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At least 73 records · Page 4

All sources NASA NTRS DOE OSTI

DOE OSTI2022

Crystal structure of ultra-humanized anti-pTau Fab reveals how germline substitutions humanize CDRs without loss of binding’

Administration of therapeutic antibodies can elicit adverse immune responses in patients through the generation of anti-drug antibodies that, in turn, reduce the efficacy of the therapeutic. Removal of foreign amino acid content by humanization can lower the immunogenic risk of the therapeutic mAb. We previously developed the ultra-humanization technology “Augmented Binary Substitution” (ABS) which enables single-step CDR germlining of antibodies. The application of ABS to a chicken anti-pTau antibody generated an ultra-humanized variant, anti-pTau C21-ABS, with increased human amino acid content in the CDRs and reduced in-silico predicted immunogenicity risk. Here, we report the high-resolution crystal structure of anti-pTau C21-ABS Fab in complex with the pTau peptide (7KQK). This study examines how ultra-humanization, via CDR germlining, is facilitated while maintaining near-identical antigen affinity (within 1.6-fold). The co-complex structure reveals that the ABS molecule targets the same antigenic epitope, accommodated by structurally-similar changes in the paratope. These findings confirm that ABS enables the germlining of amino acids within CDRs by exploiting CDR plasticity, to reduce non-human amino acid CDR content, with few alterations to the overall mechanism of binding.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1989

Expert systems should be more accurate than human experts - Evaluation procedures from human judgment and decisionmaking

Two procedures for the evaluation of the performance of expert systems are illustrated: one procedure evaluates predictive accuracy; the other procedure is complementary in that it uncovers the factors that contribute to predictive accuracy. Using these procedures, it is argued that expert systems should be more accurate than human experts in two senses. One sense is that expert systems must be more accurate to be cost-effective. Previous research is reviewed and original results are presented which show that simple statistical models typically perform better than human experts for the task of combining evidence from a given set of information sources. The results also suggest the second sense in which expert systems should be more accurate than human experts. They reveal that expert systems should share factors that contribute to human accuracy, but not factors that detract from human accuracy. Thus the thesis is that one should both require and expect systems to be more accurate than humans.

Levi, Keith↗

NASA NTRS1991

Issues on combining human and non-human intelligence

The purpose here is to call attention to some of the issues confronting the designer of a system that combines human and non-human intelligence. We do not know how to design a non-human intelligence in such a way that it will fit naturally into a human organization. The author's concern is that, without adequate understanding and consideration of the behavioral and psychological limitations and requirements of the human member(s) of the system, the introduction of artificial intelligence (AI) subsystems can exacerbate operational problems. We have seen that, when these technologies are not properly applied, an overall degradation of performance at the system level can occur. Only by understanding how human and automated systems work together can we be sure that the problems introduced by automation are not more serious than the problems solved.

Statler, Irving C.↗

NASA NTRS2008

Human Factors in Human-Systems Integration

Any large organization whose mission is to design and develop systems for humans, and train humans needs a well-developed integration and process plan to deal with the challenges that arise from managing multiple subsystems. Human capabilities, skills, and needs must be considered early in the design and development process, and must be continuously considered throughout the development lifecycle. This integration of human needs within system design is typically formalized through a Human-Systems Integration (HSI) program. By having an HSI program, an institution or organization can reduce lifecycle costs and increase the efficiency, usability, and quality of its products because human needs have been considered from the beginning.

Fitts, David J.↗

DOE OSTI2024

Theoretical modeling of hepatitis C acute infection in liver-humanized mice support pre-clinical assessment of candidate viruses for controlled-human-infection studies

Designing and carrying out a controlled human infection (CHI) model for hepatitis C virus (HCV) is critical for vaccine development. However, key considerations for a CHI model protocol include understanding of the earliest viral-host kinetic events during the acute phase and susceptibility of the viral isolate under consideration for use in the CHI model to antiviral treatment before any infections in human volunteers can take place. Humanized mouse models lack adaptive immune responses but provide a unique opportunity to obtain quantitative understanding of early HCV kinetics and develop mathematical models to further understand viral and innate immune response dynamics during acute HCV infection. We show that the models reproduce the measured HCV kinetics in humanized mice, which are consistent with early acute HCV-host dynamics in immunocompetent chimpanzees. Our findings suggest that humanized mice are well-suited to support development of a CHI model. In-silico and in-vivo modeling estimates provide a starting point to characterize candidate viruses for testing in CHI model studies.

