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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 127 records · Page 7

All sources NASA NTRS DOE OSTI

DOE OSTI2014

High-throughput identification and dendritic cell-based functional validation of MHC class I-restricted Mycobacterium tuberculosis epitopes

Emergence of drug-resistant strains of the pathogen Mycobacterium tuberculosis (Mtb) and the ineffectiveness of BCG in curtailing Mtb infection makes vaccine development for tuberculosis an important objective. Identifying immunogenic CD81 T cell peptide epitopes is necessary for peptide-based vaccine strategies. We present a three-tiered strategy for identifying and validating immunogenic peptides: first, identify peptides that form stable complexes with class I MHC molecules; second, determine whether cytotoxic T lymphocytes (CTLs) raised against the whole protein antigen recognize and lyse target cells pulsed with peptides that passed step 1; third, determine whether peptides that passed step 2, when administered in vivo as a vaccine in HLA-A2 transgenic mice, elicit CTLs that lyse target cells expressing the whole protein antigen. Our innovative approach uses dendritic cells transfected with Mtb antigen-encoding mRNA to drive antigen expression. Using this strategy, we have identified five novel peptide epitopes from the Mtb proteins Apa, Mtb8.4 and Mtb19.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing

Peptide loading of major histocompatibility complex class I (MHC-I) molecules is central to antigen presentation, self-tolerance, and CD8 + T-cell activation. TAP binding protein, related (TAPBPR), a widely expressed tapasin homolog, is not part of the classical MHC-I peptide-loading complex (PLC). Using recombinant MHC-I molecules, we show that TAPBPR binds HLA-A*02:01 and several other MHC-I molecules that are either peptide-free or loaded with low-affinity peptides. Fluorescence polarization experiments establish that TAPBPR augments peptide binding by MHC-I. The TAPBPR/MHC-I interaction is reversed by specific peptides, related to their affinity. Mutational and small-angle X-ray scattering (SAXS) studies confirm the structural similarities of TAPBPR with tapasin. These results support a role of TAPBPR in stabilizing peptide-receptive conformation(s) of MHC-I, permitting peptide editing.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes

A polymorphism at β57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9–23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IA g7 and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the β57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Design of the HELICS High-Performance Transmission-Distribution-Communication-Market Co-Simulation Framework

This paper describes the design rationale for a new cyber-physical-energy co-simulation framework for electric power systems. This new framework will support very large-scale (100,000+ federates) co-simulations with off-the-shelf power-systems, communication, and end-use models. Other key features include cross-platform operating system support, integration of both event-driven (e.g. packetized communication) and time-series (e.g. power flow) simulation, and the ability to co-iterate among federates to ensure model convergence at each time step. After describing requirements, we begin by evaluating existing co-simulation frameworks, including HLA and FMI, and conclude that none provide the required features. Then we describe the design for the new layered co-simulation architecture.

24 POWER TRANSMISSION AND DISTRIBUTION↗

DOE OSTI2020

Prediction of the development of islet autoantibodies through integration of environmental, genetic, and metabolic markers

The Environmental Determinants of the Diabetes in the Young (TEDDY) study has prospectively followed, from birth, children at increased genetic risk of type 1 diabetes. We evaluated the potential of machine learning to identify new biomarkers that predict imminent (within 6 months) development of persistent islet autoantibodies to insulin, GAD or IA-2 in TEDDY participants through integration of time-invariant risk factors with time-varying metabolomics. The predictive modeling was initiated with over 220 potential biomarkers; through ensemble-based feature evaluation, the optimal model included 42 biomarkers, returning a cross-validated receiver operating characteristic area under the curve of 0.74. The model identified a principal set of 20 time-invariant markers, including 16 single nucleotide polymorphisms and two HLA-DR genotypes, gestational age, and exposure to a prebiotic formula. Integration of the metabolome identified 22 high-priority metabolites and lipids, including adipic acid and ceramide d42:0, that predicted development of islet autoantibodies, dependent upon the time horizon. The majority (86%) of metabolites that predicted development of islet autoantibodies belonged to 3 pathways: lipid oxidation, phospholipase A2 signaling, and pentose phosphate pathway. TEDDY data suggest that these metabolic processes may play a role in triggering islet autoimmunity.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires

Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse “de novo” clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1 109 and BMLF1 280 , show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRα CDR3 motifs played a dominant role, while TCRβ played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCRβ CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRα CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Recombination-mediated escape from primary CD8+ T cells in acute HIV-1 infection

A major immune evasion mechanism of HIV-1 is the accumulation of non-synonymous mutations in and around T cell epitopes, resulting in loss of T cell recognition and virus escape. Here we analyze primary CD8+ T cell responses and virus escape in a HLA B*81 expressing subject who was infected with two T/F viruses from a single donor. In addition to classic escape through non-synonymous mutation/s, we also observed rapid selection of multiple recombinant viruses that conferred escape from T cells specific for two epitopes in Nef. Our study shows that recombination between multiple T/F viruses provide greater options for acute escape from CD8+ T cell responses than seen in cases of single T/F virus infection. This process may contribute to the rapid disease progression in patients infected by multiple T/F viruses.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation

Background: Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses. Results: The T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations. Conclusions: Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Learning epistatic polygenic phenotypes with Boolean interactions

Detecting epistatic drivers of human phenotypes is a considerable challenge. Traditional approaches use regression to sequentially test multiplicative interaction terms involving pairs of genetic variants. For higher-order interactions and genome-wide large-scale data, this strategy is computationally intractable. Moreover, multiplicative terms used in regression modeling may not capture the form of biological interactions. Building on the Predictability, Computability, Stability (PCS) framework, we introduce the epiTree pipeline to extract higher-order interactions from genomic data using tree-based models. The epiTree pipeline first selects a set of variants derived from tissue-specific estimates of gene expression. Next, it uses iterative random forests (iRF) to search training data for candidate Boolean interactions (pairwise and higher-order). We derive significance tests for interactions, based on a stabilized likelihood ratio test, by simulating Boolean tree-structured null (no epistasis) and alternative (epistasis) distributions on hold-out test data. Finally, our pipeline computes PCS epistasis p-values that probabilisticly quantify improvement in prediction accuracy via bootstrap sampling on the test set. We validate the epiTree pipeline in two case studies using data from the UK Biobank: predicting red hair and multiple sclerosis (MS). In the case of predicting red hair, epiTree recovers known epistatic interactions surrounding MC1R and novel interactions, representing non-linearities not captured by logistic regression models. In the case of predicting MS, a more complex phenotype than red hair, epiTree rankings prioritize novel interactions surrounding HLA-DRB1 , a variant previously associated with MS in several populations. Taken together, these results highlight the potential for epiTree rankings to help reduce the design space for follow up experiments.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Human APOBEC3 Induced Mutation of Human Immunodeficiency Virus Type-1 Contributes to Adaptation and Evolution in Natural Infection

Human APOBEC3 proteins are cytidine deaminases that contribute broadly to innate immunity through the control of exogenous retrovirus replication and endogenous retroelement retrotransposition. As an intrinsic antiretroviral defense mechanism, APOBEC3 proteins induce extensive guanosine-to-adenosine (G-to-A) mutagenesis and inhibit synthesis of nascent human immunodeficiency virus-type 1 (HIV-1) cDNA. Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations. Using single-cycle HIV-1 infections in culture and highly parallel DNA sequencing, we defined trinucleotide contexts of the edited sites for APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H. We then compared these APOBEC3 editing contexts with the patterns of G-to-A mutations in HIV-1 DNA in cells obtained sequentially from ten patients with primary HIV-1 infection. Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases. Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA)- appropriate epitopes that are known or predicted to enable peptide binding. Thus, APOBEC3 activity may induce mutations that influence the genetic diversity and adaptation of the HIV-1 population in natural infection.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2015

Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients

Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro , while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2015

HIV Molecular Immunology 2014

HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2014 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and binding sites within each protein, moving from left to right through the coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as crossreactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins are provided.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

HIV Molecular Immunology 2015

The scope and purpose of the HIV molecular immunology database: HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2015 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/ content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and binding sites within each protein, moving from left to right through the coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as cross-reactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins are provided. Alignments of CTL, helper T-cell, and antibody epitopes are available through the search interface on our web site at http:// www.hiv.lanl.gov/content/immunology.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Synthesis of SHAL and SHAL Precursor Standard, CRADA No. TC02174.0

