Nourishing the brain on deep space missions: nutritional psychiatry in promoting resilience.

The grueling psychological demands of a journey into deep space coupled with ever-increasing distances away from home pose a unique problem: how can we best take advantage of the benefits of fresh foods in a place that has none? Here, we consider the biggest challenges associated with our current spaceflight food system, highlight the importance of supporting optimal brain health on missions into deep space, and discuss evidence about food components that impact brain health. We propose a future food system that leverages the gut microbiota that can be individually tailored to best support the brain and mental health of crews on deep space long-duration missions. Working toward this goal, we will also be making investments in sustainable means to nourish the crew that remains here on spaceship Earth.

Internal Jugular Vein Volume During Head-Down Tilt and Carbon Dioxide Exposure in the SPACECOT Study.

BACKGROUND: Cerebral hemodynamics and venous outflow from the brain may be altered during exposure to microgravity or head-down tilt (HDT), an analog of microgravity, as well as by increased ambient CO2 exposure as experienced on the International Space Station. METHODS: Six healthy subjects underwent baseline tilt table testing at 0°, 6°, 12°, 18°, 24°, and 30° HDT. The right internal jugular (IJ) vein cross-sectional area (CSA) was measured at four intervals from the submandibular to the clavicular level and IJ volume was calculated. Further measurements of the IJ vein were made after ∼26 h of 12° HDT bed rest with either ambient air or 0.5% CO2 exposure, and plasma and blood volume were assessed after 4 h, 24 h, and 28.5 h HDT. RESULTS: IJ vein CSA and volume increased with progressively steeper HDT angles during baseline tilt table testing, with more prominent filling of the IJ vein at levels closer to the clavicle. Exposure to 26 h of 12° HDT bed rest with or without increased CO2, however, had little additional effect on the IJ vein. Further, bed rest resulted in a decrease in plasma volume and blood volume, although changes did not depend on atmospheric conditioning or correlate directly with changes in IJ vein CSA or volume. DISCUSSION: The hydrostatic effects of HDT can be clearly determined through measurement of the IJ vein CSA and volume; however, IJ vein dimensions may not be a reliable indicator of systemic fluid status during bed rest.Marshall-Goebel K, Stevens B, Rao CV, Suarez JI, Calvillo E, Arbeille P, Sangi-Haghpeykar H, Donoviel DB, Mulder E, Bershad EM, the SPACECOT Investigators Group. Internal jugular vein volume during head-down tilt and carbon dioxide exposure in the SPACECOT Study. Aerosp Med Hum Perform. 2018; 89(4):351-356.

Novel Indications for Commonly Used Medications as Radiation Protectants in Spaceflight.

BACKGROUND: In the space environment, the traditional radioprotective principles of time, distance, and shielding become difficult to implement. Additionally, the complex radiation environment inherent in space, the chronic exposure timeframe, and the presence of numerous confounding variables complicate the process of creating appropriate risk models for astronaut exposure. Pharmaceutical options hold tremendous promise to attenuate acute and late effects of radiation exposure in the astronaut population. Pharmaceuticals currently approved for other indications may also offer radiation protection, modulation, or mitigation properties along with a well-established safety profile. Currently there are only three agents which have been clinically approved to be employed for radiation exposure, and these only for very narrow indications. This review identifies a number of agents currently approved by the U.S. Food and Drug Administration (FDA) which could warrant further investigation for use in astronauts. Specifically, we examine preclinical and clinical evidence for statins, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), metformin, calcium channel blockers, ß adrenergic receptor blockers, fingolimod, N-acetylcysteine, and pentoxifylline as potential radiation countermeasures.McLaughlin MF, Donoviel DB, Jones JA. Novel indications for commonly used medications as radiation protectants in spaceflight. Aerosp Med Hum Perform. 2017; 88(7):665-676.

Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.

Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.

mdmx is a negative regulator of p53 activity in vivo.

Regulation of p53 protein activity is required for normal embryogenesis, tumor suppression, and cellular response to DNA damage. Here we report that loss of mdmx, a p53-binding protein, results in midgestational embryo lethality, a phenotype that is completely rescued by the absence of p53. Mice homozygous for both mdmx and p53 null mutations are viable and appear developmentally normal. Fibroblasts derived from embryos with reduced mdmx expression demonstrate a decreased growth rate and increased UV-induced apoptosis compared with wild-type cells and contain elevated levels of p53 and several p53 target proteins including the proapoptotic bax protein. These observations demonstrate that mdmx functions as a critical negative regulator of p53 in vivo.

Clinical Validation of a Transcranial Doppler-Based Noninvasive Intracranial Pressure Meter: A Prospective Cross-Sectional Study.

