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All sources NASA NTRS DOE OSTI

DOE OSTI2020

Crystal Structure and Characterization of Human Heavy-Chain Only Antibodies Reveals a Novel, Stable Dimeric Structure Similar to Monoclonal Antibodies

We report the novel crystal structure and characterization of symmetrical, homodimeric humanized heavy-chain-only antibodies or dimers (HC2s). HC2s were found to be significantly coexpressed and secreted along with mAbs from transient CHO HC/LC cotransfection, resulting in an unacceptable mAb developability attribute. Expression of full-length HC2s in the absence of LC followed by purification resulted in HC2s with high purity and thermal stability similar to conventional mAbs. The V H and C H 1 portion of the heavy chain (or Fd) was also efficiently expressed and yielded a stable, covalent, and reducible dimer (Fd2). Mutagenesis of all heavy chain cysteines involved in disulfide bond formation revealed that Fd2 intermolecular disulfide formation was similar to Fabs and elucidated requirements for Fd2 folding and expression. For one HC2, we solved the crystal structure of the Fd2 domain to 2.9 Å, revealing a highly symmetrical homodimer that is structurally similar to Fabs and is mediated by conserved (C H 1) and variable (V H ) contacts with all CDRs positioned outward for target binding. Interfacial dimer contacts revealed by the crystal structure were mutated for two HC2s and were found to dramatically affect HC2 formation while maintaining mAb bioactivity, offering a potential means to modulate novel HC2 formation through engineering. These findings indicate that human heavy-chain dimers can be secreted efficiently in the absence of light chains, may show good physicochemical properties and stability, are structurally similar to Fabs, offer insights into their mechanism of formation, and may be amenable as a novel therapeutic modality.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2008

The Next Giant Leap: NASA's Ares Launch Vehicles Overview

The next chapter in NASA's history also promises to write the next chapter in America's history, as the Agency makes measurable strides toward developing new space transportation capabilities that wi!! put astronauts on course to explore the Moon as the next giant leap toward the first human footprint on Mars. This paper will present top-level plans and progress being made toward fielding the Ares I crew launch vehicle in the 2013 timeframe and the Ares V cargo launch vehicle in the 2018 timeframe. It also gives insight into the objectives for the first test flight, known as the Ares I-X, which is scheduled for April 2009. The U.S. strategy to scientifically explore space will fuel innovations such as solar power and water recycling, as well as yield new knowledge that directly benefits life on Earth. For the Ares launch vehicles, NASA is building on heritage hardware and unique capabilities; as well as almost 50 years of lessons learned from the Apollo Saturn, Space Shuttle, and commercial launch vehicle programs. In the Ares I Project's inaugural year, extensive trade studies and evaluations were conducted to improve upon the designs initially recommended by the Exploration Systems Architecture Study, resulting in significant reduction of near-term and long-range technical and programmatic risks; conceptual designs were analyzed for fitness against requirements; and the contractual framework was assembled to enable a development effort unparalleled in American space flight since the Space Shuttle. The Exploration Launch Projects team completed the Ares I System Requirements Review (SRR) at the end of 2006--the first such engineering milestone for a human-rated space transportation system in over 30 years.

Cook, Stephen A.↗

NASA NTRS2012

Structural Verification of the First Orbital Wonder of the World - The Structural Testing and Analysis of the International Space Station (ISS)

