High Intensity Resistive and Rowing Exercise Countermeasures Do Not Prevent Orthostatic Intolerance Following 70 Days of Bed Rest

More than 60% of US astronauts participating in Mir and early International Space Station missions (greater than 5 months) were unable to complete a 10min 80 deg headup tilt test on landing day. This high incidence of postspaceflight orthostatic intolerance may be related to limitations of the inflight exercise hardware that prevented high intensity training. PURPOSE: This study sought to determine if a countermeasure program that included intense lowerbody resistive and rowing exercises designed to prevent cardiovascular and musculoskeletal deconditioning during 70 days of 6 deg head-down tilt bed rest (BR), a spaceflight analog, also would protect against post BR orthostatic intolerance. METHODS: Sixteen males participated in this study and performed no exercise (Control, n=10) or performed an intense supine exercise protocol with resistive and aerobic components (Exercise, n=6). On 3 days/week, exercise subjects performed lower body resistive exercise and a 30min continuous bout of rowing (greater than or equal to 75% max heart rate). On 3 other days/week, subjects performed only highintensity, intervalstyle rowing. Orthostatic intolerance was assessed using a 15min 80 deg headup tilt test performed 2 days (BR2) before and on the last day of BR (BR70). Plasma volume was measured using a carbon monoxide rebreathing technique on BR3 and before rising on the first recovery day (BR+0). RESULTS: Following 70 days of BR, tilt tolerance time decreased significantly in both the Control (BR2: 15.0 +/- 0.0, BR70: 9.9 +/- 4.6 min, mean +/- SD) and Exercise (BR2: 12.2 +/- 4.7, BR70: 4.9 +/- 1.9 min) subjects, but the decreased tilt tolerance time was not different between groups (Control: 34 +/- 31, Exercise: 56 +/- 16%). Plasma volume also decreased (Control: 0.56 +/- 0.40, Exercise: 0.48 +/- 0.33 L) from pre to postBR, with no differences between groups (Control: 18 +/- 11%, Exerciser: 15 +/-1 0%). CONCLUSIONS: These findings confirm previous reports in shorter BR studies that the performance of an exercise countermeasure protocol by itself during BR does not prevent orthostatic intolerance or plasma volume loss. This suggests that protection against orthostatic intolerance in astronauts following longduration spaceflight will require an additional intervention, such as periodic orthostatic stress, fluid repletion, and/or lowerbody compression garments

NEXT Single String Integration Test Results

As a critical part of NASA's Evolutionary Xenon Thruster (NEXT) test validation process, a single string integration test was performed on the NEXT ion propulsion system. The objectives of this test were to verify that an integrated system of major NEXT ion propulsion system elements meets project requirements, to demonstrate that the integrated system is functional across the entire power processor and xenon propellant management system input ranges, and to demonstrate to potential users that the NEXT propulsion system is ready for transition to flight. Propulsion system elements included in this system integration test were an engineering model ion thruster, an engineering model propellant management system, an engineering model power processor unit, and a digital control interface unit simulator that acted as a test console. Project requirements that were verified during this system integration test included individual element requirements ; integrated system requirements, and fault handling. This paper will present the results of these tests, which include: integrated ion propulsion system demonstrations of performance, functionality and fault handling; a thruster re-performance acceptance test to establish baseline performance: a risk-reduction PMS-thruster integration test: and propellant management system calibration checks

High Intensity Exercise Countermeasures does not Prevent Orthostatic Intolerance Following Prolonged Bed Rest

