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DOE OSTI2022

Structural and dynamic mechanisms of GABA A receptor modulators with opposing activities

γ-Aminobutyric acid type A (GABA A ) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABA A ) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABA A receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the α/γ subunit interface and two transmembrane sites at β/α interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABA A receptor allosteric modulators acting through a common site can have diverging activities.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Reducing nighttime light exposure in the urban environment to benefit human health and society

Nocturnal light pollution can have profound effects on humans and other organisms. Recent research indicates that nighttime outdoor lighting is increasing rapidly. Evidence from controlled laboratory studies demonstrates that nocturnal light exposure can strain the visual system, disrupt circadian physiology, suppress melatonin secretion, and impair sleep. There is a growing body of work pointing to adverse effects of outdoor lighting on human health, including the risk of chronic diseases, but this knowledge is in a more nascent stage. In this Review, we synthesize recent research on the context-specific factors and physiology relevant to nocturnal light exposure in relation to human health and society, identify critical areas for future research, and highlight recent policy steps and recommendations for mitigating light pollution in the urban environment.

Science & Technology - Other Topics↗

NASA NTRS1998

Later endogenous circadian temperature nadir relative to an earlier wake time in older people

The contribution of the circadian timing system to the age-related advance of sleep-wake timing was investigated in two experiments. In a constant routine protocol, we found that the average wake time and endogenous circadian phase of 44 older subjects were earlier than that of 101 young men. However, the earlier circadian phase of the older subjects actually occurred later relative to their habitual wake time than it did in young men. These results indicate that an age-related advance of circadian phase cannot fully account for the high prevalence of early morning awakening in healthy older people. In a second study, 13 older subjects and 10 young men were scheduled to a 28-h day, such that they were scheduled to sleep at many circadian phases. Self-reported awakening from scheduled sleep episodes and cognitive throughput during the second half of the wake episode varied markedly as a function of circadian phase in both groups. The rising phase of both rhythms was advanced in the older subjects, suggesting an age-related change in the circadian regulation of sleep-wake propensity. We hypothesize that under entrained conditions, these age-related changes in the relationship between circadian phase and wake time are likely associated with self-selected light exposure at an earlier circadian phase. This earlier exposure to light could account for the earlier clock hour to which the endogenous circadian pacemaker is entrained in older people and thereby further increase their propensity to awaken at an even earlier time.

NASA Discipline Regulatory Physiology↗

NASA NTRS2015

Evidence-Based Recommendations for Optimizing Light in Day-to-Day Spaceflight Operations

NASA Behavioral Health and Performance Element (BHP) personnel have previously reported on efforts to transition evidence‐based recommendations for a flexible lighting system on the International Space Station (ISS). Based on these recommendations, beginning in 2016 the ISS will replace the current fluorescent‐based lights with an LED‐based system to optimize visual performance, facilitate circadian alignment, promote sleep, and hasten schedule shifting. Additional efforts related to lighting countermeasures in spaceflight operations have also been underway. As an example, a recent BHP research study led by investigators at Harvard Medical School and Brigham and Women's Hospital, evaluated the acceptability, feasibility, and effectiveness of blue‐enriched light exposure during exercise breaks for flight controllers working the overnight shift in the Mission Control Center (MCC) at NASA Johnson Space Center. This effort, along with published laboratory studies that have demonstrated the effectiveness of appropriately timed light for promoting alertness, served as an impetus for new light options, and educational protocols for flight controllers. In addition, a separate set of guidelines related to the light emitted from electronic devices, were provided to the Astronaut Office this past year. These guidelines were based on an assessment led by NASA's Lighting Environment Test Facility that included measuring the spectral power distribution, irradiance, and radiance of light emitted from ISS‐grade laptops and I‐Pads, as well as Android devices. Evaluations were conducted with and without the use of off‐the‐shelf screen filters as well as a software application that touts minimizing the short‐wave length of the visible light spectrum. This presentation will focus on the transition for operations process related to lighting countermeasures in the MCC, as well as the evidence to support recommendations for optimal use of laptops, I‐Pads, and Android devices during all phases of spaceflight operations.