The International Space Station (ISS) can be considered one of the structural engineering wonders of the world. On par with the World Trade Center, the Colossus of Rhodes, the Statue of Liberty, the Great Pyramids, the Petronas towers and the Burj Khalifa skyscraper of Dubai, the ambition and scope of the ISS structural design, verification and assembly effort is a truly global success story. With its on-orbit life projected to be from its beginning in 1998 to the year 2020 (and perhaps beyond), all of those who participated in its development can consider themselves part of an historic engineering achievement representing all of humanity. The structural design and verification of the ISS could be the subject of many scholarly papers. Several papers have been written on the structural dynamic characterization of the ISS once it was assembled on-orbit [1], but the ground-based activities required to assure structural integrity and structural life of the individual elements from delivery to orbit through assembly and planned on-orbit operations have never been totally summarized. This paper is intended to give the reader an overview of some of the key decisions made during the structural verification planning for the elements of the U.S. On-Orbit Segment (USOS) as well as to summarize the many structural tests and structural analyses that were performed on its major elements. An effort is made for this paper to be summarily comprehensive, but as with all knowledge capture efforts of this kind, there are bound to be errors of omission. Should the reader discover any of these, please feel free to contact the principal author. The ISS (Figure 1) is composed of pre-integrated truss segments and pressurized elements supplied by NASA, the Russian Federal Space Agency (RSA), the European Space Agency (ESA) and the Japanese Aerospace Exploration Agency (JAXA). Each of these elements was delivered to orbit by a launch vehicle and connected to one another either robotically or autonomously. The primary structure of each element was assembled and verified by teams of responsible structural engineers within and among their respective agencies and agency contractors.

Zipay, John J.↗

NASA NTRS2004

Comparing NASA and ESA Cost Estimating Methods for Human Missions to Mars

To compare working methodologies between the cost engineering functions in NASA Marshall Space Flight Center (MSFC) and ESA European Space Research and Technology Centre (ESTEC), as well as to set-up cost engineering capabilities for future manned Mars projects and other studies which involve similar subsystem technologies in MSFC and ESTEC, a demonstration cost estimate exercise was organized. This exercise was a direct way of enhancing not only cooperation between agencies but also both agencies commitment to credible cost analyses. Cost engineers in MSFC and ESTEC independently prepared life-cycle cost estimates for a reference human Mars project and subsequently compared the results and estimate methods in detail. As a non-sensitive, public domain reference case for human Mars projects, the Mars Direct concept was chosen. In this paper the results of the exercise are shown; the differences and similarities in estimate methodologies, philosophies, and databases between MSFC and ESTEC, as well as the estimate results for the Mars Direct concept. The most significant differences are explained and possible estimate improvements identified. In addition, the Mars Direct plan and the extensive cost breakdown structure jointly set-up by MSFC and ESTEC for this concept are presented. It was found that NASA applied estimate models mainly based on historic Apollo and Space Shuttle cost data, taking into account the changes in technology since then. ESA used models mostly based on European satellite and launcher cost data, taking into account the higher equipment and testing standards for human space flight. Most of NASA's and ESA s estimates for the Mars Direct case are comparable, but there are some important, consistent differences in the estimates for: 1) Large Structures and Thermal Control subsystems; 2) System Level Management, Engineering, Product Assurance and Assembly, Integration and Test/Verification activities; 3) Mission Control; 4) Space Agency Program Level activities.

Hunt, Charles D.↗

NASA NTRS2016

Modifying a Commercial Centrifuge to Reduce Electromagnetic Interference and Evaluating Functionality of Ultrasound Equipment

