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NASA NTRS2014

Understanding the Effects of Long-duration Space Flight on Astronant Functional Task Performance

Space flight is known to cause alterations in multiple physiological systems including changes in sensorimotor, cardiovascular, and neuromuscular systems. These physiological changes cause balance, gait and visual disturbances, cardiovascular deconditioning, and loss of muscle mass and strength. These changes may affect a crewmember's ability to perform critical mission tasks immediately after landing on a planetary surface. To understand how changes in physiological function affect functional performance, an interdisciplinary pre- and postflight testing regimen, Functional Task Test (FTT), was developed to systematically evaluate both astronaut functional performance and related physiological changes. Ultimately this information will be used to assess performance risks and inform the design of countermeasures for exploration class missions. We are currently conducting the FTT study on International Space Station (ISS) crewmembers before and after 6-month expeditions. Additionally, in a corresponding study we are using the FTT protocol on subjects before and after 70 days of 6deg head-down bed-rest as an analog for space flight. Bed-rest provides the opportunity for us to investigate the role of prolonged axial body unloading in isolation from the other physiological effects produced by exposure to the microgravity environment of space flight. Therefore, the bed rest analog allows us to investigate the impact of body unloading on both functional tasks and on the underlying physiological factors that lead to decrement in performance and then compare them with the results obtained in our space flight study. Functional tests included ladder climbing, hatch opening, jump down, manual manipulation of objects and tool use, seat egress and obstacle avoidance, recovery from a fall and object translation tasks. Physiological measures included assessments of postural and gait control, dynamic visual acuity, fine motor control, plasma volume, heart rate, blood pressure, orthostatic intolerance, upper- and lower-body muscle strength, power, endurance, control, and neuromuscular drive. ISS crewmembers were tested three times before flight, and on 1, 6, and 30 days after landing. Bed-rest subjects were tested three times before bed-rest and immediately after getting up from bed-rest as well as 1, 6, and 12 days after reambulation.

Bloomberg, Jacob J.↗

NASA NTRS2025

Functional Task Tests in Partial Gravity During Parabolic Flight

BACKGROUND Understanding how critical mission tasks are performed in partial gravity such as on the moon or Mars is necessary to define effective and comprehensive countermeasure strategies for preserving crew performance during exploration missions. We studied the performance of tasks such as standing, balancing, walking, and jumping during the partial gravity phases of parabolic flight. We hypothesized that the acute effects of partial gravity on vestibular, proprioceptive, and sensorimotor functions would negatively impact performance. METHODS Twelve subjects (6F, 6M; 40.2 ± 8.5 years) were tested over three flights of 30 parabolas each, including 10 parabolas at 0.25g, 10 parabolas at 0.5g, and 10 parabolas at 0.75g. Subjects also performed tests in 1g between parabolas. During the seat egress and walk task, subjects rose from a seated position and walked as quickly as possible straight ahead towards a cone (4 m distance), stepped over a 30 cm high obstacle, walked around the cone making a 180° left turn, returned to the chair, and sat down in the chair. Other tasks included a tandem stance on rails, jump down from a 30cm platform, recovery from fall (prone to stand), and limits of stability tasks. Data were collected using inertial measurement units (Opal V2, APDM, Portland, OR) worn on the head and trunk, heart rate monitors (Polar, Finland), and a force plate (Bertec, Columbus, OH). During the jump down and limits of stability tasks, falls were recorded if subjects took extra steps, lifted their heels/toes, or used their arms to recover balance. RESULTS Gravity level had a significant effect on performance, with the greatest changes from 1g tending to be at the 0.25g level (Table 1). Lower gravity levels were associated with increased times to complete the seat egress and walk task and the recovery from fall task, increased head-trunk coordination, decreased tandem stance rail balance times, decreased change in heart rate during the recovery from fall task, and increased cone of stability distance in the anterior-posterior direction. In addition, there were significantly more falls recorded at the lower gravity levels: 31 falls at 0.25g, 14 falls at 0.5g, 6 falls at 0.75g, and 6 falls at 1g. DISCUSSION These data suggest that there is a dose-response relationship between gravity level and functional task performance. The largest changes in performance were expected at the lowest gravity level (0.25g) because subjects would no longer be able to use the gravitational reference for the perception of upright. Understanding the extent of performance deficits informs the risks and design of countermeasures for exploration spaceflight missions.

