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At least 271 records · Page 15

Interactions of the C-terminal Domain of Human Ku70 with DNA Substrate: A Molecular Dynamics Study

NASA is developing a systems biology approach to improve the assessment of health risks associated with space radiation. The primary toxic and mutagenic lesion following radiation exposure is the DNA double strand break (DSB), thus a model incorporating proteins and pathways important in response and repair of this lesion is critical. One key protein heterodimer for systems models of radiation effects is the Ku(sub 70/80) complex. The Ku70/80 complex is important in the initial binding of DSB ends following DNA damage, and is a component of nonhomologous end joining repair, the primary pathway for DSB repair in mammalian cells. The C-terminal domain of Ku70 (Ku70c, residues 559-609), contains an helix-extended strand-helix motif and similar motifs have been found in other nucleic acid-binding proteins critical for DNA repair. However, the exact mechanism of damage recognition and substrate specificity for the Ku heterodimer remains unclear in part due to the absence of a high-resolution structure of the Ku70c/DNA complex. We performed a series of molecular dynamics (MD) simulations on a system with the subunit Ku70c and a 14 base pairs DNA duplex, whose starting structures are designed to be variable so as to mimic their different binding modes. By analyzing conformational changes and energetic properties of the complex during MD simulations, we found that interactions are preferred at DNA ends, and within the major groove, which is consistent with previous experimental investigations. In addition, the results indicate that cooperation of Ku70c with other subunits of Ku(sub 70/80) is necessary to explain the high affinity of binding as observed in experiments.

Hu, Shaowen↗

Interactions of the SAP Domain of Human Ku70 with DNA Substrate: A Molecular Dynamics Study

NASA is developing a systems biology approach to improve the assessment of health risks associated with space radiation. The primary toxic and mutagenic lesion following radiation exposure is the DNA double strand break (DSB), thus a model incorporating proteins and pathways important in response and repair of this lesion is critical. One key protein heterodimer for systems models of radiation effects is the Ku70/80 complex. The Ku70/80 complex is important in the initial binding of DSB ends following DNA damage, and is a component of nonhomologous end joining repair, the primary pathway for DSB repair in mammalian cells. The SAP domain of Ku70 (residues 556-609), contains an a helix-extended strand-helix motif and similar motifs have been found in other nucleic acid-binding proteins critical for DNA repair. However, the exact mechanism of damage recognition and substrate specificity for the Ku heterodimer remains unclear in part due to the absence of a high-resolution structure of the SAP/DNA complex. We performed a series of molecular dynamics (MD) simulations on a system with the SAP domain of Ku70 and a 10 base pairs DNA duplex. Large-scale conformational changes were observed and some putative binding modes were suggested based on energetic analysis. These modes are consistent with previous experimental investigations. In addition, the results indicate that cooperation of SAP with other domains of Ku70/80 is necessary to explain the high affinity of binding as observed in experiments.

Hu, Shaowen↗

Autonomous and Autonomic Systems: A Paradigm for Future Space Exploration Missions

NASA increasingly will rely on autonomous systems concepts, not only in the mission control centers on the ground, but also on spacecraft and on rovers and other assets on extraterrestrial bodies. Automomy enables not only reduced operations costs, But also adaptable goal-driven functionality of mission systems. Space missions lacking autonomy will be unable to achieve the full range of advanced mission objectives, given that human control under dynamic environmental conditions will not be feasible due, in part, to the unavoidably high signal propagation latency and constrained data rates of mission communications links. While autonomy cost-effectively supports accomplishment of mission goals, autonomicity supports survivability of remote mission assets, especially when human tending is not feasible. Autonomic system properties (which ensure self-configuring, self-optimizing self-healing, and self-protecting behavior) conceptually may enable space missions of a higher order into any previously flown. Analysis of two NASA agent-based systems previously prototyped, and of a proposed future mission involving numerous cooperating spacecraft, illustrates how autonomous and autonomic system concepts may be brought to bear on future space missions.