The Project Management and Engineering Branch (SF4) supports the Human Health and Performance Directorate (HH&P) and is responsible for developing and supporting human systems hardware for the International Space Station (ISS). When a principal investigator's (PI) medical research project on the ISS is accepted, SF4 develops the necessary hardware and software to transport to the ISS. The two projects I primarily worked on were the centrifuge and ultrasound projects. Centrifuge: One concern with spacecraft such as the ISS is electromagnetic interference (EMI) from onboard equipment, typically from radio waves (frequencies of ~3 kHz to ~300 GHz), which can negatively affect nearby circuitry. Standard commercial centrifuges produce EMI above safety limits, so my task was to help reduce EMI production from this equipment. Two centrifuges were tested: one unmodified as a control and one modified. To reduce EMI below safety limits, one centrifuge was modified to become a Faraday shield, in which significant electrical contact was made between all regions of the centrifuge housing. This included removing non-conductive paint, applying conductive fabric to the lid and foam sealer, adding a 10,000 μF decoupling capacitor across the power supply, and adding copper adhesive-mount gaskets to the housing interior. EMI testing of both centrifuges was performed in the EMI/EMC Control Test and Measurement Facility. EMI for both centrifuges was below safety limits for frequencies between 10 MHz and 15 GHz (pass); however, between 14 kHz and 10 MHz, EMI for the unmodified centrifuge exceeded safety limits (fail) as expected. Alternatively, for the modified centrifuge with the Faraday shield, EMI was below the safely limit of 55 dBμV/m for electromagnetic frequencies between 14 kHz and 10 MHz. This result indicates our modifications were successful. The successful EMI test allowed us to communicate with the vendor what modifications they needed to make to their commercial unit to meet our specifications and to understand what needs to be done in lab to the new centrifuge. Our modifications will provide a standard for readying centrifuges for future missions. Once the new modified centrifuge arrives by the vendor, it will need to undergo EMI testing again for validation. The centrifuge is also in the process of compatibility testing with a custom stowage drawer, which is an ongoing project in SF4. Both of these items will be payloads on future missions to the ISS for various research purposes. Ultrasound: ISS currently has an onboard ultrasound (Ultrasound 2 system) for research and medical purposes. Every piece of medical flight hardware has an equivalent ground-unit so instrumentation can be routinely evaluated and transported to the ISS if necessary. The ground-unit ultrasound equipment must be evaluated every six months using a task performance sheet (TPS). A TPS is a document, written by the appropriate scientists and engineers, which describes how to run equipment and is written in such a way that astronauts with unspecialized training can follow the tasks. I was responsible for performing six TPSs on a combination of three ultrasounds and two video power converters (VPCs). Performing a TPS involves checking out and computationally documenting each piece of equipment removed from storage locations, setting up hardware and software, performing tasks to verify functionality, returning equipment, and logging items back into the computerized system. My work revealed all ground-unit ultrasounds were functioning properly. Because of proper function, a discrepancy report (DR) did not have to be opened. The TPS was then passed along to the Quality Engineering (QE) for review and ultimately given to Quality Assurance (QA). Other projects: In addition to my main projects, I participated in other tasks including troubleshooting an EEG headband, volunteering for an ultrasound training research study, and conformal coating printed circuit boards. My internship at SF4 has helped me understand how space systems hardware development for the ISS fits into NASA's mission and vision.

Greening, Gage J.↗

NASA NTRS2018

The Dust in the Atmosphere of Mars and Its Impact on the Human Exploration of Mars: A NESC Workshop

The NASA Engineering and Safety Center (NESC) Chief Scientist provided support to produce an NESC final report on the "Dust in the Atmosphere of Mars and Its Impact on Human Exploration" workshop held June 1315, 2017, in Houston, TX. This report follows the standard NESC report format to describe the findings, observations, and NESC recommendations developed by the workshop participants. The key stakeholders for the final report are the Mars mission designers and engineers for the precursor missions and the crewed mission, and the NESC. Further stakeholders are the mission planners deciding on the payload selections for the Mars missions.

Winterhalter, Daniel↗

NASA NTRS2021

Resilience Engineering's Potential for Advanced Air Mobility (AAM)

The national airspace (NAS) will rapidly evolve in the next ten to twenty years. Plans for Advanced Air Mobility (AAM) during that period envision highly automated airspace management systems and electrically powered vehicles. AAM concepts also anticipate limited human roles. The goal of limiting the human role is to minimize the potential for misadventures, yet how the human role is limited needs to be carefully considered in order to also preserve the potential for human successes. The field of resilience engineering (RE) focuses on how systems can change in order to seize an opportunity or withstand an unforeseen challenge. RE methods rely on the use of empirical data to optimize the ability of any system to adapt. RE studies have shown how individual and team initiatives ensure resilient system performance by creating safety through flexibility. Benefits of the RE approach include improved awareness of operational circumstances and how system elements depend on each other, and the ability to allocate limited resources and prepare for surprise. RE offers the ability to account for and incorporate the human role as an essential element in order to ensure NAS systems’ resilient performance. Data on the human contribution to safe and resilient system performance, which is termed “work as done,” are available but are not being considered as the NAS evolves. We present an approach that describes how use of RE can enable the evolving NAS to adapt, and perform, in a resilient manner.

