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At least 127 records · Page 7

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NASA NTRS2017

The Effects of CDKN1a/p21 on Oxidative Stress and Mitochondrial Function During Long Duration Spaceflight

Broad tissue degeneration and the failure of normal tissue regenerative processes in microgravity because of mechanical unloading are increasing concerns for sustaining life in space as the duration of future flight missions increases. Work in our laboratory has identified normal adult stem cell-based tissue regenerative processes, such as the formation of new bone, cartilage, and immune cells, as being particularly sensitive to the stresses of mechanical unloading in microgravity. Our studies have also identified the inhibition of differentiation of marrow mesenchymal stem cells and activation of CDKN1ap21-mediated cell cycle arrest in proliferative osteoprecursor cells on the bone surface as potential mechanisms for spaceflight-induced skeletal changes. This finding, in combination with the role of CDKN1ap21 as a suppressor of mammalian tissue regeneration, suggests that this gene could be responsible for suppressing stem cell-based tissue regeneration in response to disuse. In this work, we hypothesized that CDKN1ap21 regulates regenerative bone formation in response to alterations in mechanical load and tested this hypothesis by studying the skeletal phenotype and stem cell regenerative ability of juvenile (4-11 weeks old) and adult (18 weeks-12 months old) p21 (--) knockout (KO) mice. Additionally, we analyzed bone micro-architectural properties, bone formation rates and differentiation capacity of bone marrow stem cells (BMSCs) from male and female KO mice exposed to hindlimb unloading (HU) for 15-30 days. We found that juvenile KO mice exhibited increased femoral trabecular and cortical bone formation, whilst three-point bending of the tibias from KO mice showed decreased bone stiffness. Conversely, adult KO mice exhibited no significant differences in micro-architectural properties compared to WT (wild-type) but woven bone structure was indicative of rapid bone remodeling. Furthermore, cortical bone properties showed similar characteristics to aged bone, including increased cross-sectional area and perimeter, whilst three-point bending showed increased stiffness and toughness. Interestingly, in-vitro, KO mice exhibited increased differentiation and mineralized nodule formation in osteoblastogenesis assays compared to WT. Preliminary results from CDKN1ap21 KO mice subjected to HU suggest altered sensitivity to mechanical unloading resulting in decreased cortical thickness compared to WT mice. However, KO mice subjected to short and long-duration HU show increased in-vitro differentiation potential of BMSCs to from form mature, mineral-forming osteoblasts, indicating maintenance of regenerative potential. Analysis of bone formation rates, cell proliferation rates and key genes of interest are currently underway. These results indicate a novel role for CDKN1ap21 in load-dependent osteoprogenitor proliferation and differentiation and that deletion of CDKN1ap21 results in an age-dependent release of osteoblast proliferation inhibition and increased bone formation and turnover.

Stem Cells↗

NASA NTRS2020

Urban Air Mobility Noise: Current Practice, Gaps, and Recommendations

In 2018, NASA formed an Urban Air Mobility Noise Working Group to assemble noise experts from industry, universities and government agencies to identify, discuss, and address urban air mobility (UAM) noise issues. This paper presents a set of high-level goals intended to address barriers associated with UAM noise that may hamper their entry into service. It summarizes the current practice, identifies gaps in the current practice, and makes recommendations to address the gaps to achieve the high-level goals in four areas of interest: Tools and Technologies, Ground and Flight Testing, Human Response and Metrics, and Regulation and Policy.

urban air mobility↗

NASA NTRS1980

Renal responses to central vascular expansion are suppressed at night in conscious primates

The renal and hemodynamic responses of squirrel monkeys to central vascular volume expansion induced by lower body positive pressure (LBPP) during the day and night are investigated. Twelve unanesthetized animals trained to sit in a metabolism chair in which they were restrained only at the waist by a partition separating upper and lower body chambers were subjected to 4 h of continuous LBPP during the day and night, and hemodynamic, urinary and drinking data were monitored. LBPP during day and night is found to induce similar increases in central venous pressure, rises in heart rate and elevations in mean arterial blood pressure. However, although daytime LBPP induced a significant increase in urine flow and sodium excretion, a marked nocturnal inhibition of the renal response to LBPP is observed. Analysis of the time course and circadian regulation patterns of the urinary responses suggests that several separate efferent control pathways are involved.

