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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

A Proximity Labeling Strategy Provides Insights into the Composition and Dynamics of Lipid Droplet Proteomes

Lipid droplet (LD) functions are regulated by a complement of integral and peripheral proteins that associate with the bounding LD phospholipid monolayer. Defining the composition of the LD proteome has remained a challenge due to the presence of contaminating proteins in LD-enriched buoyant fractions. To overcome this limitation, we developed a proximity labeling strategy that exploits LD-targeted APEX2 to biotinylate LD proteins in living cells. Application of this approach to two different cell types identified the vast majority of previously validated LD proteins, excluded common contaminating proteins, and revealed new LD proteins. Moreover, quantitative analysis of LD proteome dynamics uncovered a role for endoplasmic reticulum-associated degradation in controlling the composition of the LD proteome. In conclusion, these data provide an important resource for future LD studies and demonstrate the utility of proximity labeling to study the regulation of LD proteomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

A phosphatidylinositol transfer protein integrates phosphoinositide signaling with lipid droplet metabolism to regulate a developmental program of nutrient stress-induced membrane biogenesis

Lipid droplet (LD) utilization is an important cellular activity that regulates energy balance and release of lipid second messengers. Because fatty acids exhibit both beneficial and toxic properties, their release from LDs must be controlled. Here we demonstrate that yeast Sfh3, an unusual Sec14-like phosphatidylinositol transfer protein, is an LD-associated protein that inhibits lipid mobilization from these particles. We further document a complex biochemical diversification of LDs during sporulation in which Sfh3 and select other LD proteins redistribute into discrete LD subpopulations. The data show that Sfh3 modulates the efficiency with which a neutral lipid hydrolase-rich LD subclass is consumed during biogenesis of specialized membrane envelopes that package replicated haploid meiotic genomes. These results present novel insights into the interface between phosphoinositide signaling and developmental regulation of LD metabolism and unveil meiosis-specific aspects of Sfh3 (and phosphoinositide) biology that are invisible to contemporary haploid-centric cell biological, proteomic, and functional genomics approaches.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1996

Activation of a Ca(2+)-dependent protein kinase involves intramolecular binding of a calmodulin-like regulatory domain

Ca(2+)-dependent protein kinases (CDPKs) are regulated by a C-terminal calmodulin-like domain (CaM-LD). The CaM-LD is connected to the kinase by a short junction sequence which contains a pseudosubstrate autoinhibitor. To understand how the CaM-LD regulates a CDPK, a recombinant CDPK (isoform CPK-1 from Arabidopsis, accession no. L14771) was made as a fusion protein in Escherichia coli. We show here that a truncated CDPK lacking a CaM-LD (e.g. mutant delta NC-26H) can be activated by exogenous calmodulin or an isolated CaM-LD (Kact approximately 2 microM). We propose that Ca2+ activation of a CDPK normally occurs through intramolecular binding of the CaM-LD to the junction. When the junction and CaM-LD are made as two separate polypeptides, the CaM-LD can bind the junction in a Ca(2+)-dependent fashion with a dissociation constant (KD) of 6 x 10(-6) M, as determined by kinetic binding analyses. When the junction and CaM-LD are tethered in a single polypeptide (e.g. in protein JC-1), their ability to engage in bimolecular binding is suppressed (e.g. the tethered CaM-LD cannot bind a separate junction). A mutation which disrupts the putative CaM-LD binding sequence (e.g. substitution LRV-1444 to DLPG) appears to block intramolecular binding, as indicated by the restored ability of a tethered CaM-LD to engage in bimolecular binding. This mutation, in the context of a full-length enzyme (mutant KJM46H), appears to block Ca2+ activation. Thus, a disruption of intramolecular binding correlates with a disruption of the Ca2+ activation mechanism. CDPKs provide the first example of a member of the calmodulin superfamily where a target binding sequence is located within the same polypeptide.

Non-NASA Center↗
DOE OSTI2018

The proper localization of RESPONSIVE TO DESICCATION 20 in lipid droplets depends on their biogenesis induced by STRESS-RELATED PROTEINS in vegetative tissues

Highlights: • The cellular mechanism of SRPs on response to drought stress is proposed. • The mechanism relies on enhancement of LD biogenesis. • RD20 is localized to SRPs-dependent LDs in vegetative tissues. • The enzymatic activity of RD20 is correlated with its LD-localization. Arabidopsis LD surface proteins, SRPs are found only in higher plants and are important for LD biogenesis and abiotic stress signaling. However, the cellular mechanism of SRPs is still unclear. To investigate molecular functions of SRPs, we used tobacco transient expression system. Transient expression of SRPs was sufficient and synergistic for LD biogenesis, and SRPs participated in the formation step of LD in tobacco leaves. RESPONSIVE TO DESICCATION 20 (RD20), a known LD-localizing peroxygenase, localized to LD in the presence of an SRP, and its peroxygenase activity correlated with proper localization of RD20 to LD. Our data suggest that Arabidopsis SRPs play roles as positive factors for LD biogenesis to provide a proper localization of LD-localizing proteins in vegetative tissues.