Aviation Safety↗

DOE OSTI2015

Uterine microvascular sensitivity to nanomaterial inhalation: An in vivo assessment

With the tremendous number and diverse applications of engineered nanomaterials incorporated in daily human activity, exposure can no longer be solely confined to occupational exposures of healthy male models. Cardiovascular and endothelial cell dysfunction have been established using in vitro and in situ preparations, but the translation to intact in vivo models is limited. Intravital microscopy has been used extensively to understand microvascular physiology while maintaining in vivo neurogenic, humoral, and myogenic control. However, a tissue specific model to assess the influences of nanomaterial exposure on female reproductive health has not been fully elucidated. Female Sprague Dawley (SD) rats were exposed to nano-TiO{sub 2} aerosols (171 ± 6 nm, 10.1 ± 0.39 mg/m{sup 3}, 5 h) 24-hours prior to experimentation, leading to a calculated deposition of 42.0 ± 1.65 μg. After verifying estrus status, vital signs were monitored and the right horn of the uterus was exteriorized, gently secured over an optical pedestal, and enclosed in a warmed tissue bath using intravital microscopy techniques. After equilibration, significantly higher leukocyte-endothelium interactions were recorded in the exposed group. Arteriolar responsiveness was assessed using ionophoretically applied agents: muscarinic agonist acetylcholine (0.025 M; ACh; 20, 40, 100, and 200 nA), and nitric oxide donor sodium nitroprusside (0.05 M; SNP; 20, 40, and 100 nA), or adrenergic agonist phenylephrine (0.05 M; PE; 20, 40, and 100 nA) using glass micropipettes. Passive diameter was established by tissue superfusion with 10{sup −4} M adenosine. Similar to male counterparts, female SD rats present systemic microvascular dysfunction; however the ramifications associated with female health and reproduction have yet to be elucidated. - Highlights: • Female reproductive health associated with nanomaterial exposure is understudied. • We examined uterine microvascular alterations 24-hours after nano-TiO{sub 2} inhalation. • There is an increase in uterine venular leukocyte activity post nano-TiO{sub 2} exposure. • Nano-TiO{sub 2} exposure perturbs uterine arteriolar endothelium-dependent dilation. • Intravital microscopy is a powerful tool for future toxicological assessments.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Template and target-site recognition by human LINE-1 in retrotransposition

The long interspersed element-1 (LINE-1, hereafter L1) retrotransposon has generated nearly one-third of the human genome and serves as an active source of genetic diversity and human disease. L1 spreads through a mechanism termed target-primed reverse transcription, in which the encoded enzyme (ORF2p) nicks the target DNA to prime reverse transcription of its own or non-self RNAs. Here we purified full-length L1 ORF2p and biochemically reconstituted robust target-primed reverse transcription with template RNA and target-site DNA. We report cryo-electron microscopy structures of the complete human L1 ORF2p bound to structured template RNAs and initiating cDNA synthesis. The template polyadenosine tract is recognized in a sequence-specific manner by five distinct domains. Among them, an RNA-binding domain bends the template backbone to allow engagement of an RNA hairpin stem with the L1 ORF2p C-terminal segment. Moreover, structure and biochemical reconstitutions demonstrate an unexpected target-site requirement: L1 ORF2p relies on upstream single-stranded DNA to position the adjacent duplex in the endonuclease active site for nicking of the longer DNA strand, with a single nick generating a staggered DNA break. Our research provides insights into the mechanism of ongoing transposition in the human genome and informs the engineering of retrotransposon proteins for gene therapy.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2019