Kass, D. A.↗

NASA NTRSDate not supplied

Activities of the NASA Urban Air Mobility Noise Working Group (UNWG)

The NASA-led Urban Air Mobility Noise Working Group was established in 2018 following an exploratory meeting of stakeholders from traditional and emerging aviation sectors across industry, government agencies, academia, and community groups. Its mission is to create and support a diverse community of acoustics experts to identify, discuss, and address noise issues associated with UAM vehicles and their operations. The UNWG is comprised of four subgroups including Tools and Technologies, Ground and Flight Testing, Human Response and Metrics, and Regulation and Policy. In 2020, NASA published the white paper entitled “Urban Air Mobility Noise: Current Practice, Gaps, and Recommendations,” that presents a set of high-level goals and makes recommendations to address gaps in the current practice. This presentation is about recent activities of each of the subgroups to address those recommendations, including work towards establishment of an aeroacoustic test database for model validation, development of a set of measurement guidelines to quantify vehicle acoustic emission, a remotely administered human response study for quantifying annoyance to UAM operations, and status on noise standard, regulation, policy, and community engagement developments.

Urban air mobility↗

NASA NTRS2002

Evidence for vestibular regulation of autonomic functions in a mouse genetic model

Physiological responses to changes in the gravitational field and body position, as well as symptoms of patients with anxiety-related disorders, have indicated an interrelationship between vestibular function and stress responses. However, the relative significance of cochlear and vestibular information in autonomic regulation remains unresolved because of the difficulties in distinguishing the relative contributions of other proprioceptive and interoceptive inputs, including vagal and somatic information. To investigate the role of cochlear and vestibular function in central and physiological responses, we have examined the effects of increased gravity in wild-type mice and mice lacking the POU homeodomain transcription factor Brn-3.1 (Brn-3bPou4f3). The only known phenotype of the Brn-3.1(-/-) mouse is related to hearing and balance functions, owing to the failure of cochlear and vestibular hair cells to differentiate properly. Here, we show that normal physiological responses to increased gravity (2G exposure), such as a dramatic drop in body temperature and concomitant circadian adjustment, were completely absent in Brn-3.1(-/-) mice. In line with the lack of autonomic responses, the massive increase in neuronal activity after 2G exposure normally detected in wild-type mice was virtually abolished in Brn-3.1(-/-) mice. Our results suggest that cochlear and vestibular hair cells are the primary regulators of autonomic responses to altered gravity and provide genetic evidence that these cells are sufficient to alter neural activity in regions involved in autonomic and neuroendocrine control.

Non-NASA Center↗

NASA NTRS1991

Effect of space flight on interferon production - mechanistic studies

Ground-based models were studied for the effects of space flight on immune responses. Most time was spent on the model for the antiorthostatic, hypokinetic, hypodynamic suspension model for rats. Results indicate that suspension is useful for modeling the effects of spaceflight on functional immune responses, such as interferon and interleukin production. It does not appear to be useful for modeling shifts in leukocyte sub-populations. Calcium and 1,25-dihydroxyvitamin D sub 3 appear to play a pivitol role in regulating shifts in immune responses due to suspension. The macrophage appears to be an important target cell for the effects of suspension on immune responses.

