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DOE OSTI2023

Twisted bilayer graphene as topological heavy fermion: II. Analytical approximations of the model parameters

The recently-introduced topological heavy fermion (THF) model [1] of twisted bilayer graphene (TBG) aims to reconcile the quantum-dot-like electronic structure of the latter observed by scanning tunneling microscopy, with its electron delocalization seen in transport measurements. The THF model achieves this by coupling localized (heavy) fermions with anomalous conduction electrons. Originally, the parameters of the THF model were obtained numerically from the Bistritzer–Macdonald (BM) model of TBG [1]. In this work, we derive analytical expressions for the THF model parameters as a function of the twist angle, the ratio between the tunneling amplitudes at the AA and AB regions (w 0 /w 1 ), and the screening length of the interaction potential. By numerically computing the THF model parameters across an extensive experimentally-relevant parameter space, we show that the resulting approximations are remarkably good, i.e., within the 30% relative error for almost the entire parameter space. At the single-particle level, the THF model accurately captures the energy spectrum of the BM model over a large phase space of angles and tunneling amplitude ratios. When interactions are included, we also show that the THF description of TBG is good around the magic angle for realistic values of the tunneling amplitude ratios (0.6 ≤ w 0 /w 1 ≤ 1.0), for which the hybridization between the localized and conduction fermions γ is smaller than the onsite repulsion of the heavy fermions U 1 (i.e., |γ| < U 1 ).

Approximation methods↗
DOE OSTI2018

Policy, Permit, Perform: Using City Benchmarking Data and Building Construction Permit History to Identify Energy Performance Improvements

The City of Portland (City) and Multnomah County 2015 Climate Action Plan targets a 40 percent reduction in carbon emissions below 1990 levels by 2030. To reach this goal, the plan includes a key objective to reduce the total energy use of existing buildings by 25 percent. Buildings are responsible for one-half of carbon emissions in Portland, Oregon, U.S., and improving their performance is critical to achieving the City’s climate goals. As part of its climate action planning, the City passed an ordinance on April 22, 2015, requiring commercial buildings 20,000 ft2 and larger to benchmark and disclose annual energy performance metrics through ENERGY STAR® Portfolio Manager® (ESPM), including greenhouse gas emissions, building energy use intensity (EUI) and ENERGY STAR scores. Twenty-five cities in the U.S. have adopted similar policies requiring energy benchmarking. These policies are generating a treasure trove of data about the drivers of building performance, but practitioners are only beginning to link benchmarking data to other datasets to produce actionable insight into improving building performance. In 2016, the City received a financial assistance award from the U.S. Department of Energy (DOE) through the Cities Leading through Energy Analysis and Planning project (Award Number DE-0007737). Portland’s project evaluated the application of the DOE Building Energy Asset Score Tool and rating system developed by Pacific Northwest National Laboratory (PNNL) to commercial buildings that report to the City. The City used building construction permit history to develop Asset Scores for a set of office buildings that reported energy performance for 2015 – the first year the City mandated energy benchmarking and reporting for commercial buildings 50,000 ft2 and larger. The primary project objective was to link energy benchmarking data and commercial building permit data to analyze commercial buildings systems that present the best, specific opportunities to improve energy performance. Integrating these datasets from two City departments, the Bureau of Development Services and the Bureau of Planning and Sustainability, could expand Portland’s use of analytics to inform climate policy decisions and strategic targeting of financial incentives for building owners and managers who are best positioned to improve the performance of their buildings. The project began with the commercial benchmarking data received for 340 commercial buildings that submitted calendar year 2015 energy reports. The City retained Research Into Action and Energy 350 (RIA team) to evaluate this self-reported benchmarking data. Based on a survey of 53 building managers, the RIA team found that most respondents used the City’s compliance tools, including a How-to Guide and Help Desk, and found access to utility data to be straightforward. However, almost one-third of the respondents encountered challenges when estimating the gross floor area (GFA), and some experienced confusion regarding the input of property use types and details into ESPM. Based on the RIA team’s recommendations, the City refined its How-to Guide, created online answers to frequently asked questions, and hosted office hour sessions to help building managers accurately characterize their building’s physical characteristics and operations in ESPM. Concurrently with the RIA team’s evaluation, the City worked with PNNL to estimate DOE Asset Score Preview (Preview) scores for 181 of the 340 commercial buildings that submitted ESPM reports to the City. Asset Score Tool is a web-based tool developed by PNNL for DOE to evaluate and rate the as-built energy efficiency of a building. Asset Score Tool’s full analysis capability runs a detailed energy model based on building geometry, age, envelope, lighting and mechanical systems using standard operating assumptions to give the building a score, similar to a miles per gallon rating for a car. Preview, a simplified deployment of the full Asset Score Tool, provides a preliminary score range using only seven data points, six of which are readily available in the ESPM benchmarking data. Analysis of the combined Preview scores and the operational ESPM scores identified buildings with a high potential for energy improvements through either retro-commissioning and retuning of existing operations or capital investments into building systems. The City contracted Whole Building Solutions (WBS) to mine building permit history and develop full Asset Scores for a subset of 26 office buildings that were eligible for both ENERGY STAR scores and Asset Scores. WBS researched permits and building plans to identify mechanical, lighting and envelope systems and other building characteristics necessary to complete Asset Scores. This historical data was recorded using the web-based Asset Score Tool, which evaluates the as designed energy efficiency of existing buildings. Much of this City information was available online after 2010; however, WBS had to search through microfiche files and the City’s database to obtain permit and plan history prior to 2010. Although building geometry, mechanical system type and basic envelope information was consistently identifiable, WBS found permit data gaps that prevented complete and accurate Asset Scores for most of the office buildings. If the City decides to develop Asset Scores based on building permit information in the future, WBS recommended requiring lighting plans, control diagrams and as-built drawings that reflect how the buildings are actually constructed. In addition, WBS recommended uploading plans and permits from microfiche storage into a more comprehensive, searchable database consistent with the City’s current online permit information. To identify the actual lighting types, WBS and City staff conducted site visits of all 26 office buildings. As part of managing the flow of ESPM and Asset Score data for the project, Earth Advantage, a sub-recipient of the Cities-LEAP award, created a DOE Standard Energy Efficiency Data (SEED) (USDOE 2018) instance for the City and used Asset Score’s Application Programming Interface (API) (Asset Score 2018) capabilities to develop two new features in the SEED Platform™: (1) automated Asset Score Preview ranges calculated based on benchmarking data and the City’s estimate of number of building floors; and (2) storage of full Asset Score information. Leveraging the construction permit history and site visit information for the 26 office buildings, The Cadmus Group (Cadmus) analyzed benchmarking data and Asset Score information to identify opportunities and drivers to improve performance. Correlation and regression analysis of the combined dataset was completed to determine whether building operations or specific systems – mechanical, lighting or envelope – present the best opportunities to improve energy performance. The central outcome of this project was Cadmus’ detailed analysis of the richer dataset that was created by combining the City of Portland’s commercial building permit activity and building-specific energy performance information based on metrics from ESPM and Asset Score Tool. Some of their findings collaborate with well-known facts, such as buildings with less efficient lighting systems are good targets for efficiency improvements through lighting upgrades. This analysis also helped identify that individual heating, ventilation, and air conditioning (HVAC) equipment efficiency does not necessarily correlate with building performance. However, overall HVAC system performance, as measured with the Total System Performance Ratio (TSPR) metric, is a better indicator of building performance (Goel et al. 2014). As a metric, TSPR considers whole system performance that includes equipment efficiency and system controls, such as resets for static pressure and chilled water setpoints, which can be more effective and financially feasible options for improving building performance. Given the high cost associated with envelope retrofits, opportunities to upgrade envelope insulation are likely to be limited. However, buildings with single-pane and non-thermal break windows are good candidates for window replacements, such as upgrading to double-pane windows with thermal breaks. This research project determined that developing Asset Scores based on site visits is preferable to mining City building permit data. In addition, the use of benchmarking data to develop Asset Score Preview Scores is recommended as a first step in engaging building managers to develop full Asset Scores. Asset Score Tool outputs can help building managers quickly identify opportunities for improvement and then work with the utility incentive administrator and energy service providers to develop their retrofit plan. Where full Asset Scores are available, analysis using a quadrant matrix with ENERGY STAR scores is recommended to identify buildings that present the best opportunities for operational-behavioral improvements versus ones with opportunities for upgrades to physical building systems. This workflow and the tools will help cities, utility incentive administrators, building portfolio managers and energy service providers develop energy programs and strategies for screening and analysis of buildings with the greatest energy savings potential. This report describes the project approach and research results to inform future coordination of ESPM and Asset Score data, including the use of benchmarking data to generate Preview scores. Given better awareness of energy performance, building managers can make more informed decisions to reduce energy consumption and carbon emissions. With cities, states and jurisdictions adopting benchmarking and auditing ordinances, there are substantial amounts of data submitted to cities that could be used to inform investments in energy efficiency.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗
DOE OSTI2013