Approximately 20% of Space Shuttle astronauts became presyncopal during operational stand and 80deg headup tilt tests, and the prevalence of orthostatic intolerance increases after longer missions. Greater than 60% of the US astronauts participating in Mir and early International Space Station missions experienced presyncope during postflight tilt tests, perhaps related to limitations of the exercise hardware that prevented high intensity exercise training until later ISS missions. The objective of this study was to determine whether an intense resistive and aerobic exercise countermeasure program designed to prevent cardiovascular and musculoskeletal deconditioning during 70 d of bed rest (BR), a space flight analog, would protect against postBR orthostatic intolerance. METHODS Twentysix subjects were randomly assigned to one of three groups: nonexercise controls (n=11) or one of two exercise groups (ExA, n=8; ExB, n=7). Both ExA and ExB groups performed the same resistive and aerobic exercise countermeasures during BR, but one exercise group received testosterone supplementation while the other received a placebo during BR in a doubleblinded fashion. On 3 d/wk, subjects performed lower body resistive exercise and 30 min of continuous aerobic exercise (75% max heart rate). On the other 3 d/wk, subjects performed only highintensity, intervalstyle aerobic exercise. Orthostatic intolerance was assessed using a 15min 80 headup tilt test performed 2 d (BR2) before and on the last day of BR (BR70). Plasma volume was measured using carbon monoxide rebreathing on BR3 and before rising on the first recovery day (BR+0). The code for the exercise groups has not been broken, and results are reported here without group identification. RESULTS Only one subject became presyncopal during tilt testing on BR2, but 7 of 11 (63%) controls, 3 of 8 (38%) ExA, and 4 of 7 (57%) ExB subjects were presyncopal on BR70. Survival analysis of postBR tilt tests revealed no differences (p=0.77) between groups. Plasma volume (absolute or relative to body mass index) decreased (p<0.001) from pre to postBR, with no differences between groups. CONCLUSIONS These preliminary results corroborate previous reports that the performance of a vigorous exercise countermeasure protocol during BR, even with testosterone supplementation, does not protect against orthostatic intolerance or plasma volume loss. Preventing postBR orthostatic intolerance may require additional countermeasures, such as orthostatic stress during BR or endofBR fluid infusion

Perturbation theory for anisotropic dielectric interfaces, and application to sub-pixel smoothing of discretized numerical methods

We derive a correct first-order perturbation theory in electromagnetism for cases where an interface between two anisotropic dielectric materials is slightly shifted. Most previous perturbative methods give incorrect results for this case, even to lowest order, because of the complicated discontinuous boundary conditions on the electric field at such an interface. Our final expression is simply a surface integral, over the material interface, of the continuous field components from the unperturbed structure. The derivation is based on a "localized" coordinate-transformation technique, which avoids both the problem of field discontinuities and the challenge of constructing an explicit coordinate transformation by taking a limit in which a coordinate perturbation is infinitesimally localized around the boundary. Not only is our result potentially useful in evaluating boundary perturbations, e.g. from fabrication imperfections, in highly anisotropic media such as many metamaterials, but it also has a direct application in numerical electromagnetism. In particular, we show how it leads to a sub-pixel smoothing scheme to ameliorate staircasing effects in discretized simulations of anisotropic media, in such a way as to greatly reduce the numerical errors compared to other proposed smoothing schemes.Comment: 10 page

Population activity structure of excitatory and inhibitory neurons

Many studies use population analysis approaches, such as dimensionality reduction, to characterize the activity of large groups of neurons. To date, these methods have treated each neuron equally, without taking into account whether neurons are excitatory or inhibitory. We studied population activity structure as a function of neuron type by applying factor analysis to spontaneous activity from spiking networks with balanced excitation and inhibition. Throughout the study, we characterized population activity structure by measuring its dimensionality and the percentage of overall activity variance that is shared among neurons. First, by sampling only excitatory or only inhibitory neurons, we found that the activity structures of these two populations in balanced networks are measurably different. We also found that the population activity structure is dependent on the ratio of excitatory to inhibitory neurons sampled. Finally we classified neurons from extracellular recordings in the primary visual cortex of anesthetized macaques as putative excitatory or inhibitory using waveform classification, and found similarities with the neuron type-specific population activity structure of a balanced network with excitatory clustering. These results imply that knowledge of neuron type is important, and allows for stronger statistical tests, when interpreting population activity structure

Explaining and inducing savant skills: privileged access to lower level, less-processed information

I argue that savant skills are latent in us all. My hypothesis is that savants have privileged access to lower level, less-processed information, before it is packaged into holistic concepts and meaningful labels. Owing to a failure in top-down inhibition, they can tap into information that exists in all of our brains, but is normally beyond conscious awareness. This suggests why savant skills might arise spontaneously in otherwise normal people, and why such skills might be artificially induced by low-frequency repetitive transcranial magnetic stimulation. It also suggests why autistic savants are atypically literal with a tendency to concentrate more on the parts than on the whole and why this offers advantages for particular classes of problem solving, such as those that necessitate breaking cognitive mindsets. A strategy of building from the parts to the whole could form the basis for the so-called autistic genius. Unlike the healthy mind, which has inbuilt expectations of the world (internal order), the autistic mind must simplify the world by adopting strict routines (external order)