Sonnenfeld, Gerald↗

NASA NTRSDate not supplied

Dose-Response Data Collection Preparation for the NASA Quesst Mission With the X-59

Supersonic flight has the potential to cut travel times in half; however, community annoyance to sonic booms led to the ban on overland commercial supersonic flight by the Federal Aviation Administration in 1973. As part of its Quesst mission, NASA is developing the X-59 aircraft to demonstrate quiet supersonic flight and collect dose-response data to inform regulators in their efforts to establish noise standards to replace the current supersonic speed limit. This talk presents an overview of the NASA Quesst mission and poses some challenges in collecting and analyzing X-59 dose-response data. For the upcoming community flight campaign, the noise dose is the loudness of a supersonic overflight of the X-59 and the perceptual response from participants is captured via surveys after the flyover events. Establishing a relationship between noise dose and perceptual response will be a key product of these efforts.

X-59↗

NASA NTRS1998

Molecular regulation of plant cell wall extensibility

Gravity responses in plants often involve spatial and temporal changes in cell growth, which is regulated primarily by controlling the ability of the cell wall to extend. The wall is thought to be a cellulose-hemicellulose network embedded in a hydrated matrix of complex polysaccharides and a small amount of structural protein. The wall extends by a form of polymer creep, which is mediated by expansins, a novel group of wall-loosening proteins. Expansins were discovered during a molecular dissection of the "acid growth" behavior of cell walls. Expansin alters the rheology of plant walls in profound ways, yet its molecular mechanism of action is still uncertain. It lacks detectable hydrolytic activity against the major components of the wall, but it is able to disrupt noncovalent adhesion between wall polysaccharides. The discovery of a second family of expansins (beta-expansins) sheds light on the biological role of a major group of pollen allergens and implies that expansins have evolved for diverse developmental functions. Finally, the contribution of other processes to wall extensibility is briefly summarized.

Review↗

NASA NTRS2000

Developmental regulation of collagenase-3 mRNA in normal, differentiating osteoblasts through the activator protein-1 and the runt domain binding sites

Collagenase-3 mRNA is initially detectable when osteoblasts cease proliferation, increasing during differentiation and mineralization. We showed that this developmental expression is due to an increase in collagenase-3 gene transcription. Mutation of either the activator protein-1 or the runt domain binding site decreased collagenase-3 promoter activity, demonstrating that these sites are responsible for collagenase-3 gene transcription. The activator protein-1 and runt domain binding sites bind members of the activator protein-1 and core-binding factor family of transcription factors, respectively. We identified core-binding factor a1 binding to the runt domain binding site and JunD in addition to a Fos-related antigen binding to the activator protein-1 site. Overexpression of both c-Fos and c-Jun in osteoblasts or core-binding factor a1 increased collagenase-3 promoter activity. Furthermore, overexpression of c-Fos, c-Jun, and core-binding factor a1 synergistically increased collagenase-3 promoter activity. Mutation of either the activator protein-1 or the runt domain binding site resulted in the inability of c-Fos and c-Jun or core-binding factor a1 to increase collagenase-3 promoter activity, suggesting that there is cooperative interaction between the sites and the proteins. Overexpression of Fra-2 and JunD repressed core-binding factor a1-induced collagenase-3 promoter activity. Our results suggest that members of the activator protein-1 and core-binding factor families, binding to the activator protein-1 and runt domain binding sites are responsible for the developmental regulation of collagenase-3 gene expression in osteoblasts.

NASA Discipline Musculoskeletal↗

NASA NTRSDate not supplied

Immunological Consequences of the Spaceflight Environment on Macrophage Function

The role of macrophages in the protection of multicellular organisms is critical and multifaceted.Regulation of macrophage populations and functions is key to maintaining tissue home ostasis and a healthy organism. As the bridge between the innate and adaptive immune systems, macrophages patrol every tissue in the body and show remarkable heterogeneity. Primarily, macrophages phagocytose harmful pathogens and release cytokines to regulate pro-inflammatory responses to infections and anti-inflammatory responses for wound healing. Prior research has demonstrated that spaceflight conditions, including microgravity and deep space radiation, have a detrimental effect on macrophage populations and functions. However, tissue-specific and individual spaceflight stressor-specific effects remain to be untangled. Furthermore, prior research into the effects of spaceflight on macrophages lacks experimental standardization, creating difficulty in reconciling disparate studies. Finally, due to their presence in various human tissues, easy accessibility in the bloodstream, and fast responses to immune status and spaceflight, macrophages present a unique opportunity for developing new diagnostic tools for spaceflight applications. Therefore, further targeted research on macrophage functions may support astronaut health in long-duration crewed space missions, both within and beyond lowEarth orbit. Here we present a review that summarizes previous findings on macrophagedys regulation in spaceflight, details key areas for further research and investment, and recommends potential investigations into spaceflight dysfunctions, diagnostics, and countermeasures.

