNA gene identity (≤97.10%) and in silico estimated DNA-DNA hybridization values (≤18.4%) with Thermocrinis spp. indicate that his strain is distinct from described species. Based on phenotypic, genotypic, and phylogenetic characteristics, the name Thermocrinis jamiesonii sp. nov. is proposed, with GBS1T (= JCM 19133T = DSM 27162T) as the type strain.

Environmental Molecular Sciences Laboratory↗

Single-nuclei transcriptome analysis of channel catfish spleen provides insight into the immunome of an aquaculture-relevant species

The catfish industry is the largest sector of U.S. aquaculture production. Given its role in food production, the catfish immune response to industry-relevant pathogens has been extensively studied and has provided crucial information on innate and adaptive immune function during disease progression. To further examine the channel catfish immune system, we performed single-cell RNA sequencing on nuclei isolated from whole spleens, a major lymphoid organ in teleost fish. Libraries were prepared using the 10X Genomics Chromium X with the Next GEM Single Cell 3’ reagents and sequenced on an Illumina sequencer. Each demultiplexed sample was aligned to the Coco_2.0 channel catfish reference assembly, filtered, and counted to generate feature-barcode matrices. From whole spleen samples, outputs were analyzed both individually and as an integrated dataset. The three splenic transcriptome libraries generated an average of 278,717,872 reads from a mean 8,157 cells. The integrated data included 19,613 cells, counts for 20,121 genes, with a median 665 genes/cell. Cluster analysis of all cells identified 17 clusters which were classified as erythroid, hematopoietic stem cells, B cells, T cells, myeloid cells, and endothelial cells. Subcluster analysis was carried out on the immune cell populations. Here, distinct subclusters such as immature B cells, mature B cells, plasma cells, γδ T cells, dendritic cells, and macrophages were further identified. Differential gene expression analyses allowed for the identification of the most highly expressed genes for each cluster and subcluster. This dataset is a rich cellular gene expression resource for investigation of the channel catfish and teleost splenic immunome.

Science & Technology - Other Topics↗

Molecular dynamics analysis of conformational change of paramyxovirus F protein during the initial steps of membrane fusion

Highlights: Black-Right-Pointing-Pointer Initial conformational change of paramyxovirus F protein is caused only by mechanical forces. Black-Right-Pointing-Pointer HRA region undergoes a structural change from a beta + alpha conformation to an extended coil and then to an all-alpha conformation. Black-Right-Pointing-Pointer HRS domains of F protein form three single {alpha}-helices prior to generation of the coiled coil. -- Abstract: The fusion of paramyxovirus to the cell membrane is mediated by fusion protein (F protein) present in the virus envelope, which undergoes a dramatic conformational change during the process. Unlike hemagglutinin in orthomyxovirus, this change is not mediated by an alteration of environmental pH, and its cause remains unknown. Steered molecular dynamics analysis leads us to suggest that the conformational modification is mediated only by stretching mechanical forces once the transmembrane fusion peptide of the protein is anchored to the cell membrane. Such elongating forces will generate major secondary structure rearrangement in the heptad repeat A region of the F protein; from {beta}-sheet conformation to an elongated coil and then spontaneously to an {alpha}-helix. In addition, it is proposed that the heptad repeat A region adopts a final three-helix coiled coil and that this structure appears after the formation of individual helices in each monomer.

60 APPLIED LIFE SCIENCES↗

Calcination of kaolinite clay particles for cement production: A modeling study

Kaolinite rich clay particles calcined under certain conditions can attain favorable pozzolanic properties and can be used to substitute part of the CO{sub 2} intensive clinker in cement production. To better guide calcination of a clay material, a transient one-dimensional single particle model is developed, which fully addresses the conversion process of raw kaolinite particles suspended in hot gas. Particles are discretized into a number of spherical cells, on each of which mass, momentum, energy and species conservation equations are numerically solved by using the finite volume method. Reactions considered in the model include dehydration, dehydroxylation and various phase transformations. Thermogravimetric analysis is used to determine reaction kinetic data required as inputs in the model and to validate the model. Finally, model-based sensitivity analysis is performed, from which quantitative guidelines for calcination condition optimization are derived. - Highlights: • A general 1D mathematical model for single clay particle calcination is developed. • The model fully addresses momentum, heat and mass transfer and all the reactions. • Experiments are performed to determine kinetic data of the key reactions. • The model is verified by different means, including experimental results. • Sensitivity study is done to address key assumptions and derive useful guidelines.