Truszkowski, Walter F.↗

Synthesis from Design Requirements of a Hybrid System for Transport Aircraft Longitudinal Control

Volume I of this report presents a new method for synthesizing hybrid systems directly from desi gn requirements, and applies the method to design of a hybrid system for longitudinal control of transport aircraft. The resulting system satisfies general requirement for safety and effectiveness specified a priori, enabling formal validation to be achieved. Volume II contains seven appendices intended to make the report accessible to readers with backgrounds in human factors, flight dynamics and control, and formal logic. Major design goals are (1) system design integrity based on proof of correctness at the design level, (2) significant simplification and cost reduction in system development and certification, and (3) improved operational efficiency, with significant alleviation of human-factors problems encountered by pilots in current transport aircraft. This report provides for the first time a firm technical basis for criteria governing design and certification of avionic systems for transport aircraft. It should be of primary interest to designers of next-generation avionic systems.

Hynes, Charles S.↗

Prevalence and scalable control of localized networks

The ability to control network dynamics is essential for ensuring desirable functionality of many technological, biological, and social systems. Such systems often consist of a large number of network elements, and controlling large-scale networks remains challenging because the computation and communication requirements increase prohibitively fast with network size. Here, we introduce a notion of network locality that can be exploited to make the control of networks scalable, even when the dynamics are nonlinear. We show that network locality is captured by an information metric and is almost universally observed across real and model networks. In localized networks, the optimal control actions and system responses are both shown to be necessarily concentrated in small neighborhoods induced by the information metric. This allows us to develop localized algorithms for determining network controllability and optimizing the placement of driver nodes. This also allows us to develop a localized algorithm for designing local feedback controllers that approach the performance of the corresponding best global controllers, while incurring a computational cost orders-of-magnitude lower. Here, we validate the locality, performance, and efficiency of the algorithms in Kuramoto oscillator networks, as well as three large empirical networks: synchronization dynamics in the Eastern US power grid, epidemic spreading mediated by the global air-transportation network, and Alzheimer’s disease dynamics in a human brain network. Taken together, our results establish that large networks can be controlled with computation and communication costs comparable to those for small networks.

42 ENGINEERING↗

Contamination Mitigation Strategies for Long Duration Human Spaceflight Missions

Contamination control issues are particularly challenging for long-term human spaceflight and are associated with the search for life, dynamic environmental conditions, human-robotic-environment interaction, sample collection and return, biological processes, waste management, long-term environmental disturbance, etc. These issues impact mission success, human health, planetary protection, and research and discovery. Mitigation and control techniques and strategies may include and integrate long-term environmental monitoring and reporting, contamination control and planetary protection protocols, habitation site design, habitat design, and surface exploration and traverse pathways and area access planning.

enviroment↗

USSR Space Life Sciences Digest, issue 11

This is the eleventh issue of NASA's USSR Space Life Sciences Digest. It contains abstracts of 54 papers recently published in Russian language periodicals and bound collections and of four new Soviet monographs. Selected abstracts are illustrated. Additional features include the translation of a paper presented in Russian to the United Nations, a review of a book on space ecology, and report of a conference on evaluating human functional capacities and predicting health. Current Soviet Life Sciences titles available in English are cited. The materials included in this issue have been identified as relevant to 30 areas of aerospace medicine and space biology. These areas are: adaptation, aviation physiology, biological rhythms, biospherics, body fluids, botany, cardiovascular and respiratory systems, cosmonaut training, developmental biology, endocrinology, enzymology, equipment and instrumentation, gastrointestinal systems, group dynamics, genetics, hematology, human performance, immunology, life support systems, mathematical modeling, metabolism, microbiology, musculoskeletal system, neurophysiology, nutrition, operational medicine, perception, personnel selection, psychology, and radiobiology.

Hooke, Lydia Razran↗

Systematic mapping of the conformational landscape and dynamism of soluble fibrinogen

Background: Fibrinogen is a soluble, multisubunit, and multidomain dimeric protein, which, upon its proteolytic cleavage by thrombin, is converted to insoluble fibrin, initiating polymerization that substantially contributes to clot growth. Fibrinogen contains numerous, transiently accessible “cryptic” epitopes for hemostatic and immunologic proteins, suggesting that fibrinogen exhibits conformational flexibility, which may play functional roles in its temporal and spatial interactions. Hitherto, there have been limited integrative approaches characterizing the solution structure and internal flexibility of fibrinogen. Methods: Here, utilizing a multipronged, biophysical approach involving 2 solution-based techniques, temperature-dependent hydrogen-deuterium exchange mass spectrometry and small angle X-ray scattering, corroborated by negative stain electron microscopy, we present a holistic, conformationally dynamic model of human fibrinogen in solution. Results: Our data reveal 4 major and distinct conformations of fibrinogen accommodated by a high degree of internal protein flexibility along its central scaffold. We propose that the fibrinogen structure in the solution consists of a complex, conformational landscape with multiple local minima. This is further supported by the location of numerous point mutations that are linked to dysfibrinogenemia and posttranslational modifications, residing near the identified fibrinogen flexions. Conclusion: Further, this work provides a molecular basis for the structural “dynamism” of fibrinogen that is expected to influence the broad swath of its functionally diverse macromolecular interactions and fine-tune the structural and mechanical properties of blood clots.