Artificial Intelligence

Artificial intelligence is the study of intelligence agents as demonstrated by machines. It is an interdisciplinary field involving computer science as well as, various kinds of engineering and science, for example, robotics, bio-medical engineering, that accentuates automation of human acts and intelligence through machines. AI represents state-of-the-art use of machines to bring about algorithmic computation and understanding of tasks that include learning, problem solving, mapping, perception, and reasoning. Given the data and a description of its properties and relations between objects of interest, AI methods can perform the aforementioned tasks. Widely applied AI capabilities, e.g. learning, are now achievable at large scale through machine learning (ML), large volumes of data and specialized computational machines. ML encompasses learning without any kind of supervision (unsupervised learning) and learning with full supervision (supervised learning). Widely applied supervised learning techniques include deep learning and other machine learning methods that require less data than deep learning e.g. support vector machines, random forests. Unsupervised learning examples include dictionary learning, independent component analysis, and autoencoders. For application tasks with less labeled data, both supervised and unsupervised techniques can be adapted in a semi-supervised manner to produce accurate models and to increase the size of the labeled training data.

97 MATHEMATICS AND COMPUTING↗

NASA NTRS1972

Development of a noise annoyance sensitivity scale

Examining the problem of noise pollution from the psychological rather than the engineering view, a test of human sensitivity to noise was developed against the criterion of noise annoyance. Test development evolved from a previous study in which biographical, attitudinal, and personality data was collected on a sample of 166 subjects drawn from the adult community of Raleigh. Analysis revealed that only a small subset of the data collected was predictive of noise annoyance. Item analysis yielded 74 predictive items that composed the preliminary noise sensitivity test. This was administered to a sample of 80 adults who later rate the annoyance value of six sounds (equated in terms of peak sound pressure level) presented in a simulated home, living-room environment. A predictive model involving 20 test items was developed using multiple regression techniques, and an item weighting scheme was evaluated.

Bregman, H. L.↗

NASA NTRS1978

Helicopter Acoustics

Exterior and interior noise problems are addressed both from the physics and engineering as well as the human factors point of view. The role of technology in closing the gap between what the customers and regulating agencies would like to have and what is available is explored. Noise regulation concepts, design, operations and testing for noise control, helicopter noise prediction, and research tools and measurements are among the topics covered.

Source record↗

NASA NTRS1978

Helicopter Acoustics, part 2

Exterior and interior helicopter noise problems are addressed from the physics and engineering as well as the human factors point of view. Noise regulation concepts, human factors and criteria, rotor noise generation and control, design, operations and testing for noise control, helicopter noise prediction, and research tools and measurements are covered.

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NASA NTRS1992

Space law and space resources

Space industrialization is confronting space law with problems that are changing old and shaping new legal principles. The return to the Moon, the next logical step beyond the space station, will establish a permanent human presence there. Science and engineering, manufacturing and mining will involve the astronauts in the settlement of the solar system. These pioneers, from many nations, will need a legal, political, and social framework to structure their lives and interactions. International and even domestic space law are only the beginning of this framework. Dispute resolution and simple experience will be needed in order to develop, over time, a new social system for the new regime of space.