Modeling X-Ray Thomson Scattering Spectra of Warm Dense Matter

Warm dense matter (WDM) is sometimes described as a \solid density plasma" where neither weakly coupled plasma theory nor condensed matter theory are applicable. More specifically, WDM has densities of ~ 0:1 - 50 times solid density, temperatures of ~ 1 - 100 eV, is partially ionized, globally neutral, has strongly correlated particles (due to interactions), and partial electron degeneracy. In nature, WDM may be found in the interiors of planets such as Jupiter or in the envelopes of white dwarf stars, and in man-made processes such as inertial confinement fusion (ICF), WDM exists as a transient state of matter. To model these physical systems, the equation of state as well as opacity, conductivity, and diffusion coefficients must be known. Experimentally WDM is probed with an experimental technique known as X-Ray Thomson Scattering (XRTS). In such an experiment X-rays photons are scattered off of WDM and the resulting photons are measured at a given solid angle. The resulting spectrum gives information on the density and temperature of WDM, but a model of WDM and the scattering experiment is often required to interpret the results. As a result, these experiments also serve as a method of validation for potential models of WDM. The work presented here focuses on the model of WDM proposed by Starrett and Saumon and a model for scattering based off of Chihara’s work. The model proposed by Starrett and Saumon is an average-atom model that is coupled with a two component plasma model, hereafter referred to as an AA+TCP model. The AA+TCP model is an ab initio model with no free parameters, only requiring knowledge of the element under investigation, the density, and the temperature. The outputs from the model completely determine all the input parameters needed for Chihara’s structure function (chemical potential, elastic feature, screening potential, bound-state wavefunctions, and free wavefunctions), which in turn determines the double differential scattering cross-section of the experiment. This approach to determining the outcome of an XRTS experiment parallels that of Johnson, et al., but expands the work in many respects. For example, the AA+TCP model completely determines all the input parameters to the structure function; hence no ad hoc approximations are necessary to close the system. Also, the free-electron feature and the bound-free feature are modified to include collisions and occupation of free electron states, respectively.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2021

Isotope ratio-based quantification of carbon assimilation highlights the role of plastidial isoprenoid precursor availability in photosynthesis