60 APPLIED LIFE SCIENCES↗
NASA NTRSDate not supplied

Hazards of Lunar Surface Exploration: Determining the Immunogenicity/Allergenicity of Lunar Dust

Although infrequent, there have been Apollo program reports of lunar dust (LD) exposure leading to notable upper respiratory symptoms in select crewmembers. Possible mechanisms include particulate irritation, oxidization and release of noxious gas, or legitimate adaptive immune-mediated response. Although sterile non-protein matter would not be expected to be an allergen, one Apollo flight surgeon reported increasing symptoms upon repeated exposure with associated eosinophilia, indicative of allergy (*Acta Astronautica. 2008 63 (7–10): 980–987). Many ISS crews display a pattern of persistent immune system dysregulation and latent virus reactivation (NPJ Microgravity. 2015 Sep 3; 1:15013; NPJ Microgravity. 2017 Apr 12; 3:11). Some ISS crews manifest atypical respiratory and/or dermatitis symptoms which could have an allergic pathogenesis (J Allergy Clin. Immunol. Pract. 2016 Jul-Aug; 4(4):759-762.e8). It is logical to anticipate crew immune dysregulation would worsen during prolonged deep space missions. Planetary surface hazards will only complicate crew health risks. This study with investigate if LD exposure will elicit an IgE mediated allergic response either to the LD itself or concomitant antigen exposure during spaceflight. Allergic reactivity could adversely increase clinical and operational impacts for long-duration lunar astronauts and affect countermeasure requirements for surface vehicles. Specific aims for this study are to answer two questions: (1) Does in vitro LD exposure result in increased histamine from human peripheral blood basophils? (2) Can LD impact the capacity of CD4+ T helper and/or CD19+ B-cell mediated IgE production? To address these questions, after the proposal and selection by NASA, our laboratory has separately requested and been approved for receipt of actual LD samples from the Apollo 16 mission. These samples will be used during the study to complete the proposed set of in vitro cell culture experiments (short and long term), using human peripheral blood mononuclear cells (PBMC) and basophils from both atopic and non-atopic individuals. Cells will be co-cultured with cellular mitogens, common recall antigens (Der p1), fine ground silica quartz (as a possible allergenic component of LD), or LD, to study whether LD exposure for varying time intervals will alter the generation of selective immune responses associated with clinical allergic reactions. Measured outputs include supernatant-derived IgE, tryptase, histamine, and selected cytokine levels. Cellular activation will be monitored by assessing activation markers via flow cytometry. EM/x-ray analysis will be used to determine cellular interactions with dust particles. A series of validation experiments was initiated in FY22 once the delivery of LD was received. Based on initial experimental findings, we are optimizing the culture conditions, LD concentrations, and refining our other protocol stimuli.

Audrie A. Colorado↗
NASA NTRSDate not supplied

Hazards of Lunar Surface Exploration: Determining the Immunogenicity/Allergenicity of Lunar Dust