Agent-based modeling↗

NASA NTRS2020

Deep Space Human-Systems Research Recommendations for Future Human-Automation/Robotic Integration

Appropriate integration between automation and robotics systems and their human operators is essential for future space exploration. The Human Factors and Behavioral Performance Element of NASA’s Human Research Program requires a systematic understanding of the critical human-automation/robotic (HAR) integration, or HARI, design challenges for future space exploration. This document reports the results of a systematic assessment of the spaceflight-relevant HARI technologies and research topics addressing critical gaps in spaceflight-relevant HARI knowledge, and prioritizes research required for successful human performance and HAR integration. We reviewed relevant literature across the past ten years and interviewed ten subject matter experts to investigate the current state of HARI technology, challenges facing development, the state of HARI research across a wide range of fields, and opportunities for advancing the state of the art through directed research. This information was used to identify relevant HARI technologies and research topics, as well as factors to assess relative priority of HARI technologies. We worked with NASA stakeholders to weight the factors relevant to assessing HARI specific technologies. A multi-dimensional trade analysis was performed to objectively score HARI research topics and specific technologies to recommended investment priorities for NASA.

human-automation interaction↗

NASA NTRSDate not supplied

Where is the Human in the Loop? Human Factors Analysis of Extended Visual Line of Sight Unmanned Aerial System Operations within a Remote Operations Environment

Many envisioned technological and conceptual innovations focus on allocating more functions to automation, relegating the human as an afterthought if not a nuisance. Yet, until complete autonomy is realized, the human will remain “in the loop”. The National Aeronautics and Space Administration is supporting research for the development and maturation of automated technologies and architectures for the future of advanced air mobility. Standing up a remote operations center used to control, manage, and monitor multiple highly automated vehicles is an important step towards realizing the advanced air mobility vision. At the National Aeronautics and Space Administration’s Langley Research Center, a remote operation center exists and has been tested using humans piloting simulated vehicles. In this paper, we explore the human element within live flight operations that rely on increasingly automated technologies. Four ground control station operators performed multiple live flight operations. We employed a naturalistic approach and relied on qualitative data such as interviews and discussions with subject matter experts to help facilitate discovery. The present work evaluates the functions that the human and the automation had during the live operations, lists psychological constructs that may have promoted or reduced task performance, and provides recommendations on design of the remote operations environment and training of future ground control station operators.

Advanced Air Mobility↗

NASA NTRSDate not supplied

Where is the Human in the Loop? Human Factors Analysis of Extended Visual Line of Sight Unmanned Aerial System Operations within a Remote Operations Environment

Advanced Air Mobility↗

NASA NTRS1997

Csa-19, a radiation-responsive human gene, identified by an unbiased two-gel cDNA library screening method in human cancer cells

A novel polymerase chain reaction (PCR)-based method was used to identify candidate genes whose expression is altered in cancer cells by ionizing radiation. Transcriptional induction of randomly selected genes in control versus irradiated human HL60 cells was compared. Among several complementary DNA (cDNA) clones recovered by this approach, one cDNA clone (CL68-5) was downregulated in X-irradiated HL60 cells but unaffected by 12-O-tetradecanoyl phorbol-13-acetate, forskolin, or cyclosporin-A. DNA sequencing of the CL68-5 cDNA revealed 100% nucleotide sequence homology to the reported human Csa-19 gene. Northern blot analysis of RNA from control and irradiated cells revealed the expression of a single 0.7-kilobase (kb) messenger RNA (mRNA) transcript. This 0.7-kb Csa-19 mRNA transcript was also expressed in a variety of human adult and corresponding fetal normal tissues. Moreover, when the effect of X- or fission neutron-irradiation on Csa-19 mRNA was compared in cultured human cells differing in p53 gene status (p53-/- versus p53+/+), downregulation of Csa-19 by X-rays or fission neutrons was similar in p53-wild type and p53-null cell lines. Our results provide the first known example of a radiation-responsive gene in human cancer cells whose expression is not associated with p53, adenylate cyclase or protein kinase C.