Abstract Background We report a method to estimate carbon assimilation based on isotope ratio-mass spectrometry (IRMS) of 13 CO 2 labeled plant tissue. Photosynthetic carbon assimilation is the principal experimental observable which integrates important aspects of primary plant metabolism. It is traditionally measured through gas exchange. Despite its centrality in plant research, gas exchange performs poorly with rosette growth habits typical of Arabidopsis thaliana , mutant lines with limited biomass, and accounts poorly for leaf shading. Results IRMS-based carbon assimilation values from plants labeled at different light intensities were compared to those obtained by gas exchange, and the two methods yielded similar values. Using this method, we observed a strong correlation between 13 C content and labeling time (R 2 = 0.999) for 158 wild-type plants labeled for 6 to 42 min. Plants cultivated under different light regimes showed a linear response with respect to carbon assimilation, varying from 7.38 nmol 13 C mg −1 leaf tissue min −1 at 80 PAR to 19.27 nmol 13 C mg −1 leaf tissue min −1 at 500 PAR. We applied this method to examine the link between inhibition of the 2 C -methyl- d -erythritol-4-phosphate (MEP) pathway and suppression of photosynthesis. A significant decrease in carbon assimilation was observed when metabolic activity in the MEP pathway was compromised by mutation or herbicides targeting the MEP pathway. Mutants affected in MEP pathway genes 1-DEOXY- d -XYLULOSE 5-PHOSPHATE SYNTHASE (DXS) or 1-HYDROXY-2-METHYL-2-(E)-BUTENYL 4-DIPHOSPHATE SYNTHASE (HDS) showed assimilation rates 36% and 61% lower than wild type. Similarly, wild type plants treated with the MEP pathway inhibitors clomazone or fosmidomycin showed reductions of 52% and 43%, respectively, while inhibition of the analogous mevalonic acid pathway, which supplies the same isoprenoid intermediates in the cytosol, did not, suggesting inhibition of photosynthesis was specific to disruption of the MEP pathway. Conclusions This method provides an alternative to gas exchange that offers several advantages: resilience to differences in leaf overlap, measurements based on tissue mass rather than leaf surface area, and compatibility with mutant Arabidopsis lines which are not amenable to gas exchange measurements due to low biomass and limited leaf surface area. It is suitable for screening large numbers of replicates simultaneously as well as post-hoc analysis of previously labeled plant tissue and is complementary to downstream detection of isotopic label in targeted metabolite pools.

2C‑methyl‑d‑erythritol 4‑phosphate pathway↗
DOE OSTI2021

Process Anomaly Detection for Sparsely Labeled Events in Nuclear Power Plants

An essential aspect of online monitoring, subtle anomaly detection increases the detection lead time for equipment failure and enables a nuclear power plant (NPP) to mitigate unexpected partial or full outages, resulting in significant cost saving to the plant. Once an anomaly is detected by plant staff, its cause and severity are investigated. Because the vast majority of anomalies require some level of investigation, including some that require time-consuming examination, before they are passed over to the engineering organization for further analysis, plants are often equipped with tools to assist the staff in performing anomaly detection. Those tools operate as a black box and are often based on statistical methods that establish sensor correlations using preconfigured mathematical models and flag correlation deviations as anomalies. Due to the number of anomalies detected at a given NPP on a daily basis, a significant number of flagged anomalies usually await examination for days or weeks. A primary cause of this backlog is that the methods used by the tools generate many false positives. Though this is usually attributed to oversensitive model settings due to very narrow normal operation bands, it can also be associated with the model development being inadequate for the process being monitored, or with missing model inputs that could have explained misclassified positives. The performance of anomaly detection tools impacts their plant acceptance and utilization, especially when the effort to address false positives generated by the tool depletes the value or cost saved by using that tool. Thus, means to advance anomaly detection performance have been investigated by the Department of Energy’s Light Water Reactor Sustainability program. Previous and ongoing efforts have targeted unsupervised machine-learning (ML) methods, which do not require the labeling of any data fed into the ML model. By contrast, in supervised anomaly detection methods, every data point is labeled as either a normal or abnormal process condition, and the model is trained to replicate the classification process. Supervised methods usually outperform unsupervised methods, due to the added value in differentiating normal from anomalous states of the monitored process. An NPP’s corrective action program requires it to track and document, via a dedicated report, the resolution of any issues that occur within the plant. Once created, each report is reviewed by a plant screening committee, and several classifications and decisions are made. Recently, a collaborating NPP developed an artificial intelligence and ML-based classifier to categorize a condition report (CR) into classes that can serve to label the data as normal or anomalous. Applying CRs as labels represents a semi-supervised use case. Semi-supervised ML assumes that labels exist for some data points (i.e., labeled anomalies, in this case) but not for the rest. In this effort, semi-supervised ML methods were used to fuse data from CRs with anomaly detection methods in order to test the hypothesis that partially labeled anomalies would improve the accuracy of the anomaly detection methods. Specifically, two methods were used. The first is the deep Semi-supervised Anomaly Detection (deep SAD) method, which can handle labels ranging from fully unsupervised to fully supervised cases. The second is a newly designed ML method developed specifically for this effort and referred to as the high-order feature (HOF)-based method. To evaluate these two methods in controlled environments, synthetic data generators were developed and used. The first datasets used a spring-mass-damper (SMD) system simulator commonly found in mechanical engineering references. This was used to create two use cases: a one- and a three-mass system. Anomalies were introduced by changing the spring and damper coefficients while the system was actuated by random forces. The second datasets used the commercial Dymola-Modelica software to build a simplified nuclear reactor model. Anomalies were added in the form of corrupted sensor readings and/or control commands. The deep SAD method was tested using the SMD system, while the HOF method was tested using both datasets. Application of the deep SAD semi-supervised ML method demonstrated that labels can generate increased confidence in detecting true anomalies. This helped increase the number of true positives and decrease the number of false negatives—something that would aid in addressing the backlog of possible anomalies. Application of the HOF method demonstrated that labels can aid in down selecting from a candidate set of features to a more optimal subset in order to better differentiate between normal and anomalous conditions.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2026

Exploring the impact of nucleotide length on lipid nanoparticle structure and properties

Lipid nanoparticles (LNPs) are versatile carriers for nucleic acid (NA) therapeutics, including ASOs, siRNA, mRNA, and poly-IC. While lipid composition is known to influence LNP properties, the impact of NA length on morphology and internal structure is less understood, particularly during the stages of carrier–cargo assembly. Here, we examine NA length and lipid composition immediately after mixing using high-throughput SAXS, dynamic light scattering, and cryogenic electron microscopy. All LNPs form ordered NA/lipid compartments, with longer NAs promoting inverse hexagonal (H II ) phases and larger intercompartment distances. In contrast, short NAs, especially in formulations with SM102 ionizable lipid, favor lamellar phases. SAXS peak deconvolution quantifies ordered versus disordered phases via a Robustness of Ordered Phase factor, which correlates with particle size and encapsulation efficiency. Formulations with MC3 ionizable and DOPE helper lipids exhibit the most stable H II -phase packing, highlighting the role of helper-lipid curvature in compartment stabilization. Variations in NA compartmentalization indicate differences in payload capacity, offering a framework for rational LNP design across diverse nucleic acid cargos.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Evaluation of GlassNet for physics-informed machine learning of glass stability and glass-forming ability

