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DOE OSTI2021

Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of therapeutic agents, generating remarkable responses in the clinic for a subset of human cancers. One major challenge precluding the wider implementation of CAR therapy is the paucity of tumor-specific antigens. Here, we describe the development of a CAR targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) with R140Q mutation presented on the cell surface in complex with a common human leukocyte antigen allele, HLA-B*07:02. Engineering of the hinge domain of the CAR, as well as crystal structure-guided optimization of the IDH2 R140Q- HLA-B*07:02-targeting moiety, enhances the sensitivity and specificity of CARs to enable targeting of this HLA-restricted neoantigen. This approach thus holds promise for the development and optimization of immunotherapies specific to other cancer driver mutations that are difficult to target by conventional means.

99 GENERAL AND MISCELLANEOUS↗

NASA NTRS1982

A linear decomposition method for large optimization problems. Blueprint for development

A method is proposed for decomposing large optimization problems encountered in the design of engineering systems such as an aircraft into a number of smaller subproblems. The decomposition is achieved by organizing the problem and the subordinated subproblems in a tree hierarchy and optimizing each subsystem separately. Coupling of the subproblems is accounted for by subsequent optimization of the entire system based on sensitivities of the suboptimization problem solutions at each level of the tree to variables of the next higher level. A formalization of the procedure suitable for computer implementation is developed and the state of readiness of the implementation building blocks is reviewed showing that the ingredients for the development are on the shelf. The decomposition method is also shown to be compatible with the natural human organization of the design process of engineering systems. The method is also examined with respect to the trends in computer hardware and software progress to point out that its efficiency can be amplified by network computing using parallel processors.

Sobieszczanski-Sobieski, J.↗

NASA NTRSDate not supplied

NASA Support for Commercial Crew Launch Capabilities

Since the earliest days of U.S. human spaceflight, NASA’s Marshall Space Flight Center in Huntsville, Alabama, has played a key role in American crew launch capability, from engineering support for the first Mercury-Redstone launches, to the Saturn launches to the Moon, through Shuttle and now Artemis. Today, Marshall brings that expertise gained through decades of crewed space launches to NASA’s Commercial Crew Program (CCP), providing launch vehicle engineering and programmatic support. The team’s responsibilities have included human certification of commercial launch systems for the CCP missions, including Atlas V and Falcon 9, and verifying each launch vehicle complies with flight certification. MSFC provides expertise in nearly all aspects of launch vehicle design and performance including solid motors and liquid engines, stage propulsion, thrust vector control, structural and dynamics, safety and mission assurance. During each commercial crew launch, an engineering support team is on console at Marshall’s Huntsville Operations Support Center, which has provided launch operations support since Apollo, providing real-time oversight to safety standards for the vehicle and verifying data. Launch vehicle support for Commercial Crew has come as a paradigm shift for the MSFC team, inspiring new approaches that leverage expertise and best practices from past NASA-developed launch vehicle missions, while at the same time providing new synergies from work with commercial partners on CCP. This paper will explore the role that the Marshall launch vehicle services team plays in the Commercial Crew Program, as well as lessons learned from the program that will continue to benefit a new era of spaceflight partnerships.

Commercial Crew↗

NASA NTRS2003

Evolution of the Systems Engineering Education Development (SEED) Program at NASA Goddard Space Flight Center

The Systems Engineering Education Development (SEED) Program at NASA Goddard Space Flight Center develops systems engineers from existing discipline engineers. The program has evolved significantly since the report to INCOSE in 2003. This paper describes the SEED Program as it is now, outlines the changes over the last year, discusses current status and results, and shows the value of human systems and leadership skills for practicing systems engineers.