immunology↗

NASA NTRS1999

Developmental Regulation of the Collagenase-3 Promoter in Osteoblasts

Previously, we have shown that collagenase-3 MRNA is developmentally expressed in normal, differentiating rat osteoblasts. In vivo, the gene is expressed in a tissue-specific fashion in hypertrophic chondrocytes and osteoblasts and developmentally regulated. Our studies aim at determining the promoter elements and proteins binding to the promoter responsible for tissue and developmental regulation of collagenase-3.

Partridge, N. C.↗

NASA NTRS2003

Neural Control of the Cardiovascular System in Space

During the acute transition from lying supine to standing upright, a large volume of blood suddenly moves from the chest into the legs. To prevent fainting, the blood pressure control system senses this change immediately, and rapidly adjusts flow (by increasing heart rate) and resistance to flow (by constricting the blood vessels) to restore blood pressure and maintain brain blood flow. If this system is inadequate, the brain has a backup plan. Blood vessels in the brain can adjust their diameter to keep blood flow constant. If blood pressure drops, the brain blood vessels dilate; if blood pressure increases, the brain blood vessels constrict. This process, which is called autoregulation, allows the brain to maintain a steady stream of oxygen, even when blood pressure changes. We examined what changes in the blood pressure control system or cerebral autoregulation contribute to the blood pressure control problems seen after spaceflight. We asked: (1) does the adaptation to spaceflight cause an adaptation in the blood pressure control system that impairs the ability of the system to constrict blood vessels on return to Earth?; (2) if such a defect exists, could we pinpoint the neural pathways involved?; and (3) does cerebral autoregulation become abnormal during spaceflight, impairing the body s ability to maintain constant brain blood flow when standing upright on Earth? We stressed the blood pressure control system using lower body negative pressure, upright tilt, handgrip exercise, and cold stimulation of the hand. Standard cardiovascular parameters were measured along with sympathetic nerve activity (the nerve activity causing blood vessels to constrict) and brain blood flow. We confirmed that the primary cardiovascular effect of spaceflight was a postflight reduction in upright stroke volume (the amount of blood the heart pumps per beat). Heart rate increased appropriately for the reduction in stroke volume, thereby showing that changes in heart rate regulation alone cannot be responsible for orthostatic hypotension after spaceflight. All of the astronauts in our study had an increase in sympathetic nerve activity during upright tilting on Earth postflight. This increase was well calibrated for the reduction in stroke volume induced by the upright posture. The results obtained from stimulating the sympathetic nervous system using handgrip exercise or cold stress were also entirely normal during and after spaceflight. No astronaut had reduced cerebral blood flow during upright tilt, and cerebral autoregulation was normal or even enhanced inflight. These experiments show that the cardiovascular adaptation to spaceflight does not lead to a defect in the regulation of blood vessel constriction via sympathetic nerve activity. In addition, cerebral autoregulation is well-maintained. It is possible that despite the increased sympathetic nerve activity, blood vessels did not respond with a greater degree of constriction than occurred preflight, possibly uncovering a limit of vasoconstrictor reserve.