NASA Discipline Radiation Health↗

NASA NTRS1984

The human role in space. Volume 3: Generalizations on human roles in space

The human role in space was studied. The role and the degree of direct involvement of humans that will be required in future space missions, was investigated. Valid criteria for allocating functional activities between humans and machines were established. The technology requirements, ecnomics, and benefits of the human presence in space were examined. Factors which affect crew productivity include: internal architecture; crew support; crew activities; LVA systems; IVA/EVA interfaces; and remote systems management. The accomplished work is reported and the data and analyses from which the study results are derived are included. The results provide information and guidelines to enable NASA program managers and decision makers to establish, early in the design process, the most cost effective design approach for future space programs, through the optimal application of unique human skills and capabilities in space.

Source record↗

NASA NTRS2009

Human Research Program Space Human Factors Engineering (SHFE) Standing Review Panel (SRP)

The Space Human Factors Engineering (SHFE) Standing Review Panel (SRP) evaluated 22 gaps and 39 tasks in the three risk areas assigned to the SHFE Project. The area where tasks were best designed to close the gaps and the fewest gaps were left out was the Risk of Reduced Safety and Efficiency dire to Inadequate Design of Vehicle, Environment, Tools or Equipment. The areas where there were more issues with gaps and tasks, including poor or inadequate fit of tasks to gaps and missing gaps, were Risk of Errors due to Poor Task Design and Risk of Error due to Inadequate Information. One risk, the Risk of Errors due to Inappropriate Levels of Trust in Automation, should be added. If astronauts trust automation too much in areas where it should not be trusted, but rather tempered with human judgment and decision making, they will incur errors. Conversely, if they do not trust automation when it should be trusted, as in cases where it can sense aspects of the environment such as radiation levels or distances in space, they will also incur errors. This will be a larger risk when astronauts are less able to rely on human mission control experts and are out of touch, far away, and on their own. The SRP also identified 11 new gaps and five new tasks. Although the SRP had an extremely large quantity of reading material prior to and during the meeting, we still did not feel we had an overview of the activities and tasks the astronauts would be performing in exploration missions. Without a detailed task analysis and taxonomy of activities the humans would be engaged in, we felt it was impossible to know whether the gaps and tasks were really sufficient to insure human safety, performance, and comfort in the exploration missions. The SRP had difficulty evaluating many of the gaps and tasks that were not as quantitative as those related to concrete physical danger such as excessive noise and vibration. Often the research tasks for cognitive risks that accompany poor task or information design addressed only part, but not all, of the gaps they were programmed to fill. In fact the tasks outlined will not close the gap but only scratch the surface in many cases. In other cases, the gap was written too broadly, and really should be restated in a more constrained way that can be addressed by a well-organized and complementary set of tasks. In many cases, the research results should be turned into guidelines for design. However, it was not clear whether the researchers or another group would construct and deliver these guidelines.

Wichansky, Anna↗

NASA NTRS2011

Human Modeling For Ground Processing Human Factors Engineering Analysis

There have been many advancements and accomplishments over that last few years using human modeling for human factors engineering analysis for design of spacecraft and launch vehicles. The key methods used for this are motion capture and computer generated human models. The focus of this paper is to explain the different types of human modeling used currently and in the past at Kennedy Space Center (KSC) currently, and to explain the future plans for human modeling for future spacecraft designs.

Tran, Donald↗

NASA NTRS2011

The Exploration of Mars by Humans: Why Mars? Why Humans?

As we commemorate the 50th anniversary of Yuri Gagarin's historic flight in 1961, the first flight of a human in space, plans are underway for another historic human mission. Plans are being developed for a human mission to Mars. Once we reach Mars, the human species will become the first two-planet species. Both the Bush Administration (in 2004) and the Obama Administration (in 2010) proposed a human mission to Mars as a national goal of the United States.