Whitmire, Alexandra↗

NASA NTRS2002

Astronauts Need Their Rest Too: Sleep-Wake Actigraphy and Light Exposure During Space Flight

The success and effectiveness of human space flight depends on astronauts' ability to maintain a high level of cognitive performance and vigilance. This alert state ensures the proper operation of sophisticated instrumentation. An important way for humans to remedy fatigue and maintain alertness is to get plenty of rest. Astronauts, however, commonly experience difficulty sleeping while in space. During flight, they may also experience disruption of the body's circadian rhythm - the natural phases the body goes through every day as we oscillate between states of high activity during the waking day and recuperation, rest, and repair during nighttime sleep. Both of these factors are associated with impairment of alertness and performance, which could have important consequences during a mission in space. The human body was designed to sleep at night and be alert and active during the day. We receive these cues from the time of day or amount of light, such as the rising or setting of the sun. However, in the environment of the Space Shuttle or the International Space Station where light levels are highly variable, the characteristics of a 24-hour light/dark cycle are not present to cue the astronauts' bodies about what time of the day it is. Astronauts orbiting Earth see a sunset and sunrise every 90 minutes, sending potentially disruptive signals to the area of the brain that regulates sleep. On STS-107, researchers will measure sleep-wake activity with state-of-the-art technology to quantify how much sleep astronauts obtain in space. Because light is the most powerful time cue to the body's circadian system, individual light exposure patterns of the astronauts will also be monitored to determine if light exposure is associated with sleep disruption. The results of this research could lead to the development of a new treatment for sleep disturbances, enabling crewmembers to avoid the decrements in alertness and performance due to sleep deprivation. What we learn about sleep in space informs treatment for earthbound populations, such as the elderly and insomniacs, who experience frequent sleep disturbances or altered sleep patterns.

Czeisler, Charles↗

NASA NTRS1999

Circadian and sleep-dependent regulation of hormone release in humans

Daily oscillations characterize the release of nearly every hormone. The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates circadian, approximately 24-hour rhythms in many physiologic functions. However, the observed hormonal oscillations do not simply reflect the output of this internal clock. Instead, daily hormonal profiles are the product of a complex interaction between the output of the circadian pacemaker, periodic changes in behavior, light exposure, neuroendocrine feedback mechanisms, gender, age, and the timing of sleep and wakefulness. The interaction of these factors can affect hormonal secretory pulse frequency and amplitude, with each endocrine system differentially affected by these factors. This chapter examines recent advances in understanding the effects on endocrine rhythms of a number of these factors. Sleep exerts a profound effect on endocrine secretion. Sleep is a dynamic process that is characterized by periodic changes in electrophysiologic activity. These electrophysiologic changes, which are used to mark the state and depth of sleep, are associated with periodic, short-term variations in hormonal levels. The secretion of hormones such as renin and human growth hormone are strongly influenced by sleep or wake state, while melatonin and cortisol levels are relatively unaffected by sleep or wake state. In addition, sleep is associated with changes in posture, behavior, and light exposure, each of which is known to affect endocrine secretion. Furthermore, the tight concordance of habitual sleep and wake times with certain circadian phases has made it difficult to distinguish sleep and circadian effects on these hormones. Specific protocols, designed to extract circadian and sleep information semi-independently, have been developed and have yielded important insights into the effects of these regulatory processes. These results may help to account for changes in endocrine rhythms observed in circadian rhythm sleep disorders, including the dyssomnia of shift work and visual impairment. Yet to be fully investigated are the interactions of these factors with age and gender. Characterization of the factors governing hormone secretion is critical to understanding the temporal regulation of endocrine systems and presents many exciting areas for future research.

Non-NASA Center↗

DOE OSTI2023

OpenStudio®-ERI (Energy Rating Index (ERI) Workflow) [SWR-18-72] 1.7.0 Released 12/14/2023

The OpenStudio®-ERI project allows calculating an Energy Rating Index (ERI) using the Department of Energy's open-source OpenStudio®/EnergyPlus® simulation platform. The building description is provided in an HPXML file format. The project supports: - ANSI/RESNET/ICC 301© Standard for the Calculation and Labeling of the Energy Performance of Dwelling and Sleeping Units using an Energy Rating Index - ENERGY STAR Certification System for Homes and Apartments Using an ERI Compliance Path - IECC ERI Compliance Alternative (Section R406) - DOE ZERH Certification Using an ERI Compliance Path For more information on running simulations, generating HPXML files, etc., please visit the documentation at https://openstudio-eri.readthedocs.io/en/latest/