The purpose of this CRADA was to establish a collaborative effort between SHAL Technologies and Lawrence Livermore National Laboratory that would advance the development and testing of a family of small molecule oncology drugs and companion diagnostics called selective high affinity ligands (SHALs) for the treatment of advanced non-Hodgkin’s lymphoma. These compounds were first synthesized by the LLNL chemist participating in this CRADA when the compounds were first developed (2004-2008) by the founders of SHAL Technologies (while they were employed at LLNL). This CRADA initially had five deliverables. Deliverables 1-3 involved LLNL’s synthesis of 10-50 mg of the SHALs SH7133 and SH7139 using the same bench-scale conditions used previously, their purification, and obtaining data needed to demonstrate the mass and purity of the compounds. Deliverable 4, which was to be completed by SHAL Technologies, was the comparison of the bench-scale synthetic products to the same compounds manufactured on the multigram to kilogram scale by the contract research organization (CRO) AmbioPharm Inc. The fifth deliverable was this final report. An amendment was made to add the additional tasks and deliverables needed to synthesize the third SHAL standard SH7129 (the diagnostic) and compare it to product manufactured by AmbioPharm. During the testing of the three standards synthesized by LLNL, the SHAL compounds were found to lack biological activity. When we discovered that a commercial chemical supplier provided both LLNL and our CRO AmbioPharm with a SHAL precursor that had the wrong structure, two amendments to the CRADA were made to add additional tasks and deliverables to enable us to repeat all the syntheses and conduct more extensive testing of the bench scale and manufactured products. Once the final correct products were synthesized and confirmed to have the right structures, a third amendment was added to the CRADA to enable the synthesis of two fragments of the SHALs to determine if these compounds are produced when the SHALs are metabolized. This last synthesis was included to provide the information needed to establish a second, new CRADA between SHAL Technologies and LLNL that would focus on the identifying how the SHALs are metabolized and how their metabolic products may be responsible for the selective killing of tumor cells over-expressing the protein targeted by the SHALs, HLA-DR10.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

ParameterizationBR2

In the following we detail the ramp parameterization procedure. The purpose of this procedure is in reduction of the data volume loaded into PSC. The same approach will be implemented in HLA “Booster Ramp Generator”.

42 ENGINEERING↗

DOE OSTI2018

Accelerator Physics at NSLS-II: Research Accomplishments in 2018

Scientific support for user operations is the main mission of the NSLS-II Accelerator Physics group. At the same time, NSLS-II accelerator physicists were working in 2018 on the following research and development projects: development of HLA common tools for beam studies and operations; online optimization of Injector and Storage Ring (Facility Improvement Project); development of a new operation mode for timeresolved experiments; high-brightness upgrade options for NSLS-II; ultra-fast electron diffraction (LDRD); APS upgrade project and the electron-ion collider project at BNL (MOUs). A summary of the research accomplishments of the NSLS-II Accelerator Physics group is presented in this report.

36 MATERIALS SCIENCE↗

DOE OSTI2023

DAISY Complement Protein ML-Ready Data

A total of 172 children from the DAISY study with multiple plasma samples collected over time, with up to 23 years of follow-up, were characterized via proteomics analysis. Of the children there were 40 controls and 132 cases. All 132 cases had measurements across time relative to IA. Sampling was not consistent for all children. There were 47 of the children who had samples taken and evaluated prior to IA (Pre-IA), and 131 children had measurements at or after IA, but prior to diagnosis of clinical T1D (Post-IA). The control children were frequency matched on HLA genotypes and age and sex with an observed lower frequency of first degree relatives within the control group versus the cases For machine learning the children that will develop islet autoantibodies the 40 control and 47 Pre-IA children were down-selected to a single sample time point. For the 40 control children this was the earliest sample collected and for the 47 Pre-IA children it was a random selection of the first or second time point prior to the detection of autoantibodies to assure the age distributions were not significantly different.

machine learning, proteomics, Type 1 Diabetes, com↗

DOE OSTI2023

DAISY Complement Protein ML-Ready Data

Webb-Robertson, Bobbie-Jo M↗