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At least 19 records
All sourcesNASA NTRSDOE OSTI
NASA NTRSDate not supplied

The Integrated Impact of Diet on Human Immune Response, the Gut Microbiota, and Nutritional Status During Adaptation to Spaceflight

Long-duration spaceflight impacts human physiology, including well documented immune system dysregulation. Diet, the microbiome, and immune system function are interlinked, but diet is the only one of these factors that we have the ability to easily, and significantly, alter on Earth or during flight. As we better understand dietary impacts on physiology, we may then improve the spaceflight diet to improve crew health and potentially reduce spaceflight-associated physiological decrements. Increasing the consumption of fruits and vegetables and bioactive compounds (e.g., omega-3 fatty acids, lycopene, flavonoids) and therefore enhancing overall nutritional intake from the nominal shelf-stable, fully-processed, space food system is expected to serve as a countermeasure to detrimental impacts to human physiology, including dysregulation in immunological profiles, the taxonomic profile of the gut microbiota, and nutritional status during spaceflight. In this study, first we sought to determine the effect of the nominal shelf-stable spaceflight diet compared to an "enhanced" shelf-stable spaceflight diet on human biochemistry, immunology, and the microbiome in a ground-based, simulated space mission. The ground analog portion of this study was conducted in the NASA Human Exploration Research Analog (HERA) Campaign 4 missions, which consisted of four 45-day missions with closed chamber confinement and realistic mission simulation to study effects on crew health and performance. As reported previously, analyses indicate beneficial associations between diet and markers of nutritional status, stress, the microbiome, and cognitive performance. Intake and beneficial associations varied by subject. This data will be used as a ground-based control for spaceflight, where the spaceflight environment (e.g., radiation, microgravity) will have additional impacts and the potential to evaluate effects of the diet will be greater. The second phase of this study is to occur on the International Space Station, where it is currently being implemented. The test plan is similar to that used in the HERA missions. The enhanced diet is intended to provide 25% of the crews’ diet with foods rich in omega-3 fatty acids, lycopene, and flavonoids, along with more fruits and vegetables in general (the other 75% of the diet will be obtained from standard and crew preference items available on the ISS). Biological samples (blood, urine, stool, and saliva) are being collected from participants at selected time points before, during, and after the mission. Data collection also includes dietary intake recording and body mass measurement. Currently, 6 of 9 planned astronauts have completed data collection. Analysis of immune markers, latent herpes virus reactivation, the taxonomic and metatranscriptomic profile of the gut microbiome, and nutritional status biomarkers and biochemical metabolites will occur in batch to minimize sample handling variations. Mixed models statistical analyses will be used, incorporating random effects to account for repeated measures within individuals to assess the impact of diet on physiological outcomes. We expect this study to provide evidence of beneficial impact of this enhanced diet on crew health and adaptation to spaceflight. These data will aid in evidence-based mass-risk trades for food system design and development of targeted dietary interventions for future exploration-class space missions.

Grace L. Douglas↗
NASA NTRS2010

Nutritional Biochemistry

This slide presentation reviews some of the effects that space flight has on humans nutritional biochemistry. Particular attention is devoted to the study of protein breakdown, inflammation, hypercatabolism, omega 3 fatty acids, vitamin D, calcium, urine, folate and nutrient stability of certain vitamins, the fluid shift and renal stone risk, acidosis, iron/hematology, and the effects on bone of dietary protein, potassium. inflammation, and omega-3 fatty acids

Smith, Scott M.↗
DOE OSTI2024

Do we owe our existence to gravitational waves?

Two heavy elements essential to human biology are thought to have been produced by the astrophysical r-process, which occurs in neutron-rich environments: iodine is a constituent of thyroid hormones that affect many physiological processes including growth and development, body temperature and heart rate, and bromine is essential for tissue development and architecture. Collisions of neutron stars (kilonovae) have been identified as sources of r-process elements including tellurium, which is adjacent to iodine in the periodic table, and lanthanides. Neutron-star collisions arise from energy loss due to gravitational-wave emission from binary systems, leading us to suggest that gravitational waves have played a key role in enabling human life by producing iodine and bromine. We propose probing this proposal by searching in lunar material for live 129 I deposited by a recent nearby kilonova explosion.