Glassy materials form the basis of many modern applications, including nuclear waste immobilization, touch-screen displays, and optical fibers, and also hold great potential for future medical and environmental applications. However, their structural complexity and large composition space make design and optimization challenging for certain applications. Of particular importance for glass processing and design is an estimate of a given composition's glass-forming ability (GFA). However, there remain many open questions regarding the underlying physical mechanisms of glass formation, especially in oxide glasses. It is apparent that a proxy for GFA would be highly useful in glass processing and design, but identifying such a surrogate property has proven itself to be difficult. While glass stability (GS) parameters have historically been used as a GFA surrogate, recent research has demonstrated that most of these parameters are not accurate predictors of the GFA of oxide glasses. Here, in this work, we explore the application of an open-source pre-trained neural network model, GlassNet, that can predict the characteristic temperatures necessary to compute GS with reasonable performance and assess the feasibility of using these physics-informed machine learning (PIML)-predicted GS parameters to estimate GFA. In doing so, we track the uncertainties at each step of the computation—from the original ML prediction errors to the compounding of errors during GS estimation, and finally to the final estimation of GFA. While GlassNet exhibits reasonable accuracy on all individual properties, we observe a large compounding of error in the combination of these individual predictions for the PIML prediction of GS, finding that random forest models offer similar accuracy to GlassNet. We also break down the performance of GlassNet on different glass families and find that the error in GS prediction is correlated with the error in crystallization peak temperature prediction. Lastly, we utilize this finding to assess the relationship between top-performing GS parameters and GFA for two ternary glass systems: sodium borosilicate and sodium iron phosphate glasses. We conclude that to obtain true ML predictive capability of GFA, significantly more data needs to be collected.

36 MATERIALS SCIENCE↗
DOE OSTI2022

A Systematic Review and Meta-Analysis of Tai Chi Training in Cardiorespiratory Fitness of Elderly People

Objectives. The purpose of this study was to investigate the influence of Tai Chi on cardiorespiratory fitness (CRF) in elderly people using meta-analysis. Methods. This study used seven electronic databases and data retrieved from randomized controlled trials (RCTs) investigating the role of Tai Chi on CRF in the elderly. All these 24 RCTs were screened and selected from 7 literature databases. The Stata 11.2 software (StataCorp, USA) was used for the meta-analysis, subgroup analysis, and bias test, while the Cochrane Collaboration’s tool was used for the assessment of the risk of bias (RoB). 4 researchers independently participated in sample selection, data extraction, and RoB assessment. Results. Following the inclusion criteria, 24 eligible studies were included in our analysis. The meta-analysis indicated that Tai Chi practice significantly increased the maximum rate of oxygen consumption (VO2 max) (weighted mean difference (WMD) = 3.76, 95% CI: 1.25 to 6.26, P < 0.1 ), leading to an overall reduction in the heart rate (HR) (WMD = −1.84, 95% CI: −2.04 to −1.63, P ≤ 0.001 ) and an increase in the O2 pulse (WMD = 0.94, 95% CI: 0.60 to 1.28, P ≤ 0.001 ) in individuals who practiced Tai Chi regularly compared with those who did not. The subgroup analysis suggested that overall in those who practiced Tai Chi, males (WMD = 1.48, 95% CI: 0.85 to 2.12, P ≤ 0.001 ) had higher O2 pulse than females (WMD = 0.73, 95% CI: 0.33 to 1.12, P ≤ 0.001 ). The subgroup analysis also showed an increase in the vital capacity (VC) (WMD = 316.05, 95% CI: 239.74 to 392.35, P ≤ 0.001 ) in individuals practicing Tai Chi. When the samples were further stratified by Tai Chi practicing time, the subgroup analysis suggested that individuals practicing Tai Chi over a period of 24 weeks showed no significant difference in VC (WMD = 82.95, 95% CI: -98.34 to 264.23, P = 0.370 ), while those practicing Tai Chi over a period of 48 weeks showed a significant increase (WMD = 416.62, 95% CI: 280.68 to 552.56, P ≤ 0.001 ). Furthermore, the subgroup analysis demonstrated that the increase in VC is significantly correlated with the Tai Chi practicing time (WMD = 344.97, 95% CI: 227.88 to 442.06, P ≤ 0.001 ). Conclusion. Regular Tai Chi practice could improve the CRF in the elderly, as indicated by significant improvement in indicators including VO2max, O2pulse, VC, and HR. However, gender and practice time might influence the overall beneficial outcomes.

Tan, Tianyang↗
DOE OSTI2018

Biosynthesis, Microstructural Characterisations and Investigation of In-Vitro Mutagenic and Eco-Toxicological Response of a Novel Microbial Exopolysaccharide Based Biopolymer

A modified microbial polysaccharide based biopolymer has been investigated as a potential candidate towards development of sustainable biomaterials and bioplastics. An in-depth study was carried out to biosynthesize, characterize and assess any possible mutagenic potential and ecotoxicity of the microbial polysaccharide biopolymer. Microstructural investigations using confocal microscopy, Fourier transform (FT)-Raman depth profile mapping and scanning electron microscopy (SEM) of the biosynthetically modified polysaccharide revealed internal structural perturbations, as well as occlusion of granular pores by extraneous materials. The Raman 3D mapping depth profile along with time-of-flight (MALDI-TOF) mass spectrometry also indicated important structural and surface modifications, which could be correlated to the production of microbial exopolysaccharides and secondary metabolites. The study then looked into any possible genetic mutation and ecological risks associated with the biosynthetically modified polysaccharide through the investigation of genotoxicity and ecotoxicity. The genotoxicity study was carried out through bacterial reverse gene mutation (Ames) test by using two different strains (TA98 and TA100) of bacteria. The results did not indicate any mutagenic effect against either of the strains used for the biopolymer samples and was found to be genotoxically safe. Ecotoxicity tests, carried out using bioluminescent bacteria Vibrio fisheri further indicated no ecotoxicity within the given experimental conditions. The study measured the half maximal effective concentration (EC50) to cause a 50% decrease in the light output of the bacteria, a measure of ecotoxicological response of the biopolymer. Overall, results from this study indicated that the novel biopolymer was genotoxically and ecotoxically safe, which offers immense potential for future use of this biopolymer.