Levine, Joel S.↗

NASA NTRS2011

Human Modeling for Ground Processing Human Factors Engineering Analysis

There have been many advancements and accomplishments over the last few years using human modeling for human factors engineering analysis for design of spacecraft. The key methods used for this are motion capture and computer generated human models. The focus of this paper is to explain the human modeling currently used at Kennedy Space Center (KSC), and to explain the future plans for human modeling for future spacecraft designs

Stambolian, Damon B.↗

NASA NTRS2018

Maintaining Human Health for Humans-Mars

The Human Health Research Program states that Radiation is the most challenging hazard to human spaceflight beyond LEO. The International Space Station provides an analog for evaluating techniques for dealing with Altered Gravity, the Radiation Environment of the ISS is only about 45% of the deep space values where radiation due to Galactic Cosmic Rays (GCR) dominate the spectrum. The Moon and cis-lunar space are being considered as a Mars Analog training ground for preparing crews for human mission to Mars. Spending more than 200 days in deep space is considered unsafe based on our current proxy for lifetime radiation dose. The paper outlines a way forward for spending days training near the Moon and for completing roundtrip missions to Mars while remaining below the current proxy. In the first case, a GCR overcoat shields crews from radiation during cis-lunar activities before making fast transits without in-space GCR overcoats to and from Mars. This case requires continued maturation of low TRL propulsion and power technologies currently around 4 to 5 while depending on repeatable reductions in launch costs by a factor of 6 expected of current reusable rockets. The second case requires no new technology development except for the expectation that the next near-term generation of reusable rockets will reduce launch costs by a factor of around 14. Five trajectories and GCR overcoat sizes for all mission legs are presented herein to illustrate the opportunities to maintain human health for Humans-Mars missions.

Robert W Moses↗

NASA NTRS2004

Noninfectious X4 but not R5 human immunodeficiency virus type 1 virions inhibit humoral immune responses in human lymphoid tissue ex vivo

Ex vivo human immunodeficiency virus type 1 (HIV-1) infection of human lymphoid tissue recapitulates some aspects of in vivo HIV-1 infection, including a severe depletion of CD4(+) T cells and suppression of humoral immune responses to recall antigens or to polyclonal stimuli. These effects are induced by infection with X4 HIV-1 variants, whereas infection with R5 variants results in only mild depletion of CD4(+) T cells and no suppression of immune responses. To study the mechanisms of suppression of immune responses in this ex vivo system, we used aldrithiol-2 (AT-2)-inactivated virions that have functional envelope glycoproteins but are not infectious and do not deplete CD4(+) T cells in human lymphoid tissues ex vivo. Nevertheless, AT-2-inactivated X4 (but not R5) HIV-1 virions, even with only a brief exposure, inhibit antibody responses in human lymphoid tissue ex vivo, similarly to infectious virus. This phenomenon is mediated by soluble immunosuppressive factor(s) secreted by tissue exposed to virus.

2,2'-Dipyridyl/analogs & derivatives/pharmacology↗

NASA NTRS2016

Evaluation of Human and AutomationRobotics Integration Needs for Future Human Exploration Missions

NASA employs Design Reference Missions (DRMs) to define potential architectures for future human exploration missions to deep space, the Moon, and Mars. While DRMs to these destinations share some components, each mission has different needs. This paper focuses on the human and automation/robotic integration needs for these future missions, evaluating them with respect to NASA research gaps in the area of space human factors engineering. The outcomes of our assessment is a human and automation/robotic (HAR) task list for each of the four DRMs that we reviewed (i.e., Deep Space Sortie, Lunar Visit/Habitation, Deep Space Habitation, and Planetary), a list of common critical HAR factors that drive HAR design.

design reference missions↗

DOE OSTI2020

Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase

Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime–based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are nonproductive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)–inhibited human AChE, here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-human AChE conjugates. Oxime group reorientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Finally, our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, “smart” accelerated antidotes against OP toxicity.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