Goldman, Nathan C.↗

NASA NTRS1993

Human-in-the-loop evaluation of RMS Active Damping Augmentation

Active Damping Augmentation is the insertion of Controls-Structures Integration Technology to benefit the on-orbit performance of the Space Shuttle Remote Manipulator System. The goal is to reduce the vibration decay time of the Remote Manipulator System following normal payload maneuvers and operations. Simulation of Active Damping Augmentation was conducted in the realtime human-in-the-loop Systems Engineering Simulator at the NASA Johnson Space Center. The objective of this study was to obtain a qualitative measure of operational performance improvement from astronaut operators and to obtain supporting quantitative performance data. Sensing of vibratory motions was simulated using a three-axis accelerometer mounted at the end of the lower boom of the Remote Manipulator System. The sensed motions were used in a feedback control law to generate commands to the joint servo mechanisms which reduced the unwanted oscillations. Active damping of the Remote Manipulator System with an attached 3990 lb. payload was successfully demonstrated. Six astronaut operators examined the performance of an Active Damping Augmentation control law following single-joint and coordinated six-joint translational and rotational maneuvers. Active Damping Augmentation disturbance rejection of Orbiter thruster firings was also evaluated. Significant reductions in the dynamic response of the 3990 lb. payload were observed. Astronaut operators recommended investigation of Active Damping Augmentation benefits to heavier payloads where oscillations are a bigger problem (e.g. Space Station Freedom assembly operators).

Demeo, Martha E.↗

NASA NTRS1993

Spiral Survey Expedition: A proposal to organize for the Survey, exploration and eventual colonization of the Milky Way Galaxy

This paper details a plan to explore the galaxy. Areas of interest to an era of cyberspace include the Tech-Index information system for the expedition and the role cyberspace has in increasing expedition productivity and increasing the capabilities of cyberspace by expanding the goals and data set. The paper offers lists of projects for the cybermarket pool. The expedition is described also as a developers tool for cyberspace to acknowledge the scope of the human mind far surpasses present engineering yet guides our direction of energies and materials. Maintaining the biological capability to reproduce the Terran biosphere via Evolution park conservation areas is discussed. The ecological repair of Spaceship Earth and the build up of an interstellar industrial base from simple recyling and educational programs is meshed with a proposed 'reverse engineering cyberspace' plan. A set of constructive contests are proposed with 3 new currencies offered as prizes. The Planet, The Solar System, The Galaxy are 3 areas of focus. Each of these areas are considered in a cyberspectrum of (1) Sentience; (2) Biological diversity; and (3) Energy/Matter resources.

Galloway, Scott↗

NASA NTRS1997

An Accurate and Dynamic Computer Graphics Muscle Model

A computer based musculo-skeletal model was developed at the University in the departments of Mechanical and Biomedical Engineering. This model accurately represents human shoulder kinematics. The result of this model is the graphical display of bones moving through an appropriate range of motion based on inputs of EMGs and external forces. The need existed to incorporate a geometric muscle model in the larger musculo-skeletal model. Previous muscle models did not accurately represent muscle geometries, nor did they account for the kinematics of tendons. This thesis covers the creation of a new muscle model for use in the above musculo-skeletal model. This muscle model was based on anatomical data from the Visible Human Project (VHP) cadaver study. Two-dimensional digital images from the VHP were analyzed and reconstructed to recreate the three-dimensional muscle geometries. The recreated geometries were smoothed, reduced, and sliced to form data files defining the surfaces of each muscle. The muscle modeling function opened these files during run-time and recreated the muscle surface. The modeling function applied constant volume limitations to the muscle and constant geometry limitations to the tendons.

Levine, David Asher↗

NASA NTRS2004

Securing Safety with Sensors

The Robot Systems Technology Branch at NASA's Johnson Space Center collaborated with the Defense Advanced Research Projects Agency to design Robonaut, a humanoid robot developed to assist astronauts with Extra Vehicular Activities (EVA) such as space structure assembly and repair operations. By working side-by-side with astronauts or going where risks are too great for people, Robonaut is expected to expand the Space Agency s ability for construction and discovery. NASA engineers equipped Robonaut with human-looking, dexterous hands complete with five fingers to accomplish its tasks. The Robonaut hand is one of the first being developed for space EVA use and is the closest in size and capability to a suited astronaut s hand. As part of the development process, an advanced sensor system was needed to provide an improved method to measure the movement and forces exerted by Robonaut s forearms and hands.

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