BACKGROUND: Noninvasive intracranial pressure (ICP) measurement would represent a major advance for patients with neurological problems. The Vittamed ICP meter is an ultrasound-based device reported to have high agreement with lumbar puncture cerebrospinal fluid (CSF) pressure measurement. However, previous studies included mostly patients with normal levels of ICP. The purpose of our study was to perform an independent clinical validation study of a transcranial Doppler-based noninvasive ICP meter in patients anticipated to have a wide range of ICP. METHODS: In a prospective cross-sectional design, we simultaneously measured ICP with the Vittamed device and the invasive lumbar CSF pressure. The operator of each procedure was blinded to the result of the other method. Data were analyzed using Bland-Altman plots, Pearson correlation coefficients, and receiver operator characteristic curves. RESULTS: Twenty-four independent paired measurements of Vittamed and lumbar CSF pressure were obtained; with mean absolute difference between paired measures of 4.5 mmHg (standard deviation 3.1). The 95% limits of agreement were -10.5 to +11.0. The systematic bias (mean of paired differences) was negligible at 0.25 mmHg. The sensitivity, specificity, and area under the curve for ICP >20 mmHg were 0.73, 0.77, and 0.71, respectively. CONCLUSIONS: The Vittamed ICP meter had fair agreement with lumbar CSF pressure measurement. The wide limits of agreement would preclude using this version of the device as a stand-alone method for ICP determination, but may be useful if combined with other ICP screening methods. Ongoing improvements to the Vittamed hardware and software may lead to improvements in accuracy and clinical utility of this device.

Noninvasive Brain Physiology Monitoring for Extreme Environments: A Critical Review.

Our ability to monitor the brain physiology is advancing; however, most of the technology is bulky, expensive, and designed for traditional clinical settings. With long-duration space exploration, there is a need for developing medical technologies that are reliable, low energy, portable, and semiautonomous. Our aim was to review the state of the art for noninvasive technologies capable of monitoring brain physiology in diverse settings. A literature review of PubMed and the Texas Medical Center library sites was performed using prespecified search criteria to identify portable technologies for monitoring physiological aspects of the brain physiology. Most brain-monitoring technologies require a moderate to high degree of operator skill. Some are low energy, but many require a constant external power supply. Most of the technologies lack the accuracy seen in gold standard measures, due to the need for calibration, but may be useful for screening or monitoring relative changes in a parameter. Most of the technologies use ultrasound or electromagnetic radiation as energy sources. There is an important need for further development of portable technologies that can be operated in a variety of extreme environments to monitor brain health.

The impact of sex and gender on adaptation to space: executive summary.

This review article is a compendium of six individual manuscripts, a Commentary, and an Executive Summary. This body of work is entitled "The Impact of Sex and Gender on Adaptation to Space" and was developed in response to a recommendation from the 2011 National Academy of Sciences Decadal Survey, "Recapturing a Future for Space Exploration: Life and Physical Sciences for a New Era," which emphasized the need to fully understand sex and gender differences in space. To ensure the health and safety of male and female astronauts during long-duration space missions, it is imperative to examine and understand the influences that sex and gender have on physiological and psychological changes that occur during spaceflight. In this collection of manuscripts, six workgroups investigated and summarized the current body of published and unpublished human and animal research performed to date related to sex- and gender-based differences in the areas of cardiovascular, immunological, sensorimotor, musculoskeletal, reproductive, and behavioral adaptations to human spaceflight. Each workgroup consisted of scientists and clinicians from academia, the National Aeronautics and Space Administration (NASA), and other federal agencies and was co-chaired by one representative from NASA and one from the external scientific community. The workgroups met via telephone and e-mail over 6 months to review literature and data from space- and ground-based studies to identify sex and gender factors affecting crew health. In particular, the Life Sciences Data Archive and the Lifetime Surveillance of Astronaut Health were extensively mined. The groups identified certain sex-related differences that impact the risks and the optimal medical care required by space-faring women and men. It represents innovative research in sex and gender-based biology that impacts those individuals that are at the forefront of space exploration.

High-throughput screening of mouse knockout lines identifies true lean and obese phenotypes.

We developed a high-throughput approach to knockout (KO) and phenotype mouse orthologs of the 5,000 potential drug targets in the human genome. As part of the phenotypic screen, dual-energy X-ray absorptiometry (DXA) technology estimates body-fat stores in eight KO and four wild-type (WT) littermate chow-fed mice from each line. Normalized % body fat (nBF) (mean KO % body fat/mean WT littermate % body fat) values from the first 2322 lines with viable KO mice at 14 weeks of age showed a normal distribution. We chose to determine how well this screen identifies body-fat phenotypes by selecting 13 of these 2322 KO lines to serve as benchmarks based on their published lean or obese phenotype on a chow diet. The nBF values for the eight benchmark KO lines with a lean phenotype were > or =1 s.d. below the mean for seven (perilipin, SCD1, CB1, MCH1R, PTP1B, GPAT1, PIP5K2B) but close to the mean for NPY Y4R. The nBF values for the five benchmark KO lines with an obese phenotype were >2 s.d. above the mean for four (MC4R, MC3R, BRS3, translin) but close to the mean for 5HT2cR. This screen also identifies novel body-fat phenotypes as exemplified by the obese kinase suppressor of ras 2 (KSR2) KO mice. These body-fat phenotypes were confirmed upon studying additional cohorts of mice for KSR2 and all 13 benchmark KO lines. This simple and cost-effective screen appears capable of identifying genes with a role in regulating mammalian body fat.