Human biochemistry↗
DOE OSTI2023

Energetic considerations for engineering novel biochemistries in photosynthetic organisms

Humans have been harnessing biology to make valuable compounds for generations. From beer and biofuels to pharmaceuticals, biology provides an efficient alternative to industrial processes. With the continuing advancement of molecular tools to genetically modify organisms, biotechnology is poised to solve urgent global problems related to environment, increasing population, and public health. However, the light dependent reactions of photosynthesis are constrained to produce a fixed stoichiometry of ATP and reducing equivalents that may not match the newly introduced synthetic metabolism, leading to inefficiency or damage. While photosynthetic organisms have evolved several ways to modify the ATP/NADPH output from their thylakoid electron transport chain, it is unknown if the native energy balancing mechanisms grant enough flexibility to match the demands of the synthetic metabolism. In this review we discuss the role of photosynthesis in the biotech industry, and the energetic considerations of using photosynthesis to power synthetic biology.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1991

Metabolism and biochemistry in hypogravity

The headward shift of body fluid and increase in stress-related hormones that occur in hypogravity bring about a number of changes in metabolism and biochemistry of the human body. Such alterations may have important effects on health during flight and during a recovery period after return to earth. Body fluid and electrolytes are lost, and blood levels of several hormones that control metabolism are altered during space flight. Increased serum calcium may lead to an increased risk of renal stone formation during flight, and altered drug metabolism could influence the efficacy of therapeutic agents. Orthostatic intolerance and an increased risk of fracturing weakened bones are concerns at landing. It is important to understand biochemistry and metabolism in hypogravity so that clinically important developments can be anticipated and prevented or ameliorated.

Leach, Carolyn S.↗
DOE OSTI2020

Uncovering DNA-PKcs ancient phylogeny, unique sequence motifs and insights for human disease

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key member of the phosphatidylinositol-3 kinase-like (PIKK) family of protein kinases with critical roles in DNA-double strand break repair, transcription, metastasis, mitosis, RNA processing, and innate and adaptive immunity. The absence of DNA-PKcs from many model organisms has led to the assumption that DNA-PKcs is a vertebrate-specific PIKK. Here, we find that DNA-PKcs is widely distributed in invertebrates, fungi, plants, and protists, and that threonines 2609, 2638, and 2647 of the ABCDE cluster of phosphorylation sites are highly conserved amongst most Eukaryotes. Furthermore, we identify highly conserved amino acid sequence motifs and domains that are characteristic of DNA-PKcs relative to other PIKKs. These include residues in the Forehead domain and a novel motif we have termed YRPD, located in an α helix C-terminal to the ABCDE phosphorylation site loop. Combining sequence with biochemistry plus structural data on human DNA-PKcs unveils conserved sequence and conformational features with functional insights and implications. The defined generally progressive DNA-PKcs sequence diversification uncovers conserved functionality supported by Evolutionary Trace analysis, suggesting that for many organisms both functional sites and evolutionary pressures remain identical due to fundamental cell biology. The mining of cancer genomic data and germline mutations causing human inherited disease reveal that robust DNA-PKcs activity in tumors is detrimental to patient survival, whereas germline mutations compromising function are linked to severe immunodeficiency and neuronal degeneration. We anticipate that these collective results will enable ongoing DNA-PKcs functional analyses with biological and medical implications.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Human health benefits of very-long-chain polyunsaturated fatty acids from microalgae