36 MATERIALS SCIENCE↗
DOE OSTI2019

Single-Dose Vaccination with a Hepatotropic Adeno-associated Virus Efficiently Localizes T Cell Immunity in the Liver with the Potential To Confer Rapid Protection against Hepatitis C Virus

Hepatitis C virus (HCV) is a significant contributor to the global disease burden, and development of an effective vaccine is required to eliminate HCV infections worldwide. CD4 + and CD8 + T cell immunity correlates with viral clearance in primary HCV infection, and intrahepatic CD8 + tissue-resident memory T (T RM ) cells provide lifelong and rapid protection against hepatotropic pathogens. Consequently, we aimed to develop a vaccine to elicit HCV-specific CD4 + and CD8 + T cells, including CD8 + T RM cells, in the liver, given that HCV primarily infects hepatocytes. To achieve this, we vaccinated wild-type BALB/c mice with a highly immunogenic cytolytic DNA vaccine encoding a model HCV (genotype 3a) nonstructural protein (NS5B) and a mutant perforin (pVAX-NS5B-PRF), as well as a recombinant adeno-associated virus (AAV) encoding NS5B (rAAV-NS5B). A novel fluorescent target array (FTA) was used to map immunodominant CD4 + T helper (T H ) cell and cytotoxic CD8 + T cell epitopes of NS5B in vivo , which were subsequently used to design a K d NS5B 451-459 tetramer and analyze NS5B-specific T cell responses in vaccinated mice in vivo . The data showed that intradermal prime/boost vaccination with pVAX-NS5B-PRF was effective in eliciting T H and cytotoxic CD8 + T cell responses and intrahepatic CD8 + T RM cells, but a single intravenous dose of hepatotropic rAAV-NS5B was significantly more effective. As a T-cell-based vaccine against HCV should ideally result in localized T cell responses in the liver, this study describes primary observations in the context of HCV vaccination that can be used to achieve this goal. There are currently at least 71 million individuals with chronic HCV worldwide and almost two million new infections annually. Although the advent of direct-acting antivirals (DAAs) offers highly effective therapy, considerable remaining challenges argue against reliance on DAAs for HCV elimination, including high drug cost, poorly developed health infrastructure, low screening rates, and significant reinfection rates. Accordingly, development of an effective vaccine is crucial to HCV elimination. An HCV vaccine that elicits T cell immunity in the liver will be highly protective for the following reasons: (i) T cell responses against nonstructural proteins of the virus are associated with clearance of primary infection, and (ii) long-lived liver-resident T cells alone can protect against malaria infection of hepatocytes. Thus, in this study we exploit promising vaccination platforms to highlight strategies that can be used to evoke highly functional and long-lived T cell responses in the liver for protection against HCV.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2001

A spontaneously arising mutation in connexin32 with repeated passage of FRTL-5 cells coincides with increased growth rate and reduced thyroxine release

In this study we examine changes in the cellular properties of FRTL-5 cells as a function of passage number, with particular emphasis on gap junction expression, karyotype, morphology, growth rate and thyroxine (T(4)) release. Early passage FRTL-5 follicular cells transfer dye through gap junctions from injected cell(s) to third-order neighboring cells and beyond within their respective follicles and have immuno-detectable connexin32 (Cx32) type gap junctional plaques in their lateral contacting plasma membranes. By contrast, FRTL-5 cells established as monolayers, or as follicles from cultures passed more than 15 times, did not transfer microinjected Lucifer Yellow dye to contiguous neighboring cells and did not express any immuno-detectable rat thyroid specific connexins (Cx43, Cx32 or Cx26). Western blots confirmed that total, membrane and cytosolic Cx32 protein was present only in early pass follicular cultures. To better understand the passage-dependent loss of Cx32 expression, RT-PCR primers were made to the most unique sequences of the rat Cx32 molecule, the cytoplasmic and carboxyl-terminal regions. These primers were used to screen FRTL-5 RNA from cultures of various passage numbers. The results revealed that later passage cultures had a single base deletion in the middle of the Cx32 cytoplasmic loop region at nucleotide position 378. This base deletion was in the middle position of the codon for amino acid 116, which is normally a CAC (histidine) but read with the frame shift was a CCC (proline). The four amino acids that followed this deletion were also altered with the fourth one becoming UAA, the ochre translation stop codon. This premature stopping of translation resulted in a truncation of 60% of the protein, which included the remaining cytoplasmic loop, third and fourth transmembrane regions and the carboxyl-terminus. The later passage cultures did not produce a carboxyl-terminal RT-PCR product, indicating that the mRNA was also truncated. These regions of the Cx32 molecule contain the sequences and epitopes to which probes and antibodies are directed, and as such alterations of these regions with repeated passage explains reports by others that FRTL-5 cells do not express Cx32, and implies that cultures used for these assessments were passed more than 15 times. To determine if genetic or epigenetic abnormalities existed in FRTL-5 cells we performed chromosome spreads from various passage cultures. FRTL-5 cells have been reported to be diploid and more recently non-diploid; however, we found them to be fully tetraploid. This tetraploidy appears to be unstable in that later passes are tetraploid plus two or three extra chromosomes. There were no obvious translocations, breaks or large-scale interstitial deletions of any chromosomes in the FRTL-5 cultures tested. As FRTL-5 cells were repeatedly passed their morphology changed. Monolayer areas spread from beneath the follicles, and the follicles became flattened in appearance. These physical changes were coincident with dramatically increased growth rates. Early cultures (passed 3-12 times) divided on average every 49+/-1 h, whereas later passes (passes 20-25) divided every 28+/-3 h. To correlate these changes with a measure of thyroid function we assayed T(4) output. Early passage follicular cultures incubated for 6 h with sodium iodide, released on average 5.27+/- 0.33 ng/ml of T(4)/100 follicles. Later passes, or early passes treated with heptanol to down-regulate Cx32, released an average of 3.84+/-0.50 ng/ml of T(4)/100 follicles. There was a 27% difference in T(4) release between early follicular cultures, that were coupled by Cx32, and late or down-regulated early follicular cultures, that were uncoupled (P<0.0001). Collectively, the physical changes documented in this study were coincident with the loss of functional Cx32. This implies a relationship between the loss of intercellular communication and changes in morphogenic appearance, growth rate and reduced thyroid function and supports the previously postulated, tumor-suppressor role for Cx32. FRTL-5 cultures from low passage numbers are an excellent model of primary thyroid cells. However, many reports in the literature ascribe features to FRTL-5 cells that are mutually inconsistent. These differences may be resolved in the future by addressing the passage number and the conditional differences of the cultures being studied.