T R Macaulay↗

NASA NTRS1997

Interaction of central venous pressure, intramuscular pressure, and carotid baroreflex function

Seven healthy volunteer men participated in an experiment involving lower body positive pressure (LBPP) of 30 Torr and acute volume expansions of 5-6% (VE-I) and 9-10% (VE-II) of their total blood volume (TBV) to differentiate the effect of increased intramuscular pressure and central venous pressure (CVP) on the maximal gain (Gmax) of the carotid baroreflex. During each experimental condition, the heart rate (HR), mean arterial pressure (MAP; intraradial artery or Finapres), and CVP (at the 3rd-4th intercostal space) were monitored continuously. Gmax was derived from the logistic modeling of the HR and MAP responses to ramped changes in carotid sinus transmural pressure using a protocol of pulsatile changes in neck chamber pressure from +40 to -65 Torr. The increase in CVP during +30-Torr LBPP was 1.5 mmHg (P < 0.05) and was similar to that observed during VE-I (1.7 mmHg, P > 0.05). The Gmax of the carotid baroreflex of HR and MAP was significantly decreased during LBPP by -0.145 +/- 0.039 beats x min(-1) x mmHg(-1) (38%) and -0.071 +/- 0.013 mmHg/mmHg (25%), respectively; however, VE-I did not affect Gmax. During VE-II, CVP was significantly greater than that elicited by LBPP, and the Gmax of the carotid baroreflex of the HR and MAP responses was significantly reduced. We conclude that carotid baroreflex responsiveness was selectively inhibited by increasing intramuscular pressure, possibly resulting in an activation of the intramuscular mechanoreceptors during LBPP. Furthermore, it would appear that the inhibition of the carotid baroreflex, via cardiopulmonary baroreceptor loading (increased CVP), occurred when a threshold pressure (CVP) was achieved.

NASA Discipline Cardiopulmonary↗

DOE OSTI2016

Towards quantum turbulence in cold atomic fermionic superfluids

Fermionic superfluids provide a new realization of quantum turbulence, accessible to both experiment and theory, yet relevant to phenomena from both cold atoms to nuclear astrophysics. In particular, the strongly interacting Fermi gas realized in cold-atom experiments is closely related to dilute neutron matter in neutron star crusts. Unlike the liquid superfluids 4 He (bosons) and 3 He (fermions), where quantum turbulence has been studied in laboratory for decades, superfluid Fermi gases stand apart for a number of reasons. They admit a rather reliable theoretical description based on density functional theory called the time-dependent superfluid local density approximation that describes both static and dynamic phenomena. Cold atom experiments demonstrate exquisite control over particle number, spin polarization, density, temperature, and interaction strength. Topological defects such as domain walls and quantized vortices, which lie at the heart of quantum turbulence, can be created and manipulated with time-dependent external potentials, and agree with the time-dependent theoretical techniques. While similar experimental and theoretical control exists for weakly interacting Bose gases, the unitary Fermi gas is strongly interacting. The resulting vortex line density is extremely high, and quantum turbulence may thus be realized in small systems where classical turbulence is suppressed. Fermi gases also permit the study of exotic superfluid phenomena such as the Larkin–Ovchinnikov–Fulde–Ferrell pairing mechanism for polarized superfluids which may give rise to 3D supersolids, and a pseudo-gap at finite temperatures that might affect the regime of classical turbulence. The dynamics associated with these phenomena has only started to be explored. Finally, superfluid mixtures have recently been realized, providing experimental access to phenomena like Andreev–Bashkin entrainment predicted decades ago. Superfluid Fermi gases thus provide a rich forum for addressing phenomena related to quantum turbulence with applications ranging from terrestrial superfluidity to astrophysical dynamics in neutron stars.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

DOE OSTI2014

Generalized multipolaron expansion for the spin-boson model: Environmental entanglement and the biased two-state system

We develop a systematic variational coherent state expansion for the many-body ground state of the spin-boson model, in which a quantum two-level system is coupled to a continuum of harmonic oscillators. Energetic constraints at the heart of this technique are rationalized in terms of polarons (displacements of the bath states in agreement with classical expectations) and antipolarons (counter- displacements due to quantum tunneling effects). We present a comprehensive study of the ground state two-level system population and coherence as a function of tunneling amplitude, dissipation strength, and bias (akin to asymmetry of the double well potential defining the two-state system). The entanglement among the different environmental modes is investigated by looking at spectroscopic signatures of the bipartite entanglement entropy between a given environmental mode and all the other modes. We observe a drastic change in behavior of this entropy for increasing dissipation, indicative of the entangled nature of the environmental states. In addition, the entropy spreads over a large energy range at strong dissipation, a testimony to the wide entanglement window characterizing the underlying Kondo state. Lastly, comparisons to accurate numerical renormalization group calculations and to the exact Bethe Ansatz solution of the model demonstrate the rapid convergence of our variationally-optimized multi-polaron expansion, suggesting that it should also be a useful tool for dissipative models of greater complexity, as relevant for numerous systems of interest in quantum physics and chemistry.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