Bagg, Thomas C., III↗

NASA NTRS1991

Development of biomechanical models for human factors evaluations

Previewing human capabilities in a computer-aided engineering mode has assisted greatly in planning well-designed systems without the cost and time involved in mockups and engineering models. To date, the computer models have focused on such variables as field of view, accessibility and fit, and reach envelopes. Program outputs have matured from simple static pictures to animations viewable from any eyepoint. However, while kinematics models are available, there are few biomechanical models available for estimating strength and motion patterns. Those, such as Crew Chief, that are available are based on strength measurements taken in specific positions. Johnson Space Center is pursuing a biomechanical model which will use strength data collected on single joints at two or three velocities to attempt to predict compound motions of several joint simultaneously and the resulting force at the end effector. Two lines of research are coming together to produce this result. One is an attempt to use optimal control theory to predict joint motion in complex motions, and another is the development of graphical representation of human capabilities. The progress to date in this research is described.

Woolford, Barbara↗

NASA NTRSDate not supplied

Predictive Modeling to Assess and Address Challenges and Limitations Associated with Clinical Care and Decision Support in Deep Space

Probabilistic risk assessment (PRA) is a method for assessing and integrating the risk of failure in a multivariate system. While it is often applied by engineers designing complex machines, it could also be applied to humans to assess the probability of a health “failure” treating diseases as the multiple “variables” and the human as the “complex machine.” The Medical Extensible Dynamic Probabilistic Risk Assessment Tool (MEDPRAT) was developed to apply PRA to assess medical risk for exploration spaceflight and inform the design of medical systems for space flight. The NASA engineering community utilizes event-driven and fault tree probabilistic techniques to classify risk in the space flight environment by leveraging the inherent knowledge of complex space flight system design and testing to quantify risk. However, in harmonizing the risk of human space flight, answering the question of “How do we balance astronaut health, performance and resource risks with other engineering risks on exploration space missions?” remains a profoundly challenging and largely qualitative practice. The Medical Extensible Dynamic Probabilistic Risk Assessment Tool (MEDPRAT) is one aspect of the Human Research Program’s efforts to represent space fight human health and performance risks quantitatively.

L Mcintyre↗

NASA NTRS2015

Affordable Development and Demonstration of a Small NTR Engine and Stage: How Small is Big Enough?

The Nuclear Thermal Rocket (NTR) derives its energy from fission of uranium-235 atoms contained within fuel elements that comprise the engine's reactor core. It generates high thrust and has a specific impulse potential of approximately 900 seconds - a 100% increase over today's best chemical rockets. The Nuclear Thermal Propulsion (NTP) project, funded by NASA's AES program, includes five key task activities: (1) Recapture, demonstration, and validation of heritage graphite composite (GC) fuel (selected as the "Lead Fuel" option); (2) Engine Conceptual Design; (3) Operating Requirements Definition; (4) Identification of Affordable Options for Ground Testing; and (5) Formulation of an Affordable Development Strategy. During FY'14, a preliminary DDT&E plan and schedule for NTP development was outlined by GRC, DOE and industry that involved significant system-level demonstration projects that included GTD tests at the NNSS, followed by a FTD mission. To reduce cost for the GTD tests and FTD mission, small NTR engines, in either the 7.5 or 16.5 klbf thrust class, were considered. Both engine options used GC fuel and a "common" fuel element (FE) design. The small approximately 7.5 klbf "criticality-limited" engine produces approximately 157 megawatts of thermal power (MWt) and its core is configured with parallel rows of hexagonal-shaped FEs and tie tubes (TTs) with a FE to TT ratio of approximately 1:1. The larger approximately 16.5 klbf Small Nuclear Rocket Engine (SNRE), developed by LANL at the end of the Rover program, produces approximately 367 MWt and has a FE to TT ratio of approximately 2:1. Although both engines use a common 35 inch (approximately 89 cm) long FE, the SNRE's larger diameter core contains approximately 300 more FEs needed to produce an additional 210 MWt of power. To reduce the cost of the FTD mission, a simple "1-burn" lunar flyby mission was considered to reduce the LH2 propellant loading, the stage size and complexity. Use of existing and flight proven liquid rocket and stage hardware (e.g., from the RL10B-2 engine and Delta Cryogenic Second Stage) was also maximized to further aid affordability. This paper examines the pros and cons of using these two small engine options, including their potential to support future human exploration missions to the Moon, near Earth asteroids, and Mars, and recommends a preferred size. It also provides a preliminary assessment of the key activities, development options, and schedule required to affordably build, ground test and fly a small NTR engine and stage within a 10-year timeframe.