NASA Discipline Radiation Health↗
NASA NTRS2014

Service Life Extension of the Propulsion System of Long-Term Manned Orbital Stations

One of the critical non-replaceable systems of a long-term manned orbital station is the propulsion system. Since the propulsion system operates beginning with the launch of station elements into orbit, its service life determines the service life of the station overall. Weighing almost a million pounds, the International Space Station (ISS) is about four times as large as the Russian space station Mir and about five times as large as the U.S. Skylab. Constructed over a span of more than a decade with the help of over 100 space flights, elements and modules of the ISS provide more research space than any spacecraft ever built. Originally envisaged for a service life of fifteen years, this Earth orbiting laboratory has been in orbit since 1998. Some elements that have been launched later in the assembly sequence were not yet built when the first elements were placed in orbit. Hence, some of the early modules that were launched at the inception of the program were already nearing the end of their design life when the ISS was finally ready and operational. To maximize the return on global investments on ISS, it is essential for the valuable research on ISS to continue as long as the station can be sustained safely in orbit. This paper describes the work performed to extend the service life of the ISS propulsion system. A system comprises of many components with varying failure rates. Reliability of a system is the probability that it will perform its intended function under encountered operating conditions, for a specified period of time. As we are interested in finding out how reliable a system would be in the future, reliability expressed as a function of time provides valuable insight. In a hypothetical bathtub shaped failure rate curve, the failure rate, defined as the number of failures per unit time that a currently healthy component will suffer in a given future time interval, decreases during infant-mortality period, stays nearly constant during the service life and increases at the end when the design service life ends and wear-out phase begins. However, the component failure rates do not remain constant over the entire cycle life. The failure rate depends on various factors such as design complexity, current age of the component, operating conditions, severity of environmental stress factors, etc. Development, qualification and acceptance test processes provide rigorous screening of components to weed out imperfections that might otherwise cause infant mortality failures. If sufficient samples are tested to failure, the failure time versus failure quantity can be analyzed statistically to develop a failure probability distribution function (PDF), a statistical model of the probability of failure versus time. Driven by cost and schedule constraints however, spacecraft components are generally not tested in large numbers. Uncertainties in failure rate and remaining life estimates increase when fewer units are tested. To account for this, spacecraft operators prefer to limit useful operations to a period shorter than the maximum demonstrated service life of the weakest component. Running each component to its failure to determine the maximum possible service life of a system can become overly expensive and impractical. Spacecraft operators therefore, specify the required service life and an acceptable factor of safety (FOS). The designers use these requirements to limit the life test duration. Midway through the design life, when benefits justify additional investments, supplementary life test may be performed to demonstrate the capability to safely extend the service life of the system. An innovative approach is required to evaluate the entire system, without having to go through an elaborate test program of propulsion system elements. Evaluating every component through a brute force test program would be a cost prohibitive and time consuming endeavor. ISS propulsion system components were designed and built decades ago. There are no representative ground test articles for some of the components. A 'test everything' approach would require manufacturing new test articles. The paper outlines some of the techniques used for selective testing, by way of cherry picking candidate components based on failure mode effects analysis, system level impacts, hazard analysis, etc. The type of testing required for extending the service life depends on the design and criticality of the component, failure modes and failure mechanisms, life cycle margin provided by the original certification, operational and environmental stresses encountered, etc. When specific failure mechanism being considered and the underlying relationship of that mode to the stresses provided in the test can be correlated by supporting analysis, time and effort required for conducting life extension testing can be significantly reduced. Exposure to corrosive propellants over long periods of time, for instance, lead to specific failure mechanisms in several components used in the propulsion system. Using Arrhenius model, which is tied to chemically dependent failure mechanisms such as corrosion or chemical reactions, it is possible to subject carefully selected test articles to accelerated life test. Arrhenius model reflects the proportional relationship between time to failure of a component and the exponential of the inverse of absolute temperature acting on the component. The acceleration factor is used to perform tests at higher stresses that allow direct correlation between the times to failure at a high test temperature to the temperatures to be expected in actual use. As long as the temperatures are such that new failure mechanisms are not introduced, this becomes a very useful method for testing to failure a relatively small sample of items for a much shorter amount of time. In this article, based on the example of the propulsion system of the first ISS module Zarya, theoretical approaches and practical activities of extending the service life of the propulsion system are reviewed with the goal of determining the maximum duration of its safe operation.