NASA NTRS2001

Marked exacerbation of orthostatic intolerance after long- vs. short-duration spaceflight in veteran astronauts

OBJECTIVE: The incidence of postflight orthostatic intolerance after short-duration spaceflight is about 20%. However, the incidence after long-duration spaceflight was unknown. The purpose of this study was to test the hypothesis that orthostatic intolerance is more severe after long-duration than after short-duration flight. METHODS: We performed tilt tests on six astronauts before and after long-duration (129-190 days) spaceflights and compared these data with data obtained during stand tests before and after previous short-duration missions. RESULTS: Five of the six astronauts studied became presyncopal during tilt testing after long-duration flights. Only one had become presyncopal during stand testing after short-duration flights. We also compared the long-duration flight tilt test data to tilt test data from 20 different astronauts who flew on the short-duration Shuttle missions that delivered and recovered the astronauts to and from the Mir Space Station. Five of these 20 astronauts became presyncopal on landing day. Heart rate responses to tilt were no different between astronauts on long-duration flights and astronauts on short-duration flights, but long-duration subjects had lower stroke volumes and cardiac outputs than short-duration presyncopal subjects, suggesting a possible decrease in cardiac contractile function. One subject had subnormal norepinephrine release with upright posture after the long flight but not after the short flight. Plasma volume losses were not greater after long flights. CONCLUSION: Long-duration spaceflight markedly increases orthostatic intolerance, probably with multiple contributing factors.

STS Shuttle Project↗

NASA NTRS1999

The value of assessing pulmonary venous flow velocity for predicting severity of mitral regurgitation: A quantitative assessment integrating left ventricular function

Although alteration in pulmonary venous flow has been reported to relate to mitral regurgitant severity, it is also known to vary with left ventricular (LV) systolic and diastolic dysfunction. There are few data relating pulmonary venous flow to quantitative indexes of mitral regurgitation (MR). The object of this study was to assess quantitatively the accuracy of pulmonary venous flow for predicting MR severity by using transesophageal echocardiographic measurement in patients with variable LV dysfunction. This study consisted of 73 patients undergoing heart surgery with mild to severe MR. Regurgitant orifice area (ROA), regurgitant stroke volume (RSV), and regurgitant fraction (RF) were obtained by quantitative transesophageal echocardiography and proximal isovelocity surface area. Both left and right upper pulmonary venous flow velocities were recorded and their patterns classified by the ratio of systolic to diastolic velocity: normal (>/=1), blunted (<1), and systolic reversal (<0). Twenty-three percent of patients had discordant patterns between the left and right veins. When the most abnormal patterns either in the left or right vein were used for analysis, the ratio of peak systolic to diastolic flow velocity was negatively correlated with ROA (r = -0.74, P <.001), RSV (r = -0.70, P <.001), and RF (r = -0.66, P <.001) calculated by the Doppler thermodilution method; values were r = -0.70, r = -0.67, and r = -0.57, respectively (all P <.001), for indexes calculated by the proximal isovelocity surface area method. The sensitivity, specificity, and predictive values of the reversed pulmonary venous flow pattern for detecting a large ROA (>0.3 cm(2)) were 69%, 98%, and 97%, respectively. The sensitivity, specificity, and predictive values of the normal pulmonary venous flow pattern for detecting a small ROA (<0.3 cm(2)) were 60%, 96%, and 94%, respectively. However, the blunted pattern had low sensitivity (22%), specificity (61%), and predictive values (30%) for detecting ROA of greater than 0.3 cm(2) with significant overlap with the reversed and normal patterns. Among patients with the blunted pattern, the correlation between the systolic to diastolic velocity ratio was worse in those with LV dysfunction (ejection fraction <50%, r = 0.23, P >.05) than in those with normal LV function (r = -0.57, P <.05). Stepwise linear regression analysis showed that the peak systolic to diastolic velocity ratio was independently correlated with RF (P <.001) and effective stroke volume (P <.01), with a multiple correlation coefficient of 0.71 (P <.001). In conclusion, reversed pulmonary venous flow in systole is a highly specific and reliable marker of moderately severe or severe MR with an ROA greater than 0.3 cm(2), whereas the normal pattern accurately predicts mild to moderate MR. Blunted pulmonary venous flow can be seen in all grades of MR with low predictive value for severity of MR, especially in the presence of LV dysfunction. The blunted pulmonary venous flow pattern must therefore be interpreted cautiously in clinical practice as a marker for severity of MR.