Spacecraft design↗

NASA NTRS2016

Affordable Development and Demonstration of a Small Nuclear Thermal Rocket (NTR) Engine and Stage: How Small Is Big Enough?

The Nuclear Thermal Rocket (NTR) derives its energy from fission of uranium-235 atoms contained within fuel elements that comprise the engine's reactor core. It generates high thrust and has a specific impulse potential of approximately 900 specific impulse - a 100 percent increase over today's best chemical rockets. The Nuclear Thermal Propulsion (NTP) project, funded by NASA's Advanced Exploration Systems (AES) program, includes five key task activities: (1) Recapture, demonstration, and validation of heritage graphite composite (GC) fuel (selected as the Lead Fuel option); (2) Engine Conceptual Design; (3) Operating Requirements Definition; (4) Identification of Affordable Options for Ground Testing; and (5) Formulation of an Affordable Development Strategy. During fiscal year (FY) 2014, a preliminary Design Development Test and Evaluation (DDT&E) plan and schedule for NTP development was outlined by the NASA Glenn Research Center (GRC), Department of Energy (DOE) and industry that involved significant system-level demonstration projects that included Ground Technology Demonstration (GTD) tests at the Nevada National Security Site (NNSS), followed by a Flight Technology Demonstration (FTD) mission. To reduce cost for the GTD tests and FTD mission, small NTR engines, in either the 7.5 or 16.5 kilopound-force thrust class, were considered. Both engine options used GC fuel and a common fuel element (FE) design. The small approximately 7.5 kilopound-force criticality-limited engine produces approximately157 thermal megawatts and its core is configured with parallel rows of hexagonal-shaped FEs and tie tubes (TTs) with a FE to TT ratio of approximately 1:1. The larger approximately 16.5 kilopound-force Small Nuclear Rocket Engine (SNRE), developed by Los Alamos National Laboratory (LANL) at the end of the Rover program, produces approximately 367 thermal megawatts and has a FE to TT ratio of approximately 2:1. Although both engines use a common 35-inch (approximately 89-centimeters) -long FE, the SNRE's larger diameter core contains approximately 300 more FEs needed to produce an additional 210 thermal megawatts of power. To reduce the cost of the FTD mission, a simple one-burn lunar flyby mission was considered to reduce the liquid hydrogen (LH2) propellant loading, the stage size and complexity. Use of existing and flight proven liquid rocket and stage hardware (e.g., from the RL10B-2 engine and Delta Cryogenic Second Stage) was also maximized to further aid affordability. This paper examines the pros and cons of using these two small engine options, including their potential to support future human exploration missions to the Moon, near Earth asteroids (NEA), and Mars, and recommends a preferred size. It also provides a preliminary assessment of the key activities, development options, and schedule required to affordably build, ground test and fly a small NTR engine and stage within a 10-year timeframe.