Microalgae are single-cell, photosynthetic organisms whose biodiversity places them at the forefront of biological producers of high-value molecules including lipids and pigments. Some of these organisms particular are capable of synthesizing n-3 very long chain polyunsaturated fatty acids (VLC-PUFAs), known to have beneficial effects on human health. Indeed, VLC-PUFAs are the precursors of many signaling molecules in humans involved in the complexities of inflammatory processes. Herein, this mini-review provides an inventory of knowledge on the synthesis of VLC-PUFAs in microalgae and on the diversity of signaling molecules (prostanoids, leukotrienes, SPMs, EFOX, isoprostanoids) that arise in humans from VLC-PUFAs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Dinickel enzyme evolved to metabolize the pharmaceutical metformin and its implications for wastewater and human microbiomes

Metformin is the first-line treatment for type II diabetes patients and a pervasive pollutant with more than 180 million kg ingested globally and entering wastewater. The drug’s direct mode of action is currently unknown but is linked to effects on gut microbiomes and may involve specific gut microbial reactions to the drug. In wastewater treatment plants, metformin is known to be transformed by microbes to guanylurea, although genes encoding this metabolism had not been elucidated. In the present study, we revealed the function of two genes responsible for metformin decomposition (mfmA and mfmB) found in isolated bacteria from activated sludge. MfmA and MfmB form an active heterocomplex (MfmAB) and are members of the ureohydrolase protein superfamily with binuclear metal-dependent activity. MfmAB is nickel-dependent and catalyzes the hydrolysis of metformin to dimethylamine and guanylurea with a catalytic efficiency (k cat /K M ) of 9.6 × 10 3 M -1 s -1 and KM for metformin of 0.82 mM. MfmAB shows preferential activity for metformin, being able to discriminate other close substrates by several orders of magnitude. Crystal structures of MfmAB show coordination of binuclear nickel bound in the active site of the MfmA subunit but not MfmB subunits, indicating that MfmA is the active site for the MfmAB complex. Mutagenesis of residues conserved in the MfmA active site revealed those critical to metformin hydrolase activity and its small substrate binding pocket allowed for modeling of bound metformin. In conclusion, this study characterizes the products of the mfmAB genes identified in wastewater treatment plants on three continents, suggesting that metformin hydrolase is widespread globally in wastewater.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Enzymatic carbon–fluorine bond cleavage by human gut microbes

Fluorinated compounds are used for agrochemical, pharmaceutical, and numerous industrial applications, resulting in global contamination. In many molecules, fluorine is incorporated to enhance the half-life and improve bioavailability. Fluorinated compounds enter the human body through food, water, and xenobiotics including pharmaceuticals, exposing gut microbes to these substances. The human gut microbiota is known for its xenobiotic biotransformation capabilities, but it was not previously known whether gut microbial enzymes could break carbon-fluorine bonds, potentially altering the toxicity of these compounds. Here, through the development of a rapid, miniaturized fluoride detection assay for whole-cell screening, we identified active gut microbial defluorinases. We biochemically characterized enzymes from diverse human gut microbial classes including Clostridia, Bacilli, and Coriobacteriia, with the capacity to hydrolyze (di)fluorinated organic acids and a fluorinated amino acid. Whole-protein alanine scanning, molecular dynamics simulations, and chimeric protein design enabled the identification of a disordered C-terminal protein segment involved in defluorination activity. Domain swapping exclusively of the C-terminus conferred defluorination activity to a nondefluorinating dehalogenase. To advance our understanding of the structural and sequence differences between defluorinating and nondefluorinating dehalogenases, we trained machine learning models which identified protein termini as important features. Models trained on 41-amino acid segments from protein C termini alone predicted defluorination activity with 83% accuracy (compared to 95% accuracy based on full-length protein features). This work is relevant for therapeutic interventions and environmental and human health by uncovering specificity-determining signatures of fluorine biochemistry from the gut microbiome.