Horowitz, Scott↗

NASA NTRS1993

A comparison of low-gravity measurements on-board Columbia during STS-40

The first NASA Spacelab Life Sciences mission (SLS-1) flew 5 June to 14 June 1991 on the orbiter Columbia (STS-40). The purpose of the mission was to investigate the human body's adaptation to the low-gravity conditions of space flight and the body's readjustment after the mission to the 1g environment of earth. In addition to the life sciences experiments manifested for the Spacelab module, a variety of experiments in other scientific disciplines flew in the Spacelab and in Get Away Special (GAS) Canisters on the GAS Bridge Assembly. Several principal investigators designed and flew specialized accelerometer systems to better assess the results of their experiments by means of a low-gravity environment characterization. This was also the first flight of the NASA Microgravity Science and Applications Division (MSAD) sponsored Space Acceleration Measurement System (SAMS) and the first flight of the NASA Orbiter Experiments Office (OEX) sponsored Orbital Acceleration Research Experiment accelerometer (OARE). We present a brief introduction to seven STS-40 accelerometer systems and discuss and compare the resulting data. During crew sleep periods, acceleration magnitudes in the 10(exp -6) to 10(exp -5)g range were recorded in the Spacelab module and on the GAS Bridge Assembly. Magnitudes increased to the 10(exp -4) level during periods of nominal crew activity. Vernier thruster firings caused acceleration shifts on the order of 10(exp -4)g and primary thruster firings caused accelerations as great as 10(exp -2) g. Frequency domain analysis revealed typical excitation of Orbiter and Spacelab structural modes at 3.5, 4.7, 5.2, 6.2, 7, and 17 Hz.

Rogers, M. J. B.↗

NASA NTRS2022

Light in Ecological Settings: Entrainment, Circadian Disruption, and Interventions

Light is the predominant signal for the human circadian clock to synchronize to the solar 24-h day through an active process called entrainment. Modern light profiles are characterized by exposure to both natural daylight and artificial lighting. A mismatch between these self-selected light profiles and the solar day-night alternation can disrupt the circadian system, resulting in acute and chronic effects for health and safety. In this chapter, we describe (i) how entrainment works in the real world, illustrating the major role of light for this process; (ii) ways in which the circadian system can be disrupted by (external) factors such as irregular sleep, shift work, daylight saving time, and longitudinal position in a time zone; and (iii) how field studies have used light interventions to reduce direct and indirect effects of circadian disruption in ecological settings.

light interventions↗

NASA NTRS2009

Spaceflight Human System Standards

NASA created a new approach for human system integration and human performance standards. NASA created two documents a standard and a reference handbook. The standard is titled NASA Space Flight Human-System Standard (SFHSS) and consists of two-volumes: Volume 1- Crew Health This volume covers standards needed to support astronaut health (medical care, nutrition, sleep, exercise, etc.) Volume 2 Human Factors, Habitability and Environmental Health This volume covers the standards for system design that will maintain astronaut performance (ie., environmental factors, design of facilities, layout of workstations, and lighting requirements). It includes classic human factors requirements. The new standards document is written in terms so that it is applicable to a broad range of present and future NASA systems. The document states that all new programs prepare system-specific requirements that will meet the general standards. For example, the new standard does not specify a design should accommodate specific percentiles of a defined population. Rather, NASA-STD-3001, Volume 2 states that all programs shall prepare program-specific requirements that define the user population and their size ranges. The design shall then accommodate the full size range of those users. The companion reference handbook, Human Integration Design Handbook (HIDH), was developed to capture the design consideration information from NASA-STD-3000, and adds spaceflight lessons learned, gaps in knowledge, example solutions, and suggests research to further mature specific disciplines. The HIDH serves two major purposes: HIDH is the reference document for writing human factors requirements for specific systems. HIDH contains design guidance information that helps insure that designers create systems which safely and effectively accommodate the capabilities and limitations of space flight crews.