Levine, Benjamin D.↗

NASA NTRS2002

Shear stress stimulates phosphorylation of eNOS at Ser(635) by a protein kinase A-dependent mechanism

Shear stress stimulates nitric oxide (NO) production by phosphorylating endothelial NO synthase (eNOS) at Ser(1179) in a phosphoinositide-3-kinase (PI3K)- and protein kinase A (PKA)-dependent manner. The eNOS has additional potential phosphorylation sites, including Ser(116), Thr(497), and Ser(635). Here, we studied these potential phosphorylation sites in response to shear, vascular endothelial growth factor (VEGF), and 8-bromocAMP (8-BRcAMP) in bovine aortic endothelial cells (BAEC). All three stimuli induced phosphorylation of eNOS at Ser(635), which was consistently slower than that at Ser(1179). Thr(497) was rapidly dephosphorylated by 8-BRcAMP but not by shear and VEGF. None of the stimuli phosphorylated Ser(116). Whereas shear-stimulated Ser(635) phosphorylation was not affected by phosphoinositide-3-kinase inhibitors wortmannin and LY-294002, it was blocked by either treating the cells with a PKA inhibitor H89 or infecting them with a recombinant adenovirus-expressing PKA inhibitor. These results suggest that shear stress stimulates eNOS by two different mechanisms: 1) PKA- and PI3K-dependent and 2) PKA-dependent but PI3K-independent pathways. Phosphorylation of Ser(635) may play an important role in chronic regulation of eNOS in response to mechanical and humoral stimuli.

Non-NASA Center↗

NASA NTRS1975

Test procedures and performance measures sensitive to automobile steering dynamics

A maneuver complex and related performance measures used to evaluate driver/vehicle system responses as effected by variations in the directional response characteristics of passenger cars are described. The complex consists of normal and emergency maneuvers (including random and discrete disturbances) which, taken as a whole, represent all classes of steering functions and all modes of driver response behavior. Measures of driver/vehicle system response and performance in regulation tasks included direct describing function measurements and rms yaw velocity. In transient maneuvers, measures such as steering activity and cone strikes were used.

Klein, R. H.↗

NASA NTRS1979

Potential for cogeneration of heat and electricity in California industry, phase 2

The nontechnical issues of industrial cogeneration for 12 California firms were analyzed under three categories of institutional settings: (1) industrial ownership without firm sales of power; (2) industrial ownership with firm sales of power; and (3) utility or third party ownership. Institutional issues were analyzed from the independent viewpoints of the primary parties of interest: the industrial firms, the electric utilities and the California Public utilities Commission. Air quality regulations and the agencies responsible for their promulgation were examined, and a life cycle costing model was used to evaluate the economic merits of representative conceptual cogeneration systems at these sites. Specific recommendations were made for mitigating measures and regulatory action relevant to industrial cogeneration in California.

Davis, H. S.↗

NASA NTRS1982

Overheat Prevention in Solar-Powered Stirling Engines

Proposed controller for solar-powered Stirling engine prevents engine from burning up when energy added by Sun exceeds that withdrawn by load. Head-temperature controller used existing electrical control unit of Stirling engine to regulate power output in response to head temperature. Power out-put is varied so keeps head temperature fairly constant.

Garrigus, W. E.↗

NASA NTRS1982

Improving Power-Supply Regulation for Pulsed Loads

Power supply voltage-regulator circuit speeds up response to sudden load changes. As load increases, additional feedback path is enabled. Path bypasses and provides faster loop response than normal feedback path. Steady-state instability due to faster loop response avoided by progressively disabling bypass loop and allowing normal feedback path to take over.

Gulick, C. R.↗

NASA NTRS1984

Decoupled control analysis of a large flexible space antenna with linear quadratic regulator comparisons

A decoupled-control analysis was performed for a large flexible space antenna. Control involved commanding changes in the rigid-body modes or nulling disturbances in the flexible modes. The study provides parametric-type data which could be useful in the final design of a large space antenna control system. Results are presented to illustrate the effect on control requirements of (1) the number of modes controlled; (2) the number, type, and location of control actuators; and (3) variations in the closed-loop dynamics of the control system. Comparisons are given between the decoupled-control results and those obtained by using a linear quadratic regulator approach. Time history responses are presented to illustrate the effects of the control procedures.

Young, J. W.↗