Spacecraft design↗

NASA NTRS2013

From STEM to STEAM: Toward a Human-Centered Education

The 20th century was based on local linear engineering of complicated systems. We made cars, airplanes and chemical plants for example. The 21st century has opened a new basis for holistic non-linear design of complex systems, such as the Internet, air traffic management and nanotechnologies. Complexity, interconnectivity, interaction and communication are major attributes of our evolving society. But, more interestingly, we have started to understand that chaos theories may be more important than reductionism, to better understand and thrive on our planet. Systems need to be investigated and tested as wholes, which requires a cross-disciplinary approach and new conceptual principles and tools. Consequently, schools cannot continue to teach isolated disciplines based on simple reductionism. Science; Technology, Engineering, and Mathematics (STEM) should be integrated together with the Arts1 to promote creativity together with rationalization, and move to STEAM (with an "A" for Arts). This new concept emphasizes the possibility of longer-term socio-technical futures instead of short-term financial predictions that currently lead to uncontrolled economies. Human-centered design (HCD) can contribute to improving STEAM education technologies, systems and practices. HCD not only provides tools and techniques to build useful and usable things, but also an integrated approach to learning by doing, expressing and critiquing, exploring possible futures, and understanding complex systems.

Boy, Guy A.↗

NASA NTRS2005

Opportunities for Launch Site Integrated System Health Engineering and Management

The launch site processing flow involves operations such as functional verification, preflight servicing and launch. These operations often include hazards that must be controlled to protect human life and critical space hardware assets. Existing command and control capabilities are limited to simple limit checking durig automated monitoring. Contingency actions are highly dependent on human recognition, decision making, and execution. Many opportunities for Integrated System Health Engineering and Management (ISHEM) exist throughout the processing flow. This paper will present the current human-centered approach to health management as performed today for the shuttle and space station programs. In addition, it will address some of the more critical ISHEM needs, and provide recommendations for future implementation of ISHEM at the launch site.

Waterman, Robert D.↗

NASA NTRS1989

Identification and interpretation of patterns in rocket engine data: Artificial intelligence and neural network approaches

This paper describes an expert system which is designed to perform automatic data analysis, identify anomalous events, and determine the characteristic features of these events. We have employed both artificial intelligence and neural net approaches in the design of this expert system. The artificial intelligence approach is useful because it provides (1) the use of human experts' knowledge of sensor behavior and faulty engine conditions in interpreting data; (2) the use of engine design knowledge and physical sensor locations in establishing relationships among the events of multiple sensors; (3) the use of stored analysis of past data of faulty engine conditions; and (4) the use of knowledge-based reasoning in distinguishing sensor failure from actual faults. The neural network approach appears promising because neural nets (1) can be trained on extremely noisy data and produce classifications which are more robust under noisy conditions than other classification techniques; (2) avoid the necessity of noise removal by digital filtering and therefore avoid the need to make assumptions about frequency bands or other signal characteristics of anomalous behavior; (3) can, in effect, generate their own feature detectors based on the characteristics of the sensor data used in training; and (4) are inherently parallel and therefore are potentially implementable in special-purpose parallel hardware.

Ali, Moonis↗

NASA NTRS2022

NASA Engineering and Safety Center Technical Bulletin No. 22-06: Treatment of Slosh Stability Margin Reductions for Human-Rated Launch Vehicles

Slosh dynamics pose a stability concern for human-rated launch vehicles during ascent. Historical perspectives on the treatment of slosh dynamics, newly developed rules of thumb, the utility of flight data, and methods for analyzing and dispositioning slosh instability risks should be considered when linear stability margins are lower than typically accepted for human-rated systems.

Fuel Slosh↗

NASA NTRS2010

Intelligent Flexible Materials for Space Structures: Expandable Habitat Engineering Development Unit

Expandable habitable elements are an enabling technology for human exploration in space and on planetary surfaces. Large geometries can be deployed from a small launch volume, allowing greater mission capability while reducing mass and improving robustness over traditional rigid shells. This report describes research performed by ILC Dover under the Intelligent Flexible Materials for Space Structures program on the design and manufacture of softgoods for LaRC's Expandable Habitat Engineering Development Unit (EDU). The EDU is a full-scale structural test article of an expandable hybrid habitat, integrating an expandable softgoods center section with two rigid end caps. The design of the bladder, restraint layer and a mock-up Thermal Micrometeoroid Cover is detailed together with the design of the interface hardware used to attach them to the end caps. The integration and design of two windows and a floor are also covered. Analysis was performed to study the effects of the open weave design, and to determine the correct webbing and fabric configuration. Stress analyses were also carried out on the interfaces between the softgoods and the end caps and windows. Testing experimentally determined the strength of the fabric and straps, and component testing was used to proof several critical parts of the design. This program established new manufacturing and design techniques that can be applied to future applications in expandable structures.