Holubec, Keith↗

NASA NTRS2001

Consequences of contamination of the spacecraft environment: immunologic consequences

Long-term space voyages pose numerous known and unknown health hazards, to the human immune system. Well-studied clinical examples of secondary immunodeficiencies created on Earth, lead one to predict that the conditions of prolonged space flight would weaken the human immune responses that normally hold infection and cancer in check. From evidence gathered from humans flown for prolonged periods in space and from human models of space flight studied on Earth it is reasonable to suspect that space travelers to the planet Mars would experience a weakening of immunity. Subtle defects of immune cell structure and function have been observed in astronauts, such as weakening of specific T-lymphocyte recall of specific antigens. Ground-based models also have demonstrated alterations of immune function, such as the elevation of neuroendocrine immune system messengers, interleukin-6, and soluble tumor necrosis factor-alpha receptor in sleep deprivation. Since severe immune compromise the clinical consequences of reactivation of latent virus infections and the development of cancer, has yet to be seen in space flight or in the Earth models, it is extremely important to begin to quantify early changes in immunity to predict the development of immune system collapse with poor clinical outcomes. This approach is designed to validate a number of surrogate markers that will predict trouble ahead. Inherent in this research is the development of countermeasures to reduce the risks of infection and cancer in the first humans going to Mars.

Non-NASA Center↗

NASA NTRSDate not supplied

Isolation Standard Measures: A Set of Validated and Feasible Measurements Ensuring Comparability Across Isolation and Confinement Studies

Isolation and confinement studies have been essential to the preparation of crewed long-duration space missions, acting as analogues that facilitate the study of psychological and physiological responses to isolation and confinement. They also serve as opportunities for the development, testing, and validation of countermeasures and coping methods to handle the challenges that arise in such scenarios. Due to the small sample sizes in combination with high inter-individual variability, single isolation campaigns are not always sufficient for obtaining statistically significant scientific findings. To address this issue and improve comparability between different studies, the need for standardized measures to be collected in all future isolation and confinement studies was identified. Additionally, these measures should also be shown to be generally valid, reliable, feasible and acceptable in analogue and spaceflight environments. Standard measures in isolation and confinement studies allow for more direct comparisons of results and synthesis of data across isolation and confinement studies as well as provide an important step toward standard measures in spaceflight. An international expert group with representatives from different space agencies worldwide was brought together to define a core set of standard measures for isolation and confinement studies. This paper provides an overview of the expert group’s recommendations for international standard measures for future isolation and confinement studies, along with subsequent updates coordinated by the International Countermeasures Working Group (ICMWG), which was established as a sub-Working Group under the International Space Life Sciences Working Group (ISLSWG). Additional experts were consulted by the ICMWG partner agencies as required. The collection of the described set of isolation standard measures will provide data on the following parameters: sleep, mood, psychological state, psychophysiology, cognitive performance, stress and the immune system, general health and well-being, team measures, nutritional measures, and environmental conditions. For each measure, recommendations were made about duration and frequency of administration, along with specific implementation recommendations in relation to the duration of the isolation study. The set of isolation standard measures will be reassessed every two years at a minimum to ensure they are up to date and reflect the current state-of-the-art.

Isolation↗

NASA NTRS2002

Crew Factors in Flight Operations XIV: Alertness Management in Regional Flight Operations Education Module

Regional operations encompass a broad range of pilots and equipment. This module is intended to help all those involved in regional aviation, including pilots, schedulers, dispatchers, maintenance technicians, policy makers, and others, to understand the physiological factors underlying fatigue, how flight operations affect fatigue, and what can be done to counteract fatigue and maximize alertness and performance in their operations. The overall purpose of this module is to promote aviation safety, performance, and productivity. It is intended to meet three specific objectives: (1) to explain the current state of knowledge about the physiological mechanisms underlying fatigue; (2) to demonstrate how this knowledge can be applied to improving flight crew sleep, performance, and alertness; and (3) to offer strategies for alertness management. Aviation Safety Reporting System (ASRS) and National Transportation Safety Board (NISH) reports are used throughout this module to demonstrate that fatigue is a safety issue in the regional operations community. The appendices at the end of this module include the ASRS reports used for the examples contained in this publication, brief introductions to sleep disorders and relaxation techniques, summaries of relevant NASA publications, and a list of general readings on sleep, sleep disorders, and circadian rhythms.