Non-NASA Center↗

NASA NTRSDate not supplied

Functional Task Tests in Partial Gravity During Parabolic Flight

BACKGROUND Critical mission tasks that are required by crews immediately after landing on a planetary surface are seat egress, jump, and walk. To be able to define an effective and comprehensive countermeasure strategy for preserving crew performance during exploration-class missions, there is a need to understand how these functional tasks are actually performed in partial gravity such as on the Moon or Mars. We propose to study the performance in the execution of these tasks during the partial gravity and hypergravity phases of parabolic flight. These tasks will be completed using the same equipment and procedures as the Standard Measures Sensorimotor protocol, which is performed by astronauts returning from spaceflight and by ground-based subjects after prolonged axial body unloading during bed rest. HYPOTHESIS We hypothesize that partial gravity during parabolic flight will cause acute changes in vestibular, proprioceptive, and sensorimotor functions, and these changes will impact the performance of mission critical tasks such as standing, walking, and jumping. The largest changes in performance are expected at the lowest gravity level (0.25g) because subjects will no longer be able to use the gravitational reference for the perception of vertical. Ultimately, this information could be used to assess performance risks and inform the design of countermeasures for NASA exploration-class human missions. METHODS Twelve subjects will be tested during three flights of 30 parabolas, including 10 parabolas at 0.25g, 10 parabolas at 0.5g and 10 parabolas at 0.75g. Subject also will perform tests in 1g between parabolas and in hypergravity (1.8g) during the pull-out phases. Subjects will perform the same tasks as those tested on astronauts returning from spaceflight: sit-to-stand and obstacle walk, tandem walk, jump down, and recovery from fall. Measurements will include: (a) the time for the subject to complete the test (sit-to-stand and obstacle walk, recovery from fall); (b) the time elapsed between the start of motion and the stabilization of upright posture (recovery from fall, jump down); (c) the mean sway speed during quiet standing (recovery from fall, jump down); (d) changes in heart rate and blood pressure (recovery from fall); (e) the percentage of correct steps and torso acceleration (tandem walk); and (f) the severity of motion sickness symptoms. RELEVANCE Although gravitational dose-response curves have been obtained for some biochemical systems in animals, these dose-responses are unknown for most human physiologic systems. Our study will compare the outcomes of 5 functional task tests in 0.25g, 0.5g, 0.75g, 1g, and 1.8g with those previously obtained in ground-based subjects after prolonged axial body unloading and in astronauts immediately after spaceflight. This comparison will help understanding the true extent of functional task performance deficits in partial gravity. The dose-response relationship between gravity level and task performance decrement also will help determining the gravity threshold for these functional tasks. ACKNOWLEDGEMENT This work is supported by the NASA’s Human Research Program Human Health Countermeasures Element

Gilles Clement↗

DOE OSTI2019

Scalable Synthesis of the Transparent Conductive Oxide SrVO 3

The correlated metal SrVO 3 is an attractive earth-abundant transparent conducting oxide (TCO), a critical component of many optoelectronic and renewable energy devices. A key challenge is to synthesize films with low resistivity, due to the prevalence of defects that cause electron scattering. In addition to the material's promise as a TCO, its interesting correlated-electron physics is often obscured by a high defect concentration, which inhibits its further development into new types of devices. A route to synthesize low-defect SrVO 3 films by scalable, industry-compatible molecular beam epitaxy (MBE) is demonstrated. The resulting films consistently exhibit a residual resistivity ratio in the excess of 10 and room temperature resistivity as low as 32 µΩ cm, an indication of their high quality and potential for applications. Analysis of the structural and electronic properties of SrVO 3 films provides insights that are applicable to other conductive oxides, and highlights a route for further improvement in their quality and low temperature performance. MBE is the only growth method that allows atomically abrupt epitaxial interfaces between oxides and semiconductors such as Si and GaAs. Such interfaces are essential for efficient charge transport that is at the heart of the performance of most optoelectronic and solar devices.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