Kamath, Ulhas↗
DOE OSTI2019

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Further, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Climate data, analysis and models for the study of natural variability and anthropogenic change

Gridded Temperature Under prior/current support, we completed and published (Jones et al., 2012) the fourth major update to our global land dataset of near-surface air temperatures, CRUTEM4. This is one of the most widely used records of the climate system, having been updated, maintained and further developed with DoE support since the 1980s. We have continued to update the CRUTEM4 (Jones et al., 2012) database that is combined with marine data to produce HadCRUT4 (Morice et al., 2012). The emphasis in our use of station temperature data is to access as many land series that have been homogenized by National Meteorological Services (NMSs, including NCDC/NOAA, Asheville, NC). Unlike the three US groups monitoring surface temperatures in a similar way, we do not infill areas that have no or missing data. We can only infill such regions in CRUTEM4 by accessing more station temperature series. During early 2014, we have begun the extensive task of updating as many of these series as possible using data provided by some NMSs and also through a number of research projects and programs around the world. All the station data used in CRUTEM4 have been available since 2009, but in Osborn and Jones (2014) we have made this more usable using a Google Earth interface (http://www.cru.uea.ac.uk/cru/data/crutem/ge/ ). We have recently completed the update of our infilled land multi-variable dataset (CRU TS 3.10, Harris et al., 2014). This additionally produces complete land fields (except for the Antarctic) for temperature, precipitation, diurnal temperature range, vapour pressure and sunshine/cloud. Using this dataset we have calculated sc-PDSI (self-calibrating Palmer Drought Severity Index) data and compared with other PDSI datasets (Trenberth et al., 2014). Also using CRU TS 3.10 and Reanalysis datasets, we showed no overall increase in global temperature variability despite changing regional patterns (Huntingford et al., 2013). Harris et al. (2014) is an update of an earlier dataset (Mitchell and Jones, 2005) which also had earlier DoE support. The earlier dataset has been cited over 1700 times according to ResearcherID on 31/July/2014 and the recent paper has already been cited 22 times. Analyses of Temperature Data Using the ERA-Interim estimate of the absolute surface air temperature of the Earth (instead of in the more normal form of anomalies) we compared the result against estimates we produced in 1999 with earlier DoE support. The two estimates are surprisingly close (differing by a couple of tenths of a degree Celsius), with the average temperature of the world (for 1981-2010) being very close to 14°C (Jones and Harpham, 2013). We have assessed ERA-Interim against station temperatures from manned and automatic weather station measurements across the Antarctic (Jones and Lister, 2014). Agreement is generally excellent across the Antarctic Peninsula and the sparsely sampled western parts of Antarctica. Differences tend to occur over eastern Antarctica where ERA-Interim is biased warm (up to 6°C) in the interior of the continent and biased cool (up to 6°C) for some of the coastal locations. Opportunities presented themselves during 2012 for collaborative work with a couple of Chinese groups. Three papers develop new temperature series for China as a whole and also for the eastern third of China (Wang et al., 2014, Cao et al., 2013 and Zhao et al., 2014). A dataset of ~400 daily Chinese temperature stations has been added to the CRU datasets. The latter paper finds that urban effects are generally about 10% of the long-term warming trend across eastern China. A fourth paper (Wang et al., 2013) illustrates issues with comparisons between reanalyses and surface temperatures across China, a method that has been widely used by some to suggest urban heating effects are much larger in the region. ERA-Interim can be used but NCEP/NCAR comparisons are very dependent on the period analysed. Earlier a new temperature dataset of homogenized records was developed for China (Li et al., 2009). Urbanization has also been addressed for London (Jones and Lister, 2009) where two rural sites have not warmed more than a city centre site since 1900. Additionally, in Ethymiadis and Jones (2010) we show that land air temperatures agree with marine data around coastal areas, further illustrating that urbanization is not a major component of large-scale surface air temperature change. Early instrumental data (before the development of modern thermometer screens) have always been suspected of being biased warm in summer, due to possible direct exposure to the sun. Two studies (Böhm et al., 2010 and Brunet et al., 2010) show this for the Greater Alpine Region (GAR) and for mainland Spain respectively. The issue is important before about 1870 in the GAR and before about 1900 in Spain. After correction for the problems, summer temperature estimates before these dates are cooler by about 0.4°C. In Jones and Wigley (2010), we discussed the importance of the biases in global temperature estimation. Exposure and to a lesser extent urbanization are the most important biases for the land areas, but both are dwarfed by the necessary adjustments for bucket SST measurements before about 1950. Individual station homogeneity is only important at the local scale. This was additionally illustrated by Hawkins and Jones (2013) where we replicated the temperature record developed by Guy Stewart Callendar in papers in 1938 and 1961. Analyses of Daily Climate Data Work here indicates that ERA-Interim (at least in Europe, Cornes and Jones, 2013, discussed in more detail in this proposal) can be used to monitor extremes (using the ETCCDI software – see Zhang et al., 2011). Additionally, also as a result of Chinese collaboration, a new method of daily temperature homogenization has been developed (Li et al., 2014). In Cornes and Jones (2011) we assessed storm activity in the northeast Atlantic region using daily gridded data. Even though the grid resolution is coarse (5° by 5° lat/long) the changes in storm activity are similar to those developed from the pressure triangle approach with station data. Analyses of humidity and pressure data In Simmons et al. (2010) we showed a reduction in relative humidity over low-latitude and mid-latitude land areas for the 10 years to 2008, based on monthly anomalies of surface air temperature and humidity from ECMWF reanalyses (ERA-40 and ERA-Interim) and our earlier land-only dataset (CRUTEM3) and synoptic humidity observations (HadCRUH). Updates of this station-based humidity dataset (now called HadISDH) extend the record, showing continued reductions (Willett et al., 2013). Analyses of Proxy Temperature Data In Vinther et al. (2010), relationships between the seasonal stable isotope data from Greenland Ice Cores and Greenland and Icelandic instrumental temperatures were investigated for the past 150-200 years. The winter season stable isotope data are found to be influenced by the North Atlantic Oscillation (NAO) and very closely related to SW Greenland temperatures. The summer season stable isotope data display higher correlations with Icelandic summer temperatures and North Atlantic SST conditions than with local SW Greenland temperatures. In Jones et al. (2014) we use these winter isotope reconstructions to show the expected inverse correlation (due to the NAO) with winter-season documentary reconstructions from the Netherlands and Sweden over the last 800 years. Finally, in this section Jones et al. (2013) shows the agreement between tree-ring width measurements from Northern Sweden and Finland and an assessment of the link to explosive volcanic eruptions. An instrumental record for the region in the early 19th century indicates that the summer of 1816 was only slightly below normal, explaining why this year has normal growth for both ring width and density. GCM/RCM/Reanalysis Evaluation In this section we have intercompared daily temperature extremes across Europe in Cornes and Jones (2013) using station data, E-OBS and ERA-Interim. We have additionally considered the impact of the urban issue on the global scale using the results of the Compo et al. (2011) Reanalyses, 20CR. These only make use of SST and station pressure data. Across the world’s land areas, they indicate similar warming since 1900 to that which has occurred (Compo et al., 2013), again illustrating that urbanization is not the cause of the long-term warming. Changes in HadCRUH global land surface specific humidity and CRUTEM3 surface temperatures from 1973 to 1999 were compared to the CMIP3 archive of climate model simulations with 20th Century forcings (Willett et al., 2010). The models reproduce the magnitude of observed interannual variance over all large regions. Observed and modelled trends and temperature-humidity relationships are comparable with the exception of the extra-tropical Southern Hemisphere where observations exhibit no trend but models exhibit moistening.