Hinkle, Jon↗

NASA NTRS2012

Organizational Influences on Interdisciplinary Interactions during Research and Design of Large-Scale Complex Engineered Systems

The design of large-scale complex engineered systems (LaCES) such as an aircraft is inherently interdisciplinary. Multiple engineering disciplines, drawing from a team of hundreds to thousands of engineers and scientists, are woven together throughout the research, development, and systems engineering processes to realize one system. Though research and development (R&D) is typically focused in single disciplines, the interdependencies involved in LaCES require interdisciplinary R&D efforts. This study investigates the interdisciplinary interactions that take place during the R&D and early conceptual design phases in the design of LaCES. Our theoretical framework is informed by both engineering practices and social science research on complex organizations. This paper provides preliminary perspective on some of the organizational influences on interdisciplinary interactions based on organization theory (specifically sensemaking), data from a survey of LaCES experts, and the authors experience in the research and design. The analysis reveals couplings between the engineered system and the organization that creates it. Survey respondents noted the importance of interdisciplinary interactions and their significant benefit to the engineered system, such as innovation and problem mitigation. Substantial obstacles to interdisciplinarity are uncovered beyond engineering that include communication and organizational challenges. Addressing these challenges may ultimately foster greater efficiencies in the design and development of LaCES and improved system performance by assisting with the collective integration of interdependent knowledge bases early in the R&D effort. This research suggests that organizational and human dynamics heavily influence and even constrain the engineering effort for large-scale complex systems.

McGowan, Anna-Maria R.↗

NASA NTRS2010

STEM Education Efforts in the Ares Projects

According to the National Science Foundation, of the more than 4 million first university degrees awarded in science and engineering in 2006, students in China earned about 21%, those in the European Union earned about 19%, and those in the United States earned about 11%. Statistics like these are of great interest to NASA's Ares Projects, which are responsible for building the rockets for the U.S. Constellation Program to send humans beyond low-Earth orbit. Science, technology, engineering, and mathematics students are essential for the long-term sustainability of any space program. Since the Projects creation, the Ares Outreach Team has used a variety of STEM-related media, methods, and materials to engage students, educators, and the general public in Constellation's mission. Like Project Apollo, the nation s exploration destinations and the vehicles used to get there can inspire students to learn more about STEM. Ares has been particularly active in public outreach to schools in Northern Alabama; on the Internet via outreach and grade-specific educational materials; and in more informal social media settings such as YouTube and Facebook. These combined efforts remain integral to America s space program, regardless of its future direction.

Doreswamy, Rajiv↗

DOE OSTI2015

Development of Human Factors Awareness for Criticality Safety Specialists at Westinghouse Nuclear Fuels - 14223