NASA NTRS1975

Elastic modulus of the human intact left ventricle - Determination and physiological interpretation

The left ventricle (l.v.) is represented as a shell of muscle whose performance is characterized in terms of the chamber pressure and stress/strain in the ventricular wall; the effective elastic modulus of the l.v. relates these performance variables, and hence represents the transfer function of the left ventricular physiological system. A method is presented for indirectly determining the effective modulus E for the left ventricle. The method employs a thick-walled mathematical model of the l.v. having a homogeneous isotropic medium. Instantaneous values of E are determined for subjects with heart diseases of varied etiologies, in order to assess the responses of the l.v. to chronic overloads of pressure and volume. Resulting values for E are used diagnostically to characterize the physiological state of the l.v. Normal values of E, at systole, indicate that the strength of contraction exercised by the l.v. is normal, and hence is an indication of the l.v. having adjusted to the heart disease.

Ghista, D. N.↗

NASA NTRS1992

Left ventricular dimensions and mass using magnetic resonance imaging in female endurance athletes

Few published studies of left ventricular (LV) mass in female endurance athletes have been performed with M-mode echocardiography, which involves assumptions of LV geometry. Therefore, magnetic resonance imaging, a 3-dimensional technique, was used to examine LV mass, LV end-diastolic volume and mean wall thickness in female long distance runners (n = 13; mean age 29 years), cyclists (n = 12; mean age 26 years) and cross-country skiers (n = 11; mean age 24 years), and the findings were compared with sedentary control subjects (n = 10; mean age 27 years) matched for height and body weight. The physical characteristics for all subjects included height (mean 166 cm, and body weight (mean 56 kg). The percent body fat (mean 11.7) and maximal oxygen uptake (VO2max, mean 63 ml.kg-1.min-1) were similar (p greater than 0.05) among all athletic groups, but significantly different from the control group (body fat, mean 22.5%; VO2max, mean 35 ml.kg-1.min-1). LV mass (mean 159 kg), LV end-diastolic volume (mean 122 ml), and mean wall thickness (mean 11.5 mm) were also similar among the athletic groups and significantly larger than the following control values: LV mass (mean 115 g), LV end-diastolic volume (mean 93 ml) and mean wall thickness (mean 9.8 mm). Ratios of LV mass to lean body weight were similar among all athletic groups, although athletic groups had larger ratios (p less than 0.05) than the sedentary control subjects. LV mass/LV end-diastolic volume ratio was similar (p greater than 0.05) among all groups.(ABSTRACT TRUNCATED AT 250 WORDS).

NASA Discipline Cardiopulmonary↗

NASA NTRSDate not supplied

Functional Task Tests in Partial Gravity During Parabolic Flight

BACKGROUND Critical mission tasks required by crews immediately after landing on a planetary surface include walking, jumping, and egressing from a seat. Understanding how these functional tasks are performed in partial gravity such as on the moon or Mars is necessary to define effective and comprehensive countermeasure strategies for preserving crew performance during exploration-class missions. We propose to study the performance of these tasks during the partial gravity phases of parabolic flight. These tasks will be performed using the same equipment and procedures as those used with astronauts returning from spaceflight and with ground-based subjects after prolonged axial body unloading during bed rest (sensorimotor standard measures). HYPOTHESIS We hypothesize that partial gravity during parabolic flight will cause acute changes in vestibular, proprioceptive, and sensorimotor functions, and these changes will impact the performance of mission critical tasks such as standing, walking, and jumping. The largest changes in performance are expected at the lowest gravity level (0.25g) because subjects will no longer be able to use the gravitational reference for the perception of upright. Ultimately, this information could be used to assess performance risks and inform the design of countermeasures for NASA exploration-class human missions. METHODS Twelve subjects will be tested during three flights of 30 parabolas, including 10 parabolas at 0.25g, 10 parabolas at 0.5g, and 10 parabolas at 0.75g. Subjects also will perform tests in 1g between parabolas. The tasks will be the same as those tested on astronauts returning from spaceflight: sit-to-stand with obstacle walk, tandem rail balance, jump down, and recovery from fall. Measurements will include: (a) time to test completion (sit-to-stand with obstacle walk, recovery from fall); (b) time elapsed between the start of motion and the stabilization of upright posture (recovery from fall, jump down); (c) mean sway speed during quiet standing (recovery from fall, jump down); (d) changes in heart rate and blood pressure (recovery from fall); (e) balance time and torso accelerations (tandem rail balance); (f) cone of stability (jump down); and (g) severity of motion sickness symptoms. RELEVANCE Although gravitational dose-response curves have been obtained for some biochemical systems in animals, these dose-responses are unknown for most human physiologic systems. Our study will compare the outcomes of four functional task tests in 0.25g, 0.5g, 0.75g, and 1g with those previously obtained in ground-based subjects after prolonged axial body unloading and in astronauts immediately after spaceflight. These comparisons will help us understand the true extent of functional task performance deficits in partial gravity. The dose-response relationship between gravity level and task performance decrement also will help determining the gravity threshold for these functional tasks. ACKNOWLEDGEMENT This work is supported by the NASA’s Human Research Program Human Health Countermeasures Element.