59 BASIC BIOLOGICAL SCIENCES↗

Modeling strategic behavior in human-automation interaction - Why an 'aid' can (and should) go unused

Task-offload aids (e.g., an autopilot, an 'intelligent' assistant) can be selectively engaged by the human operator to dynamically delegate tasks to automation. Introducing such aids eliminates some task demands but creates new ones associated with programming, engaging, and disengaging the aiding device via an interface. The burdens associated with managing automation can sometimes outweigh the potential benefits of automation to improved system performance. Aid design parameters and features of the overall multitask context combine to determine whether or not a task-offload aid will effectively support the operator. A modeling and sensitivity analysis approach is presented that identifies effective strategies for human-automation interaction as a function of three task-context parameters and three aid design parameters. The analysis and modeling approaches provide resources for predicting how a well-adapted operator will use a given task-offload aid, and for specifying aid design features that ensure that automation will provide effective operator support in a multitask environment.

Kirlik, Alex↗

Risks of Increased Earth Independence

As human space exploration begins to extend beyond the immediate vicinity of Earth, the ability of expertise on the ground to support operations will progressively decrease. Ground control expertise has been the primary countermeasure preventing loss of life and mission over the past sixty years and it will be gradually stripped away as expeditions reach further into space. The large, flexible and adaptive teams of experts on the ground, provide not only engineering analysis and problem-solving but also greatly increased work capacity. Monitoring of the large and fast moving stream of telemetry data is carried out around the clock by 20-30 flight controllers per shift. Analysis of that data and troubleshooting is carried out by an additional 50-100 engineers per shift. Artificial intelligence capabilities will need to be part of the solution but will not the entire solution. As progress continues to be made on intelligent systems, especially those for use in complex, dynamic environments where humans will remain a part of the activity, there is an ever increasing need to focus on how those systems will interact with the humans. Although capabilities such as natural language processing and facial recognition have become common place, even basic aspects of problem-solving, causal reasoning and generative decision-making remain well-beyond of our current capabilities. Advanced data visualization, procedure execution support, and new training approaches will be needed to close the gap between what is currently provided by experts on the ground and what the crew will need to do in increasingly autonomous ways with greater distance from Earth.

human-systems integration architecture↗

Increased abundance of a common scavenger affects allocation of carrion but not efficiency of carcass removal in the Fukushima Exclusion Zone

Abstract The 2011 nuclear accident in Fukushima, Japan caused the evacuation of > 100,000 people and prompted studies on environmental impacts of radiological contamination. However, few researchers have explored how the human evacuation has affected ecosystem processes. Despite contamination, one common scavenger (wild boar, Sus scrofa ) is 2–3× more abundant inside the Fukushima Exclusion Zone (FEZ). Shifts in abundance of some scavenger species can have cascading effects on ecosystems, so our objective was to investigate impacts of the evacuation and the resulting increase in wild boar on vertebrate scavenger communities. We deployed cameras at 300 carcasses in the FEZ and a nearby inhabited area, and quantified carcass fate, scavenger species, and detection/persistence times. We also tested effects of carcass size and habitat on scavenger community composition and efficiency by balancing trials across two carcass sizes and habitats in each zone. Overall scavenger richness and carcass removal rates (73%) were similar in the FEZ and inhabited area, but species-specific carcass removal rates and occurrence differed between zones. Wild boar removed substantially more carcasses inside the FEZ, with implications for nutrient and contaminant distribution. Our results suggest carcass size affects scavenging dynamics more than human activity or habitat, and abundance changes of common scavengers can influence carrion resource allocation.