Although human factors assessment typically involves specialist expertise, it is considered that enhanced local knowledge of this area for criticality safety specialists supports the incorporation of human factors consideration into tasks such as safety assessment, design and hazard reviews, development of operational and engineered criticality controls, training, incident investigation and emergency response. At the Westinghouse Springfields Fuel Manufacturing Site in the United Kingdom, specialist human factor support has been engaged to identify key competencies and training plans for criticality safety specialists. In addition, discussions have been held with the UK's Office for Nuclear Regulation (ONR) to outline the proposal and to discuss the approach. Following completion of an internationally recognised human factors training course the learning is now being applied by criticality safety specialists. Recent examples of learning applied include: 1) Review of past events and incidents to support the consideration of operator/equipment interfaces, leading to improved designs and processes. 2) Identification of critical tasks and the level of human factor assessment that is likely to be required. To support this, guidance has been produced by the criticality section for staff and contractors performing criticality safety assessments. 3) Assessment of the 'aims and operability' of engineered and procedural controls derived as part of the criticality safety assessment process. This involves participation of plant management and operators. 4) Consideration of human factors in emergency response activities such as infrequent tasks and tasks being undertaken under time pressures etc. This has been examined in recent emergency exercises and in the development of a recent criticality exercise scenario. 5) Criticality training has been reviewed with Plant Management, focussing on the methods utilised to deliver training (e.g. classroom based, computer training, on plant walk-downs); the aims and scope of training and how understanding is validated. 6) The link between criticality safety assessment and how the operations are / will be conducted has been reviewed as part of formal and informal criticality meetings and inspections. A key aspect of this is the criticality specialist's interaction with both plant management and operational staff. The development of human factors awareness into the criticality safety specialist's competency framework continues to be developed at Westinghouse but real benefits to criticality safety are already being demonstrated by this approach. (author)

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗

DOE OSTI2019

Machine learning framework for assessment of microbial factory performance

Metabolic models can estimate intrinsic product yields for microbial factories, but such frameworks struggle to predict cell performance (including product titer or rate) under suboptimal metabolism and complex bioprocess conditions. On the other hand, machine learning, complementary to metabolic modeling necessitates large amounts of data. Building such a database for metabolic engineering designs requires significant manpower and is prone to human errors and bias. We propose an approach to integrate data-driven methods with genome scale metabolic model for assessment of microbial bio-production (yield, titer and rate). Using engineered E. coli as an example, we manually extracted and curated a data set comprising about 1200 experimentally realized cell factories from ~100 papers. We furthermore augmented the key design features (e.g., genetic modifications and bioprocess variables) extracted from literature with additional features derived from running the genome-scale metabolic model iML1515 simulations with constraints that match the experimental data. Then, data augmentation and ensemble learning (e.g., support vector machines, gradient boosted trees, and neural networks in a stacked regressor model) are employed to alleviate the challenges of sparse, non-standardized, and incomplete data sets, while multiple correspondence analysis/principal component analysis are used to rank influential factors on bio-production. The hybrid framework demonstrates a reasonably high cross-validation accuracy for prediction of E.coli factory performance metrics under presumed bioprocess and pathway conditions (Pearson correlation coefficients between 0.8 and 0.93 on new data not seen by the model).

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Block Design with Common Reference Samples Enables Robust Large-Scale Label-Free Quantitative Proteome Profiling

Label-free quantitative proteomics has become an increasingly popular tool for profiling global protein abundances. However, one major weakness is the potential performance drift of the LC-MS platform over time, which in turn limits its utility for analyzing large-scale sample sets. To address this, in this work we introduce an experimental and data analysis scheme based on a block-design with common controls within each block for enabling LC-MS-based large-scale label-free quantification. In this scheme, a large number of samples (e.g., >100 samples) are analyzed in smaller, and more manageable blocks, minimizing instrument drift and variability within a block. Furthermore, each designated block also contains common controls (or reference) samples for normalization within and across blocks. We demonstrated the effectiveness of this method by profiling the proteome response of human macrophage THP-1 cells to 11 engineered nanomaterials (ENMs) at two different doses. A total of 116 samples were analyzed in six blocks, yielding an average coverage of 4500 proteins per sample. The data revealed consistent quantification of proteins across all six blocks, as shown by highly stable quantification of house-keeping proteins in all samples and high levels of quantification correlation among samples from different blocks. The data also demonstrated that label-free quantification is robust and accurate enough to quantify even very subtle abundance changes as well as large fold-changes without potential ratio compression as often encountered with isobaric labeling. Our streamlined workflow is easy to implement and can be readily adapted to other large cohort studies for reproducible label-free proteome quantification.

59 BASIC BIOLOGICAL SCIENCES↗