T. R. Macaulay↗

DOE OSTI2013

Assessment of cisplatin-induced kidney injury using an integrated rodent platform

Current diagnosis of drug-induced kidney injury (DIKI) primarily relies on detection of elevated plasma creatinine (Cr) or blood urea nitrogen (BUN) levels; however, both are indices of overall kidney function and changes are delayed with respect to onset of nephron injury. Our aim was to investigate whether early changes in new urinary DIKI biomarkers predict plasma Cr, BUN, renal hemodynamic and kidney morphological changes associated with kidney injury following a single dose of cisplatin (CDDP) using an integrated platform in rodent. Conscious surgically prepared male Han Wistar rats were given a single intraperitoneal dose of CDDP (15 mg/kg). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), urinalysis, DIKI biomarkers, CDDP pharmacokinetics, blood pressures, heart rate, body temperature and electroencephalogram (EEG) were measured in the same vehicle- or CDDP-treated animals over 72 h. Plasma chemistry (including Cr and BUN) and renal tissues were examined at study termination. Cisplatin caused progressive reductions of GFR, ERPF, heart rate and body temperature from day 1 (0–24 h). DIKI biomarkers including alpha-glutathione S-transferase (α-GST) significantly increased as early as 6 h post-dose, which preceded significant declines of GFR and ERPF (24 h), increased plasma Cr and BUN (72 h), and associated with renal acute tubular necrosis at 72 h post-dose. The present study adds to the current understanding of CDDP action by demonstrating that early increases in urinary excretion of α-GST predict DIKI risk following acute exposure to CDDP in rats, before changes in traditional DIKI markers are evident. - Highlights: ► CDDP causes direct damage to kidneys without affecting EEG or CVS function. ► α-GST and albumin detect DIKI earlier when compared with traditional indices. ► Integrated “cardiovascular-EEG-renal” model to better understand DIKI mechanisms ► Promotes 3R's principles in drug discovery and development.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions

Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca 2+ , 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) β-adrenergic (β-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca 2+ increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca 2+ and passive lengthening can shift mavacamten-ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dt max , an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that β-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

Direct detection of SERCA calcium transport and small-molecule inhibition in giant unilamellar vesicles

We have developed a charge-mediated fusion method to reconstitute the sarco/endoplasmic reticulum Ca{sup 2+}-ATPase (SERCA) in giant unilamellar vesicles (GUV). Intracellular Ca{sup 2+} transport by SERCA controls key processes in human cells such as proliferation, signaling, and contraction. Small-molecule effectors of SERCA are urgently needed as therapeutics for Ca{sup 2+} dysregulation in human diseases including cancer, diabetes, and heart failure. Here we report the development of a method for efficiently reconstituting SERCA in GUV, and we describe a streamlined protocol based on optimized parameters (e.g., lipid components, SERCA preparation, and activity assay requirements). ATP-dependent Ca{sup 2+} transport by SERCA in single GUV was detected directly using confocal fluorescence microscopy with the Ca{sup 2+} indicator Fluo-5F. The GUV reconstitution system was validated for functional screening of Ca{sup 2+} transport using thapsigargin (TG), a small-molecule inhibitor of SERCA currently in clinical trials as a prostate cancer prodrug. The GUV system overcomes the problem of inhibitory Ca{sup 2+} accumulation for SERCA in native and reconstituted small unilamellar vesicles (SUV). We propose that charge-mediated fusion provides a widely-applicable method for GUV reconstitution of clinically-important membrane transport proteins. We conclude that GUV reconstitution is a technological advancement for evaluating small-molecule effectors of SERCA.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1984