A presenilin-independent aspartyl protease prefers the gamma-42 site cleavage.

beta-Amyloid peptides (Abeta40 and Abeta42) are the major constituents of amyloid plaques, which are one of the hallmarks of Alzheimer's disease (AD). The Abeta is derived from sequential cleavages of amyloid precursor protein (APP) by beta- and gamma-secretases. gamma-Secretase consists of at least four proteins where presenilins (PS1 and PS2 or PS) are the catalytic subunit involved in the gamma-site cleavage of APP. Secretion of both Abeta40 and Abeta42 is significantly reduced in PS1 knock-out cells and completely abolished in cells deficient for both PS1 and PS2. Consequently, both the PS proteins play essential roles in the production of the secretory of Abeta from cells. Recent studies in primary neurons, however, suggest that PSs are not required for intracellular Abeta42 accumulation; thus the intracellular Abeta42 appears to be generated in a PS-independent manner. Here we present the first biochemical evidence indicating that Abeta, especially Abeta42, can be generated in the absence of PS based on an in vitrogamma-secretase assay employing membranes prepared from PS-deficient Blastocyst-derived (BD) cells. This PS-independent gamma-secretase (PSIG) activity is sensitive to the changes in pH and displays an optimal activity at pH 6.0. Pepstatin A is a potent inhibitor for this proteolytic activity with IC50 of 1.2 nm and 0.4 nm for Abeta40 and Abeta42 generation, respectively. These results indicate that these PS-independent gamma-site cleavages are mediated by an aspartyl protease. More importantly, the PSIG activity displays a distinct preference in mediating the 42-site cleavage over the 40-site cleavage, thereby generating Abeta42 as the predominant product.

Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities.

Presenilin-1 (PS1) and presenilin 2 (PS2) are proposed to be transmembrane aspartyl proteases that cleave amyloid precursor protein and Notch. PS1- and PS2-mediated activities were individually characterized using blastocyst-derived (BD) cells and membranes from PS1+/--PS2-/- and PS1-/-PS2+/+ mice, respectively. The relative amounts of PS1 and PS2 in the various BD cells were determined from the intensities of the anti-PS1 and anti-PS2 immunoblot signals by comparison with standard curves using radiolabeled PS1 and PS2 standards produced by in vitro transcription and translation. Cellular membranes from wild type, PS1-/-PS2+/+, and PS1+/--PS2-/- but not PS1-/-PS2-/- BD cells generated the Abeta40 and Abeta42 products from the C100FLAG substrate. PS1-associated gamma-secretase displays considerably higher specific activity than PS2-associated gamma-secretase. Moreover, the PS1+/-PS2-/- BD cells and corresponding membranes exhibited much higher gamma-secretase activity as compared with other BD cells and membranes. The PS1-mediated gamma-secretase activity correlated better with the amount of PS1 that is modifiable by a photoactivated active site-directed gamma-secretase inhibitor rather than total PS1; hence, only a small portion (<14%) of the PS1 in wild-type membranes appears to be engaged in an active gamma-secretase complex. This finding suggests that PS1 may serve other biological functions in addition to that associated with its gamma-secretase activity. Furthermore, the PS1 gamma-secretase complex and the PS2 gamma-secretase complex activities can be discriminated on the basis of their susceptibility to inhibition by a potent gamma-secretase inhibitor. The distinct yet overlapping enzymatic properties of the PS1 gamma-secretase complex and the PS2 gamma-secretase complex imply that these two putative aspartyl class proteases may contribute to different biological processes.

Identification and characterization of presenilin-independent Notch signaling.

Presenilin (PS) proteins control the proteolytic cleavage that precedes nuclear access of the Notch intracellular domain. Here we observe that a partial activation of the HES1 promoter can be detected in PS1/PS2 (PS1/2) double null cells using Notch1 Delta E constructs or following Delta 1 stimulation, despite an apparent abolition of the production and nuclear accumulation of the Notch intracellular domain. PS1/2-independent Notch activation is sensitive to Numblike, a physiological inhibitor of Notch. PS1/2-independent Notch signaling is also inhibited by an active gamma-secretase inhibitor in the low micromolar range and is not inhibited by an inactive analogue, similar to PS-dependent Notch signaling. However, experiments using a Notch1-Gal4-VP16 fusion protein indicate that the PS1/2-independent activity does not release Gal4-VP16 and is therefore unlikely to proceed via an intramembranous cleavage. These data reveal that a novel PS1/2-independent mechanism plays a partial role in Notch signal transduction.