Rosekind, Mark R.↗

NASA NTRS2002

Crew Factors in Flight Operations XV: Alertness Management in General Aviation Education Module

Rosekind, Mark R.↗

NASA NTRS2016

Computational Modeling to Limit the Impact Displays and Indicator Lights Have on Habitable Volume Operational Lighting Constraints

Even with no ambient lighting system "on", the International Space Station glows at night. The glow is caused by indicator lamps and displays that are not included with the specification of the ambient lighting system. How does this impact efforts to improve the astronaut's lighting environment to promote more effective sleep patterns? Do the extra indicators and displays add enough light to change the spectrum of light the crew sees during the day as well? If spacecraft environments are specifically engineered to have an ambient lighting system that emits a spectrum promoting a healthy circadian response, is there a way control the impact? The goal of this project is to investigate how additional light sources, such as displays and indicators change the effective light spectrum of the architectural lighting system and how impacts can be mitigated.

Clark, T. A.↗

NASA NTRS1985

Circadian Rhythm Control: Neurophysiological Investigations

The suprachiasmatic nucleus (SCN) was implicated as a primary component in central nervous system mechanisms governing circadian rhythms. Disruption of the normal synchronization of temperature, activity, and other rhythms is detrimental to health. Sleep wake disorders, decreases in vigilance and performance, and certain affective disorders may result from or be exacerbated by such desynchronization. To study the basic neurophysiological mechanisms involved in entrainment of circadian systems by the environment, Parylene-coated, etched microwire electrode bundles were used to record extracellular action potentials from the small somata of the SCN and neighboring hypothalamic nuclei in unanesthetized, behaving animals. Male Wistar rats were anesthetized and chronically prepared with EEG ane EMG electrodes in addition to a moveable microdrive assembly. The majority of cells had firing rates 10 Hz and distinct populations of cells which had either the highest firing rate or lowest firing rate during sleep were seen.

Glotzbach, S. F.↗

NASA NTRS1984

Primate body temperature and sleep responses to lower body positive pressure

Cephalic fluid shifts, induced by lower body positive pressure (LBPP) are known to influence various physiological systems (i.e., cardiovascular and renal). In earlier experiments, an apparent change in the arousal state of primates in such LBPP conditions was observed. This study was designed to examine the effects of LBPP on arousal state and body temperature level which is normally correlated with sleep. Chair-restrained male squirrel monkeys were exposed to 40 mmHg LBPP for 90-100 minutes between the daytime hours of 13:00-15:00. Each monkey was placed in a specially modified restraint chair to which they were highly trained. Deep body temperature (DBT) was collected from 10 animals. Sleep parameters were obtained from six animals chronically implanted for sleep recording. A video camera was used to observe each animal's apparent state of arousal. LBPP resulted in an approximate 0.9 C decrease in DBT. During video observation, some animals appeared drowsy during LBPP; however, sleep recording revealed no significant changes in the state of arousal. Thus, LBPP is capable of inducing a mild hyperthermia. Further, the mechanisms underlying the observed lowering of body temperature appear to be independent of arousal state.

Edgar, D. M.↗

NASA NTRS1993

Noise levels and their effects on Shuttle crewmembers' performance: Operational concerns

When excessive, noise can result in sleep interference, fatigue, interference with verbal communication, and hearing damage. Shuttle crewmembers are exposed to noise throughout their mission. The contribution of noise to decrements in crew performance over these extended exposure durations was the focus of this study. On the STS-40/SLS-1, mission noise levels were evaluated through the use of a sound level meter and a crew questionnaire. Crewmembers noted that sleep, concentration, and relaxation were negatively impacted by high noise levels. Speech Interference Levels (SIL's), calculated from the sound level measurements, suggested that crewmembers were required to raise their voice in order to be heard. No difficulty detecting caution and warning alarms was noted. The higher than desirable noise levels in Spacelab were attributed to flight specific payloads for which acoustic waivers were granted. It is recommended that current noise levels be reduced in Spacelab and the Orbiter Middeck especially as longer missions are planned for the buildup of Space Station Freedom. Levels of NC 50 are recommended in areas where speech communication is required and NC 40 in sleep areas. These levels are in accordance with the NASA Man-Systems Integration Standards. Measurements proposed for subsequent orbiter missions are discussed.

Koros, Anton S.↗