36 MATERIALS SCIENCE↗

Novel Carbon (C)-Boron (B)-Nitrogen (N)-Containing H2 Storage Materials

The following summarizes the research conducted for DOE project DE-EE0005658 “Novel Carbon(C)-Boron(B)-Nitrogen(N)-Containing H2 Storage Materials”. This work focused in part on the continued study of two materials identified from the preceding project DE-FG360GO18143 (“Hydrogen Storage by Novel CBN Heterocycle Materials”) as lead candidates to meet the DOE technical targets for either vehicular or non-automotive hydrogen storage applications. Specifically, a room-temperature liquid, 3-methyl-1,2-cyclopentane (B), and a high H2 capacity solid, 1,2-BN-cyclohexane (J), were selected for further characterization and performance optimization. In addition to these compounds, the current project also aimed to prepare several new materials predicted to be disposed towards direct reversibility of H2 release and uptake, a feature deemed critical to achieving efficient recycling of spent fuel end products. To assist in the rational design of these and other next-generation materials, this project undertook to investigate the mechanism of hydrogen release from established compounds (mainly B and J) using a combined experimental/computational approach. Among this project’s signature accomplishments, the preliminary synthetic route to B was optimized for production on decagram scale. With such quantities of material available, its performance in powering an actual 30 W proton exchange membrane (PEM) fuel cell stack was tested and found to be identical to that of facility H2. Despite this positive proof-of-concept achievement, however, further consideration of neat B as a potential hydrogen storage material was abandoned due to evidence of thermal instability. Specifically, mass spectrometry-coupled thermogravimetric analysis (TGA-MS) revealed significant H2 release from B to initiate at 50 °C, well below the 60 °C minimum threshold set by the DOE. This result prompted a more extensive investigation in the decomposition mechanism of B vis-à-vis that of J, which exhibited in neat form a substantially higher onset temperature for spontaneous H2 release (70 °C). Solution-phase kinetic experiments using ReactIR established a second-order dependence for the initial loss of H2 from both B and J; Arrhenius analysis, however, revealed the activation barrier for this reaction was lower for B than for J, which presumably contributes to the diminished thermal stability of the former. On the basis of these and other experimental results, extensive computational efforts yielded a reasonable mechanistic model for the dehydrogenation of 1,2-BN-cycloalkane materials. While the prospect of neat B as a suitable hydrogen storage material was discarded, it was proposed that the combination of B with more thermally stable amine-borane-based materials might afford mixtures with improved properties. Indeed, when B was combined with ammonia borane (AB) in a 2:1 molar ratio, the two materials formed a liquid. More significantly, this mixture remained liquid even after complete dehydrogenation, thus establishing the potential for a single-phase fuel cycle. (In contrast, the dehydrogenation product of neat B is a low melting solid (mp = 28-30 °C).) Another advantage conferred by the blend formulation was a dramatic reduction in the amount of borazine produced by AB. Borazine is a well-known contaminant of H2 produced by the thermal decomposition of neat AB, and exerts deleterious effects on fuel cell performance. Residual gas analysis (RGA) of the gas stream generated from the B-AB blend, however, detected just 0.01% borazine content when a Pt-Ni nanoparticle dehydrogenation catalyst was used. In all ii then, the 2:1 B-AB blend marks a major achievement in the effort to develop a suitable liquid amine-borane hydrogen storage material, and merits further investigation into the optimization for practical adoption. Similar realization of the potential of J as a high % wt. H2 material required a method to dehydrogenate the carbonaceous components of the molecule without the use of a sacrificial hydrogen acceptor, as had been reported in the previous project. Ultimately, this reaction was achieved for a B,N-disubstituted BN-cyclohexene model substrate using a gas flow system with a fixed Pd/C catalyst bed. Considerable work remains, however, to translate these initial results into a general protocol for complete dehydrogenation of fully saturated BN-cycloalkane materials such as J. With concrete confirmation of the possibility to perform both BN and CC dehydrogenation on a single theoretical substrate, COMSOL modeling was used to evaluate the effects of thermodynamically coupling the two reactions. It was hypothesized that the heat generated from exothermic BN dehydrogenation would partially drive the endothermic CC dehydrogenation reaction; this additional heat consumption was expected to in turn confer the benefit of lowering the maximum reactor temperature. A two-dimensional model of an axisymmetric reactor including experimental kinetic and calculated thermodynamic parameters for both reactions did indeed predict these outcomes. The extent to which the effects of thermodynamic coupling actually manifested, however, were also revealed to depend strongly on the relative rates of the two reactions, as well as the magnitude of the equilibrium constant governing the progress of the endothermic process. Given the evident complexity of attaining high effective % wt. H2 capacity with J, alternative systems were investigated for greater facility of extensive H2 release. Among those studied, 1,2,4,5-bis-BN-cyclohexane (H) demonstrated the most favorable properties, particularly with respect to thermal stability: rather than decompose, a neat sample instead sublimed when heated above 150 °C. Nevertheless, two commercially available catalytic systems were identified to effect release of two H2 equivalents from H. Release of further equivalents were apparently impeded by the formation of either polymeric material or one of two dimeric cage compounds depending on the catalyst used. Notably, a method to regenerate H from these product mixtures remains to be developed. Thus, while H may prove useful for certain long-term energy storage needs, it is currently less suited applications involving frequent fuel consumption. Similar difficulties were also encountered in attempts to realize the complete fuel cycle of 1,3-BN-cyclohexane (E) and B,N-substituted derivatives thereof. It had been initially proposed that E would provide for readily reversible BN dehydrogenation through a measure of frustrated Lewis pair-type character. Indeed, computations predicted this reaction would be essentially thermoneutral in solution. In the course of attempts to fully hydrogenate the spent fuel, however, dimeric species formed and proved resistant to further BN reduction. While a number of monomeric cyclic compounds were also successfully synthesized as formal boron-nitrogen frustrated Lewis pairs, none demonstrated any capacity to split H2 across the BN unit. The challenge of developing a practical amine-borane-based material for readily reversible hydrogen storage thus remains unresolved at this time. As such, it deserves consideration as a major objective of any future work.