Large-scale coherent structure and far-field jet noise

The phenomenon of broadband noise amplification/suppression under controlled excitation is investigated. The suppression is found to occur only at low jet speeds when the exit boundary layer is laminar; excitation at a Strouhal St(theta) number of about 0.017 results in optimum suppression of the far-field broadband noise as well as of the near-flow-field turbulence. The noise amplification is found to be a function of the Mach number, the amplification is higher at higher Mach number for a given excitation Strouhal number and level. The amplification also depends on the Strouhal number (St D), the maximum occurring in the range 0.65-0.85. Vortex pairing induced by the excitation appears to be at the heart of the noise amplification phenomenon under excitation.

Zaman, K. B. M. Q.↗

NASA NTRS1989

Beat to beat variability in cardiovascular variables: noise or music?

Cardiovascular variables such as heart rate, arterial blood pressure, stroke volume and the shape of electrocardiographic complexes all fluctuate on a beat to beat basis. These fluctuations have traditionally been ignored or, at best, treated as noise to be averaged out. The variability in cardiovascular signals reflects the homeodynamic interplay between perturbations to cardiovascular function and the dynamic response of the cardiovascular regulatory systems. Modern signal processing techniques provide a means of analyzing beat to beat fluctuations in cardiovascular signals, so as to permit a quantitative, noninvasive or minimally invasive method of assessing closed loop hemodynamic regulation and cardiac electrical stability. This method promises to provide a new approach to the clinical diagnosis and management of alterations in cardiovascular regulation and stability.

Non-NASA Center↗

NASA NTRS2015

Initial Sensorimotor and Cardiovascular Data Acquired from Soyuz Landings: Establishing a Functional Performance Recovery Time Constant

INTRODUCTION Testing of crew responses following long-duration flights has not been previously possible until a minimum of more than 24 hours after landing. As a result, it has not been possible to determine the trend of the early recovery process, nor has it been possible to accurately assess the full impact of the decrements associated with long-duration flight. To overcome these limitations, both the Russian and U.S. programs have implemented joint testing at the Soyuz landing site. This International Space Station research effort has been identified as the functional Field Test, and represents data collect on NASA, Russian, European Space Agency, and Japanese Aerospace Exploration Agency crews. RESEARCH The primary goal of this research is to determine functional abilities associated with long-duration space flight crews beginning as soon after landing as possible on the day of landing (typically within 1 to 1.5 hours). This goal has both sensorimotor and cardiovascular elements. To date, a total of 15 subjects have participated in a 'pilot' version of the full 'field test'. The full version of the 'field test' will assess functional sensorimotor measurements included hand/eye coordination, standing from a seated position (sit-to-stand), walking normally without falling, measurement of dynamic visual acuity, discriminating different forces generated with the hands (both strength and ability to judge just noticeable differences of force), standing from a prone position, coordinated walking involving tandem heel-to-toe placement (tested with eyes both closed and open), walking normally while avoiding obstacles of differing heights, and determining postural ataxia while standing (measurement of quiet stance). Sensorimotor performance has been obtained using video records, and data from body worn inertial sensors. The cardiovascular portion of the investigation has measured blood pressure and heart rate during a timed stand test in conjunction with postural ataxia testing (quiet stance sway) as well as cardiovascular responses during sensorimotor testing on all of the above measures. We have also collected motion sickness data associated with each of the postflight tests. When possible rudimentary cerebellar assessment was undertaken. In addition to the immediate post-landing collection of data, postflight data has been acquired twice more within 24 hours after landing and measurements continue until sensorimotor and cardiovascular responses have returned to preflight normative values (approximately 60 days postflight). SUMMARY The level of functional deficit observed in the crew tested to date is more severe than expected, clearly triggered by the acquisition of gravity loads immediately after landing when the demands for crew intervention in response to emergency operations will be greatest. Measureable performance parameters such as ability to perform a seat egress, recover from a fall or the ability to see clearly when walking, and related physiologic data (orthostatic responses) are required to provide an evidence base for characterizing programmatic risks and the degree of variability among crewmembers for exploration missions where the crew will be unassisted after landing. Overall, these early functional and related physiologic measurements will allow the estimation of nonlinear sensorimotor and cardiovascular recovery trends that have not been previously captured.

Reschke, M. F.↗