59 BASIC BIOLOGICAL SCIENCES↗

A deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases

Human diseases are characterized by intricate cellular dynamics. Single-cell transcriptomics provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in silico drug interventions. Here we introduce UNAGI, a deep generative neural network tailored to analyse time-series single-cell transcriptomic data. This tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modelling and screening. When applied to a dataset from patients with idiopathic pulmonary fibrosis, UNAGI learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation using proteomics reveals the accuracy of UNAGI’s cellular dynamics analysis, and the use of the fibrotic cocktail-treated human precision-cut lung slices confirms UNAGI’s predictions that nifedipine, an antihypertensive drug, may have anti-fibrotic effects on human tissues. UNAGI’s versatility extends to other diseases, including COVID, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond idiopathic pulmonary fibrosis, amplifying its use in the quest for therapeutic solutions across diverse pathological landscapes.

Neural Network↗

A level-of-details framework for representing occupant behavior in agent-based models

We report agent-based modeling is an advanced computational technique capable of representing complex and dynamic processes of human behavior in building performance simulation. Though the agent-based approach supports diverse applications concerning human behavior modeling within the built environment, there is no consensus on the optimal amount of information or level of granularity needed for occupant information representation. This paper attempts to formalize the level of details (LoD) needed for occupant behavior representation in agent-based environments. A novel framework, grounded on the concept of LoD, is proposed to select the required details in representing occupants in agent-based models. Ten attributes related to occupants' presence, movement, behavioral processes, and repertoire are considered to define the LoD. The framework identifies use case parameters as the guiding principle and allows a hybrid approach for selecting varying degrees of occupant attributes to serve the purpose of simulation. A discussion on the pertinence of different occupant behavior LoDs in relation to the desired objective and simulation context is also presented. The study intends to support the occupant behavior research by advancing agent-based occupant modeling in building performance simulation.

42 ENGINEERING↗

Issues in the design of an executive controller shell for Space Station automation

A major goal of NASA's Systems Autonomy Demonstration Project is to focus research in artificial intelligence, human factors, and dynamic control systems in support of Space Station automation. Another goal is to demonstrate the use of these technologies in real space systems, for both round-based mission support and on-board operations. The design, construction, and evaluation of an intelligent autonomous system shell is recognized as an important part of the Systems Autonomy research program. His paper describes autonomous systems and executive controllers, outlines how these intelligent systems can be utilized within the Space Station, and discusses a number of key design issues that have been raised during some preliminary work to develop an autonomous executive controller shell at NASA Ames Research Center.

Erickson, William K.↗

Flight simulator requirements for airline transport pilot training - An evaluation of motion system design alternatives

The effect of motion platform systems on pilot behavior is considered with emphasis placed on civil aviation applications. A dynamic model for human spatial orientation based on the physiological structure and function of the human vestibular system is presented. Motion platform alternatives were evaluated on the basis of the following motion platform conditions: motion with six degrees-of-freedom required for Phase II simulators and two limited motion conditions. Consideration was given to engine flameout, airwork, and approach and landing scenarios.

Lee, A. T.↗

The use of vestibular models for design and evaluation of flight simulator motion

Quantitative models for the dynamics of the human vestibular system are applied to the design and evaluation of flight simulator platform motion. An optimal simulator motion control algorithm is generated to minimize the vector difference between perceived spatial orientation estimated in flight and in simulation. The motion controller has been implemented on the Vertical Motion Simulator at NASA Ames Research Center and evaluated experimentally through measurement of pilot performance and subjective rating during VTOL aircraft simulation. In general, pilot performance in a longitudinal tracking task (formation flight) did not appear to be sensitive to variations in platform motion condition as long as motion was present. However, pilot assessment of motion fidelity by means of a rating scale designed for this purpose, were sensitive to motion controller design. Platform motion generated with the optimal motion controller was found to be generally equivalent to that generated by conventional linear crossfeed washout. The vestibular models are used to evaluate the motion fidelity of transport category aircraft (Boeing 727) simulation in a pilot performance and simulator acceptability study at the Man-Vehicle Systems Research Facility at NASA Ames Research Center. Eighteen airline pilots, currently flying B-727, were given a series of flight scenarios in the simulator under various conditions of simulator motion. The scenarios were chosen to reflect the flight maneuvers that these pilots might expect to be given during a routine pilot proficiency check. Pilot performance and subjective rating of simulator fidelity was relatively insensitive to the motion condition, despite large differences in the amplitude of motion provided. This lack of sensitivity may be explained by means of the vestibular models, which predict little difference in the modeled motion sensations of the pilots when different motion conditions are imposed.

Bussolari, Steven R.↗