Probst, Silke I↗
NASA NTRS2005

Kinetic Studies of Iron Deposition Catalyzed by Recombinant Human Liver Heavy, and Light Ferritins and Azotobacter Vinelandii Bacterioferritin Using O2 and H2O2 as Oxidants

The discrepancy between predicted and measured H2O2 formation during iron deposition with recombinant heavy human liver ferritin (rHF) was attributed to reaction with the iron protein complex [Biochemistry 40 (2001) 10832-10838]. This proposal was examined by stopped-flow kinetic studies and analysis for H2O2 production using (1) rHF, and Azotobacter vinelandii bacterial ferritin (AvBF), each containing 24 identical subunits with ferroxidase centers; (2) site-altered rHF mutants with functional and dysfunctional ferroxidase centers; and (3) rccombinant human liver light ferritin (rLF), containing 110 ferroxidase center. For rHF, nearly identical pseudo-first-order rate constants of 0.18 per second at pH 7.5 were measured for Fe(2+) oxidation by both O2 and H2O2, but for rLF, the rate with O2 was 200-fold slower than that for H2O2 (k-0.22 per second). A Fe(2+)/O2 stoichiometry near 2.4 was measured for rHF and its site altered forms, suggesting formation of H2O2. Direct measurements revealed no H2O2 free in solution 0.5-10 min after all Fe(2+) was oxidized at pH 6.5 or 7.5. These results are consistent with initial H2O2 formation, which rapidly reacts in a secondary reaction with unidentified solution components. Using measured rate constants for rHF, simulations showed that steady-state H2O2 concentrations peaked at 14 pM at approx. 600 ms and decreased to zero at 10-30 s. rLF did not produce measurable H2O2 but apparently conducted the secondary reaction with H2O2. Fe(2+)/O2 values of 4.0 were measured for AvBF. Stopped-flow measurements with AvBF showed that both H2O2 and O2 react at the same rate (k=0.34 per second), that is faster than the reactions with rHF. Simulations suggest that AvBF reduces O2 directly to H2O without intermediate H2O2 formation.

Bunker, Jared↗
NASA NTRS2001

E057: Renal Stone Risk Assessment During Space Flight: Assessment and Countermeasure Validation

Exposure to the microgravity environment results in many metabolic and physiological changes to humans. Body fluid volumes, electrolyte levels, and bone and muscle undergo changes as the human body adapts to the weightless environment. Changes in the urinary biochemistry occur as early as flight day 3-4 in the short duration Shuttle crewmembers. Significant decreases were observed both in fluid intake and urinary output. Other significant changes were observed in the urinary pH, calcium, potassium and uric acid levels. During Shuttle missions, the risk of calcium oxalate stone formation increased early in the flight, continued at elevated levels throughout the flight and remained in the increased risk range on landing day. The calcium phosphate risk was significantly increased early in-flight and remained significantly elevated throughout the remainder of the mission. Results from the long duration Shuttle-Mir missions followed a similar trend. Most long duration crewmembers demonstrated increased urinary calcium levels despite lower dietary calcium intake. Fluid intake and urine volumes were significantly lower during the flight than during the preflight. The calcium oxalate risk was increased relative to the preflight levels during the early in-flight period and continued in the elevated risk range for the remainder of the space flight and through two weeks postflight. Calcium phosphate risk for these long duration crewmembers increased during flight and remained in the increased risk range throughout the flight and following landing. The complexity, expense and visibility of the human space program require that every effort be made to protect the health of the crewmembers and ensure the success of the mission. Results from our early investigations clearly indicate that exposure to the microgravity environment of space significantly increases the risk of renal stone formation. The early studies have indicated specific avenues for development of countermeasures for the increased renal stone risk observed during and following space flight. Increased hydration and implementation of pharmacological countermeasures are being tested for their efficacy in mitigating the in-flight risk of renal stones. Maintaining the health and well-being of crewmembers during space flight requires a means of minimizing potential detrimental health effects of microgravity. The formation of a renal stone during flight obviously has severe consequences for the affected crewmember as well as the success of the mission.