54 ENVIRONMENTAL SCIENCES↗
NASA NTRS2016

Risk of Performance Decrements and Adverse Health Outcomes Resulting from Sleep Loss, Circadian Desynchronization, and Work Overload

Sleep loss, circadian desynchronization, and work overload occur to some extent for ground and flight crews, prior to and during spaceflight missions. Ground evidence indicates that such risk factors may lead to performance decrements and adverse health outcomes, which could potentially compromise mission objectives. Efforts are needed to identify the environmental and mission conditions that interfere with sleep and circadian alignment, as well as individual differences in vulnerability and resiliency to sleep loss and circadian desynchronization. Specifically, this report highlights a collection of new evidence to better characterize the risk and reveals new gaps in this risk as follows: Sleep loss is apparent during spaceflight. Astronauts consistently average less sleep during spaceflight relative to on the ground. The causes of this sleep loss remain unknown, however ground-based evidence suggests that the sleep duration of astronauts is likely to lead to performance impairment and short and long-term health consequences. Further research is needed in this area in order to develop screening tools to assess individual astronaut sleep need in order to quantify the magnitude of sleep loss during spaceflight; current and planned efforts in BHP's research portfolio address this need. In addition, it is still unclear whether the conditions of spaceflight environment lead to sleep loss or whether other factors, such as work overload lead to the reduced sleep duration. Future data mining efforts and continued data collection on the ISS will help to further characterize factors contributing to sleep loss. Sleep inertia has not been evaluated during spaceflight. Ground-based studies confirm that it takes two to four hours to achieve optimal performance after waking from a sleep episode. Sleep inertia has been associated with increased accidents and reduced performance in operational environments. Sleep inertia poses considerable risk during spaceflight when emergency situations necessitate that crewmembers wake from sleep and make quick decisions. A recently completed BHP investigation assesses the effects of sleep inertia upon abrupt awakening, with and without hypnotics currently used in spaceflight; results from this investigation will help to inform strategies relative to sleep inertia effects on performance. Circadian desynchrony has been observed during spaceflight. Circadian desynchrony during spaceflight develops due to schedule constraints requiring non-24 operations or 'slam-shifts' and due to insufficient or mis-timed light exposure. In addition, circadian misalignment has been associated with reduced sleep duration and increased medication use. In ground-based studies, circadian desynchrony has been associated with significant performance impairment and increased risk of accidents when operations coincide with the circadian nadir. There is a great deal of information available on how to manage circadian misalignment, however, there are currently no easily collected biomarkers that can be used during spaceflight to determine circadian phase. Current research efforts are addressing this gap. Work overload has been documented during current spaceflight operations. NASA has established work hour guidelines that limit shift duration, however, schedule creep, where duty requirements necessitate working beyond scheduled work hours, has been reported. This observation warrants the documentation of actual work hours in order to improve planning and in order to ensure that astronauts receive adequate down time. In addition to concerns about work overload, ground based evidence suggests that work underload may be a concern during deep space missions, where torpor may develop and physically demanding workload will be exchanged for monitoring of autonomous systems. Given that increased automation is anticipated for exploration vehicles, fatigue effects in the context of such systems needs to be further understood. Performance metrics are needed to evaluate fitness-for-duty during spaceflight. Although ground-based evidence supports the notion that sleep loss, circadian desynchronization and work overload lead to performance impairment, inconsistency in the measures used to evaluate performance during spaceflight make it difficult to evaluate the magnitude of performance impairment during spaceflight. Work is underway to standardize measures of performance evaluation during spaceflight. Once established, such performance indicators need to be correlated with operational performance. Individual differences in sleep need and circadian preference, phase shifting ability and period have been documented in ground-based studies. Individual differences in response to sleep loss and circadian misalignment have also been documented and are presumed to be associated with genetic polymorphisms. No studies have systematically reported individual differences in sleep or circadian-related outcomes during spaceflight. More work is needed in this area in order to identify genetic or phenotypic biomarkers that predict resilience or vulnerability to sleep loss in order to personalize countermeasure strategies and mitigate performance impairment during spaceflight. Two laboratory and field investigations specific to this topic are currently ongoing; additional efforts, including an effort to mine existing biological data from spaceflight relative to sleep and circadian outcomes, are planned. Sex differences in sleep need and circadian period and phase have been reported in ground-based studies. The impact of these sex differences on performance is unclear. Sex differences in sleep need and circadian rhythms have not been systematically studied during spaceflight, presumably due to the small number of women that have flown in space. More research is needed in this area to evaluate whether any of the observed sex differences in physiology lead to altered performance in spaceflight and on the ground.

Flynn-Evans, Erin↗