Defining the Relationship Between Biomarkers of Oxidative and Inflammatory Stress and the Risk for Atherosclerosis in Astronauts During and After Long-Duration Spaceflight

Future human space travel will primarily consist of long-duration missions aboard the International Space Station (ISS) or exploration class missions to Mars, its moons, or nearby asteroids. These missions will expose astronauts to increased risk of oxidative and inflammatory damage primarily from radiation, but also from psychological stress, reduced physical activity, diminished nutritional status, and, in the case of extravehicular activity, hyperoxic exposure. There is evidence that increased oxidative damage and inflammation can accelerate the development of atherosclerosis. PURPOSE The purpose of this proposal is to identify biomarkers of oxidative and inflammatory stress and to correlate them to indices of atherosclerosis risk before, during, and after long-duration spaceflight. METHODS To meet the objectives of the study, we will study astronauts before, during, and up to 5 years after long-duration missions aboard ISS. Biomarkers of oxidative and inflammatory stress, some of which we have previously shown to be elevated with spaceflight, will be measured before, during, and after spaceflight. Arterial structure will be monitored using ultrasound to measure carotid intima-medial thickness before, during, and after weightlessness. Carotid intima-medial thickness has been shown to be a better indicator than Framingham Risk scores for prediction of atherosclerosis. Arterial function will be monitored using brachial flow-mediated dilation before flight and after landing. Brachial flow-mediated dilation is a good index of endothelium-dependent vasodilation, which is a sensitive predictor of atherosclerotic risk. This is the first study to propose assessing atherosclerotic risk using biochemical, structural, and functional measures before, during, and immediately after spaceflight and structural functional measures for up to 5 years after landing. EXPECTED RESULTS We hypothesize that these biomarkers of oxidative and inflammatory stress will be increased with spaceflight and will correlate with increased carotid intima-medial thickness in- and postflight and with decreased flow-mediated dilation after the mission. Furthermore, we hypothesize that measures of oxidative stress will return to baseline after flight, but that biomarkers of inflammatory stress and vascular indices of atherosclerosis risk will remain elevated

Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties.

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies

T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor-stimulated macrophages

Toll-like receptor (TLR) agonists represent potentially useful cancer vaccine adjuvants in their ability to stimulate antigen-presenting cells (APCs) and subsequently amplify the cytotoxic T-cell response. The purpose of this study was to characterize APC responses to TLR activation and to determine the subsequent effect on lymphocyte activation. We exposed murine primary bone marrow-derived macrophages to increasing concentrations of agonists to TLRs 2, 3, 4, and 9. This resulted in a dose-dependent increase in production of not only tumor necrosis factor–alpha (TNF-α), a surrogate marker of the proinflammatory response, but also interleukin 10 (IL-10), a well-described inhibitory cytokine. Importantly, IL-10 secretion was not induced by low concentrations of TLR agonists that readily produced TNF-α. We subsequently stimulated lymphocytes with anti-CD3 antibody in the presence of media from macrophages activated with higher doses of TLR agonists and observed suppression of interferon gamma release. Use of both IL-10 knockout macrophages and IL-10 small-interfering RNA (siRNA) ablated this suppressive effect. Finally, IL-10 siRNA was successfully used to suppress CpG-induced IL-10 production in vivo. We conclude that TLR-mediated APC stimulation can induce a paradoxical inhibitory effect on T-cell activation mediated by IL-10

Oxygen Uptake Responses to Submaximal Exercise Loads Do Not Change During Long-Duration Space Flight

In previous publications we have reported that the heart rate (HR) responses to graded submaximal exercise tests are elevated during long-duration International Space Station (ISS) flights. Furthermore, the elevation in HR appears greater earlier, rather than later, during the missions. A potential confounder in the interpretation of HR results from graded exercise tests on ISS is that the cycle ergometer used (CEVIS) is vibration-isolated from the station structure. This feature causes the CEVIS assembly to sway slightly during its use and debriefing comments by some crewmembers indicate that there is a "learning curve" associated with CEVIS use. Therefore, one could not exclude the possibility that the elevated HRs experienced in the early stages of ISS missions were related to a lowered metabolic efficiency of CEVIS exercise that would raise the submaximal oxygen uptake (VO2) associated with graded exercise testing work rates