Whitson, Peggy A.↗
DOE OSTI2022

G4Boost: a machine learning-based tool for quadruplex identification and stability prediction

Background: G-quadruplexes (G4s), formed within guanine-rich nucleic acids, are secondary structures involved in important biological processes. Although every G4 motif has the potential to form a stable G4 structure, not every G4 motif would, and accurate energy-based methods are needed to assess their structural stability. Here, we present a decision tree-based prediction tool, G4Boost, to identify G4 motifs and predict their secondary structure folding probability and thermodynamic stability based on their sequences, nucleotide compositions, and estimated structural topologies. Results: G4Boost predicted the quadruplex folding state with an accuracy greater then 93% and an F1-score of 0.96, and the folding energy with an RMSE of 4.28 and R 2 of 0.95 only by the means of sequence intrinsic feature. G4Boost was successfully applied and validated to predict the stability of experimentally-determined G4 structures, including for plants and humans. Conclusion: G4Boost outperformed the three machine-learning based prediction tools, DeepG4, Quadron, and G4RNA Screener, in terms of both accuracy and F1-score, and can be highly useful for G4 prediction to understand gene regulation across species including plants and humans.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2000

Nutritional Biochemistry of Space Flight

Adequate nutrition is critical for maintenance of crew health during and after extended-duration space flight. The impact of weightlessness on human physiology is profound, with effects on many systems related to nutrition, including bone, muscle, hematology, fluid and electrolyte regulation. Additionally, we have much to learn regarding the impact of weightlessness on absorption, m~tabolism , and excretion of nutrients, and this will ultimately determine the nutrient requirements for extended-duration space flight. Existing nutritional requirements for extended-duration space flight have been formulated based on limited flight research, and extrapolation from ground-based research. NASA's Nutritional Biochemistry Laboratory is charged with defining the nutritional requirements for space flight. This is accomplished through both operational and research projects. A nutritional status assessment program is included operationally for all International Space Station astronauts. This medical requirement includes biochemical and dietary assessments, and is completed before, during, and after the missions. This program will provide information about crew health and nutritional status, and will also provide assessments of countermeasure efficacy. Ongoing research projects include studies of calcium and bone metabolism, and iron absorption and metabolism. The calcium studies include measurements of endocrine regulation of calcium homeostasis, biochemical marker~ of bone metabolism, and tracer kinetic studies of calcium movement in the body. These calcium kinetic studies allow for estimation of intestinal absorption, urinary excretion, and perhaps most importantly - deposition and resorption of calcium from bone. The Calcium Kinetics experiment is currently being prepared for flight on the Space Shuttle in 2001, and potentially for subsequent Shuttle and International Space Station missions. The iron study is intended to assess whether iron absorption is down-regulated dUl1ng space flight. This is critical due to the red blood cell changes which occur, and the increase in iron storage that has been observed after space flight. The Iron Absorption and Metabolism experiment is currently planned for long-term flights on the International Space Station.

Smith, Scott M.↗
DOE OSTI2024

Genome organization and botanical diversity

Abstract The rich diversity of angiosperms, both the planet's dominant flora and the cornerstone of agriculture, is integrally intertwined with a distinctive evolutionary history. Here, we explore the interplay between angiosperm genome organization and botanical diversity, empowered by genomic approaches ranging from genetic linkage mapping to analysis of gene regulation. Commonality in the genetic hardware of plants has enabled robust comparative genomics that has provided a broad picture of angiosperm evolution and implicated both general processes and specific elements in contributing to botanical diversity. We argue that the hardware of plant genomes—both in content and in dynamics—has been shaped by selection for rather substantial differences in gene regulation between plants and animals such as maize and human, organisms of comparable genome size and gene number. Their distinctive genome content and dynamics may reflect in part the indeterminate development of plants that puts strikingly different demands on gene regulation than in animals. Repeated polyploidization of plant genomes and multiplication of individual genes together with extensive rearrangement and differential retention provide rich raw material for selection of morphological and/or physiological variations conferring fitness in specific niches, whether natural or artificial. These findings exemplify the burgeoning information available to employ in increasing knowledge of plant biology and in modifying selected plants to better meet human needs.

Biochemistry & Molecular Biology↗