08 HYDROGEN↗

An analysis of multi-frequency high resolution radar rain rate data

Approximately 100,000 records of data at 3.05, 9.35, and 15.56 GHz, each set associated with a single look angle, are edited and analyzed to determine the characteristic dimensions of the rain cells observed and the rain rate distributions within these cells. The results, consistent with earlier results, demonstrate the feasibility of using attenuating frequency radars for high resolution rain rate measurements.

Devasirvatham, D. M. J.↗

WIMS/PANTHER analysis of UO{sub 2}/MOX cores using embedded super-cells

This paper describes a method of analysing PWR UO{sub 2}MOX cores with WIMS/PANTHER. Embedded super-cells, run within the reactor code, are used to correct the standard methodology of using 2-group smeared data from single assembly lattice calculations. In many other codes the weakness of this standard approach has been improved for MOX by imposing a more realistic environment in the lattice code, or by improving the sophistication of the reactor code. In this approach an intermediate set of calculations is introduced, leaving both lattice and reactor calculations broadly unchanged. The essence of the approach is that the whole core is broken down into a set of 'embedded' super-cells, each extending over just four quarter assemblies, with zero leakage imposed at the assembly mid-lines. Each supercell is solved twice, first with a detailed multi-group pin-by-pin solution, and then with the standard single assembly approach. Correction factors are defined by comparing the two solutions, and these can be applied in whole core calculations. The restriction that all such calculations are modelled with zero leakage means that they are independent of each other and of the core-wide flux shape. This allows parallel pre-calculation for the entire cycle once the loading pattern has been determined, in much the same way that single assembly lattice calculations can be pre-calculated once the range of fuel types is known. Comparisons against a whole core pin-by-pin reference demonstrates that the embedding process does not introduce a significant error, even after burnup and refuelling. Comparisons against a WIMS reference demonstrate that a pin-by-pin multi-group diffusion solution is capable of capturing the main interface effects. This therefore defines a practical approach for achieving results close to lattice code accuracy, but broadly at the cost of a standard reactor calculation. (authors)

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗

Outcome of Patients Treated With a Single-Fraction Dose of Palliative Radiation for Cutaneous T-Cell Lymphoma

Purpose: Cutaneous T-cell lymphoma (CTCL) is a radiosensitive tumor. Presently, treatment with radiation is given in multiple fractions. The current literature lacks data that support single-fraction treatment for CTCL. This retrospective review assesses the clinical response in patients treated with a single fraction of radiation. Methods and Materials: This study reviewed the records of 58 patients with CTCL, primarily mycosis fungoides, treated with a single fraction of palliative radiation therapy (RT) between October 1991 and January 2011. Patient and tumor characteristics were reviewed. Response rates were compared using Fisher's exact test and multiple logistic regressions. Survival rates were determined using the Kaplan-Meier method. Cost-effectiveness analysis was performed to assess the cost of a single vs a multifractionated treatment regimen. Results: Two hundred seventy individual lesions were treated, with the majority (97%) treated with ≥700 cGy; mean follow-up was 41.3 months (range, 3-180 months). Response rate by lesion was assessed, with a complete response (CR) in 255 (94.4%) lesions, a partial response in 10 (3.7%) lesions, a partial response converted to a CR after a second treatment in 4 (1.5%) lesions, and no response in 1 (0.4%) lesion. The CR in lower extremity lesions was lower than in other sites (P=.0016). Lesions treated with photons had lower CR than those treated with electrons (P=.017). Patients with lesions exhibiting large cell transformation and tumor morphology had lower CR (P=.04 and P=.035, respectively). Immunophenotype did not impact response rate (P=.23). Overall survival was significantly lower for patients with Sézary syndrome (P=.0003) and erythroderma (P<.0001). The cost of multifractionated radiation was >200% higher than that for single-fraction radiation. Conclusions: A single fraction of 700 cGy-800 cGy provides excellent palliation for CTCL lesions and is cost effective and convenient for the patient.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Local Atomic Structure in Photo-isomerized Ruthenium Sulfur Dioxide Complexes Revealed by Pair Distribution Function Analysis

SO 2 linkage photoisomerization in crystalline ruthenium-based complexes has demonstrated nanophotonic phenomena such as optical switching and nano-optomechanical transduction. Molecular insights into these materials have been explored largely via the characterization of their photoinduced crystal structures via in situ single-crystal X-ray diffraction, known as photocrystallography. Photoinduced molecular disorder is present, which photocrystallography can model to the extent that it is confined within the periodic boundary of a unit cell. However, non-periodic molecular disorder is suspected to exist as well. In situ total scattering experiments were therefore carried out on finely powdered crystals of four ruthenium-sulfur dioxide complexes. Data were modeled using light-minus-dark' difference pair distribution function analysis, which afforded photoinduced structural changes exclusively. This revealed structural features that were first compared against models of photoinduced crystal structures known a priori from photocrystallography. Furthermore, statistical inference was then employed, which evidenced generally good agreement between the total scattering data and the photocrystallographic models, while revealing real differences that are indicative of a structure with only a short-range order. Overall, our findings demonstrate that in situ light-induced total scattering experiments on finely powdered crystals are able to reveal the photoinduced structure. Overall, the evidence suggests that such structure could include a short-range order as well as photocrystallographic content. Our demonstration experiment offers a pathway to develop studies that capture the short-range order in linkage photoisomers, while we have outlined the procedure for testing the validity of associated structural models.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DESIGN CHARACTERISTICS OF THE IDAHO NATIONAL LABORATORY HIGH-TEMPERATURE GAS-COOLED TEST REACTOR

Uncertainty and sensitivity analysis is an indispensable element of any substantial attempt in reactor simulation validation. The quantification of uncertainties in nuclear engineering has grown more important and the IAEA Coordinated Research Program (CRP) on High-Temperature Gas Cooled Reactor (HTGR) initiated in 2012 aims to investigate the various uncertainty quantification methodologies for this type of reactors. The first phase of the CRP is dedicated to the estimation of cell and lattice model uncertainties due to the neutron cross sections co-variances. Phase II is oriented towards the investigation of propagated uncertainties from the lattice to the coupled neutronics/thermal hydraulics core calculations. Nominal results for the prismatic single block (Ex.I-2a) and super cell models (Ex.I-2c) have been obtained using the SCALE 6.1.3 two-dimensional lattice code NEWT coupled to the TRITON sequence for cross section generation. In this work, the TRITON/NEWT-flux-weighted cross sections obtained for Ex.I-2a and various models of Ex.I-2c is utilized to perform a sensitivity analysis of the MHTGR-350 core power densities and eigenvalues. The core solutions are obtained with the INL coupled code PHISICS/RELAP5-3D, utilizing a fixed-temperature feedback for Ex. II-1a.. It is observed that the core power density does not vary significantly in shape, but the magnitude of these variations increases as the moderator-to-fuel ratio increases in the super cell lattice models.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗

Development of a Prototype Simulation Executive with Zooming in the Numerical Propulsion System Simulation

A major difficulty in designing aeropropulsion systems is that of identifying and understanding the interactions between the separate engine components and disciplines (e.g., fluid mechanics, structural mechanics, heat transfer, material properties, etc.). The traditional analysis approach is to decompose the system into separate components with the interaction between components being evaluated by the application of each of the single disciplines in a sequential manner. Here, one discipline uses information from the calculation of another discipline to determine the effects of component coupling. This approach, however, may not properly identify the consequences of these effects during the design phase, leaving the interactions to be discovered and evaluated during engine testing. This contributes to the time and cost of developing new propulsion systems as, typically, several design-build-test cycles are needed to fully identify multidisciplinary effects and reach the desired system performance. The alternative to sequential isolated component analysis is to use multidisciplinary coupling at a more fundamental level. This approach has been made more plausible due to recent advancements in computation simulation along with application of concurrent engineering concepts. Computer simulation systems designed to provide an environment which is capable of integrating the various disciplines into a single simulation system have been proposed and are currently being developed. One such system is being developed by the Numerical Propulsion System Simulation (NPSS) project. The NPSS project, being developed at the Interdisciplinary Technology Office at the NASA Lewis Research Center is a 'numerical test cell' designed to provide for comprehensive computational design and analysis of aerospace propulsion systems. It will provide multi-disciplinary analyses on a variety of computational platforms, and a user-interface consisting of expert systems, data base management and visualization tools, to allow the designer to investigate the complex interactions inherent in these systems. An interactive programming software system, known as the Application Visualization System (AVS), was utilized for the development of the propulsion system simulation. The modularity of this system provides the ability to couple propulsion system components, as well as disciplines, and provides for the ability to integrate existing, well established analysis codes into the overall system simulation. This feature allows the user to customize the simulation model by inserting desired analysis codes. The prototypical simulation environment for multidisciplinary analysis, called Turbofan Engine System Simulation (TESS), which incorporates many of the characteristics of the simulation environment proposed herein, is detailed.

Reed, John A.↗

Cone-Beam CT-Based Delineation of Stereotactic Lung Targets: The Influence of Image Modality and Target Size on Interobserver Variability

Purpose: It is generally agreed that the safe implementation of stereotactic body radiotherapy requires image guidance. The aim of this work was to assess interobserver variability in the delineation of lung lesions on cone-beam CT (CBCT) images compared with CT-based contouring for adaptive stereotactic body radiotherapy. The influence of target size was also evaluated. Methods and Materials: Eight radiation oncologists delineated gross tumor volumes in 12 patient cases (non-small cell lung cancer I-II or solitary metastasis) on planning CTs and on CBCTs. Cases were divided into two groups with tumor diameters of less than (Group A) or more than 2 cm (Group B). Comparison of mean volumes delineated by all observers and range and coefficient of variation were reported for each case and image modality. Interobserver variability was assessed by means of standard error of measurement, conformity index (CI), and its generalized observer-independent approach. The variance between single observers on CT and CBCT images was measured via interobserver reliability coefficient. Results: Interobserver variability on CT images was 17% with 0.79 reliability, compared with 21% variability on CBCT and 0.76 reliability. On both image modalities, values of the intraobserver reliability coefficient (0.99 for CT and 0.97 for CBCT) indicated high reproducibility of results. In general, lower interobserver agreement was observed for small lesions (CI{sub genA} = 0.62 {+-} 0.06 vs. CI{sub genB} = 0.70 {+-} 0.03, p < 0.05). The analysis of single patient cases revealed that presence of spicules, diffuse infiltrations, proximity of the tumors to the vessels and thoracic wall, and respiration motion artifacts presented the main sources of the variability. Conclusion: Interobserver variability for Stage I-II non-small cell lung cancer and lung metastasis was slightly higher on CBCT compared with CT. Absence of significant differences in interobserver variability suggests that CBCT imaging provides an effective tool for tumor localization, and image data could be also used for target volume delineation purposes.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Design of the First‐in‐Class, Highly Potent Irreversible Inhibitor Targeting the Menin‐MLL Protein–Protein Interaction

Abstract The structure‐based design of M‐525 as the first‐in‐class, highly potent, irreversible small‐molecule inhibitor of the menin‐MLL interaction is presented. M‐525 targets cellular menin protein at sub‐nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL‐regulated gene expression in MLL leukemia cells. M‐525 demonstrates high cellular specificity over non‐MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co‐crystal structure of M‐525 in complex with menin firmly establish its mode of action. A single administration of M‐525 effectively suppresses MLL‐regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M‐525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.

Xu, Shilin↗

Characterizing Sustained Solar-to-Hydrogen Electrocatalysis at Low Cell Potentials Enabled by Crude Glycerol Oxidation

Unassisted solar-driven water electrolysis as a sustainable source for H 2 is limited by the high overpotential necessary to drive the oxygen evolution reaction (OER). Crude glycerol is an extremely alkaline byproduct of biodiesel synthesis that can be valorized or refined to produce more desirable chemicals. Glycerol can also be directly oxidized on an anode, replacing water oxidation, to reduce the applied cell potential requirements of electrolytic H 2 production or CO 2 reduction. An advantage of oxidizing glycerol in its crude form is the opportunity to valorize it without initial refinement. We describe an approach to replace the OER half-reaction with the sacrificial crude glycerol electrooxidation on a layered Au–Pt–Bi electrocatalyst on a Ni substrate. Compared to compositions with fewer components, the AuPtBi–Ni electrocatalyst improved the duration of performance and reduced the overall cell potential for glycerol electrooxidation in the extreme alkaline solutions representative of crude glycerol. These enhancements facilitated extended, unassisted hydrogen evolution from crude glycerol electrolysis, even under the power of a single-junction silicon solar cell at less than 1 sun illumination. We characterized the oxidation products of crude glycerol electrolysis and the subsequent products formed spontaneously in the electrolyte in the highly alkaline solution. This analysis helps to both identify the stoichiometric limits of glycerol oxidation at the low cell potentials of interest here and to understand the chemical control imparted by electrocatalysis on the ultimate compounds formed in the crude solution. Furthermore, the results for the AuPtBi electrocatalyst show that incorporating crude glycerol oxidation into integrated electrochemical systems can simultaneously simplify their design and significantly improve solar-to-hydrogen rates.

08 HYDROGEN↗

Loss of Cadherin-11 in pancreatic ductal adenocarcinoma alters tumor-immune microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest forms of cancer with very few treatment options. The 5-year survival rate for PDAC is 10% following diagnosis. Cadherin 11 (Cdh11), a cell-to-cell adhesion molecule, has been suggested to promote tumor growth and immunosuppression in PDAC, and Cdh11 inhibition significantly extended survival in mice with PDAC. However, the mechanisms by which Cdh11 deficiency influences PDAC progression and anti-tumor immune responses have yet to be fully elucidated. To investigate Cdh11-deficiency induced changes in PDAC tumor microenvironment (TME), we crossed p48-Cre; LSL-Kras G12D/+ ; LSLTrp53 R172H/+ (KPC) mice with Cdh11 +/- mice and performed single-cell RNA sequencing (scRNA-seq) of the non-immune (CD45 - ) and immune (CD45 + ) compartment of KPC tumor-bearing Cdh11 proficient (KPC-Cdh11 +/+ ) and Cdh11 deficient (KPC-Cdh11 +/- ) mice. Our analysis showed that Cdh11 is expressed primarily in cancer-associated fibroblasts (CAFs) and at low levels in epithelial cells undergoing epithelial-to-mesenchymal transition (EMT). Cdh11 deficiency altered the molecular profile of CAFs, leading to a decrease in the expression of myofibroblast markers such as Acta2 and Tagln and cytokines such as Il6, Il33 and Midkine (Mdk). We also observed a significant decrease in the presence of monocytes/macrophages and neutrophils in KPC-Cdh11 +/- tumors while the proportion of T cells was increased. Additionally, myeloid lineage cells from Cdh11-deficient tumors had reduced expression of immunosuppressive cytokines that have previously been shown to play a role in immune suppression. In summary, our data suggests that Cdh11 deficiency significantly alters the fibroblast and immune microenvironments and contributes to the reduction of immunosuppressive cytokines, leading to an increase in anti-tumor immunity and enhanced survival.

59 BASIC BIOLOGICAL SCIENCES↗