Although infrequent, there have been Apollo program reports of lunar dust (LD) exposure leading to notable upper respiratory symptoms in select crewmembers. Possible mechanisms include particulate irritation, oxidization and release of noxious gas, or legitimate adaptive immune-mediated response. Although sterile non-protein matter would not be expected to be an allergen, one Apollo flight surgeon reported increasing symptoms upon repeated exposure with associated eosinophilia, indicative of allergy (*Acta Astronautica. 2008 63 (7–10): 980–987). Many ISS crews display a pattern of persistent immune system dysregulation and latent virus reactivation (NPJ Microgravity. 2015 Sep 3; 1:15013; NPJ Microgravity. 2017 Apr 12; 3:11). Some ISS crews manifest atypical respiratory and/or dermatitis symptoms which could have an allergic pathogenesis (J Allergy Clin. Immunol. Pract. 2016 Jul-Aug; 4(4):759-762.e8). It is logical to anticipate crew immune dysregulation would worsen during prolonged deep space missions. Planetary surface hazards will only complicate crew health risks. This study with investigate if LD exposure will elicit an IgE mediated allergic response either to the LD itself or concomitant antigen exposure during spaceflight. Allergic reactivity could adversely increase clinical and operational impacts for long-duration lunar astronauts and affect countermeasure requirements for surface vehicles. Specific aims for this study are to answer two questions: (1) Does in vitro LD exposure result in increased histamine from human peripheral blood basophils? (2) Can LD impact the capacity of CD4+ T helper and/or CD19+ B-cell mediated IgE production? To address these questions, after the proposal and selection by NASA, our laboratory has separately requested and been approved for receipt of actual LD samples from the Apollo 16 mission. These samples will be used during the study to complete the proposed set of in vitro cell culture experiments (short and long term), using human peripheral blood mononuclear cells (PBMC) and basophils from both atopic and non-atopic individuals. Cells will be co-cultured with cellular mitogens, common recall antigens (Der p1), fine ground silica quartz (as a possible allergenic component of LD), or LD, to study whether LD exposure for varying time intervals will alter the generation of selective immune responses associated with clinical allergic reactions. Measured outputs include supernatant-derived IgE, tryptase, histamine, and selected cytokine levels. Cellular activation will be monitored by assessing activation markers via flow cytometry. EM/x-ray analysis will be used to determine cellular interactions with dust particles. A series of validation experiments was initiated in FY22 once the delivery of LD was received. Based on initial experimental findings, we are optimizing the culture conditions, LD concentrations, and refining our other protocol stimuli.

immunology↗
DOE OSTI2025

LIPID DROPLET PROTEIN OF SEEDS is involved in the control of lipid droplet size in Arabidopsis seeds and seedlings

Abstract In oilseeds, energy-rich carbon is stored as triacylglycerols in organelles called lipid droplets (LDs). While several of the major biogenetic proteins involved in LD formation have been identified, the full repertoire of LD proteins and their functional roles remains incomplete. Here, we show that the low-abundance, seed-specific LD protein LIPID DROPLET PROTEIN OF SEEDS (LDPS) contains an amphipathic α-helix and proline hairpin motif that serves as an LD-targeting signal and a separate region that binds to the LD protein OLEOSIN 1 (OLEO1). Loss of LDPS function results in smaller LDs and less seed oil in comparison with wild type, while overexpression of LDPS results in an increase in LD size and seed oil content. Loss of LDPS function also results in an inability of LDs to undergo fusion during postgerminative seedling growth. Analysis of oleo1 and ldps single- and double-mutant seeds and freeze–thaw treatment of seeds revealed that OLEO1 suppresses the ability of LDPS to promote larger LDs. Collectively, our results identify LDPS as an important player in LD biology that functions together with OLEO1 to determine LD size in Arabidopsis (Arabidopsis thaliana) seeds and seedlings through a process that involves LD–LD fusion.

Biochemistry & Molecular Biology↗
DOE OSTI2021

Tick bite frequency, prevention practices and Lyme disease diagnoses among U.S. Hispanic survey respondents

Abstract Tick bite prevention practices, knowledge of Lyme disease (LD) symptoms and transmission, and patterns of LD diagnoses among Hispanic persons have been reported but not comprehensively evaluated. In 2014, CDC examined questions from a prospective nationwide survey of U.S. Hispanic adults conducted via the Offerwise QueOpinas panel regarding ticks and LD. From October to November, a total of 2,649 surveys were released and 1,006 completed surveys returned. Overall, 44% of respondents reported routinely practising at least one form of personal protection against tick bites, and wearing repellent was the most commonly reported method (29%). Approximately 6% of respondents reported a tick bite for either themselves or someone in their household during the previous 12 months. An individual or household diagnosis of LD in the previous year was reported by 2% of respondents, with the highest proportion of diagnoses reported by respondents from high LD incidence states. The annual incidence of healthcare provider‐diagnosed LD in the survey population was higher than national surveillance estimates for reported LD among U.S. Hispanic persons during 2000–2013. As annual incidence of LD continues to increase, it is important to ensure equitable access to information about LD, including disease transmission, manifestations, and prevention recommendations. Results from this survey can help inform public health outreach focused on effective tick bite prevention methods and early recognition of LD.

Beck, Alyssa↗
DOE OSTI2021

LDIP cooperates with SEIPIN and LDAP to facilitate lipid droplet biogenesis in Arabidopsis

Cytoplasmic lipid droplets (LDs) are evolutionarily conserved organelles that store neutral lipids and play critical roles in plant growth, development, and stress responses. However, the molecular mechanisms underlying their biogenesis at the endoplasmic reticulum (ER) remain obscure. Here we show that a recently identified protein termed LD-associated protein [LDAP]-interacting protein (LDIP) works together with both endoplasmic reticulum-localized SEIPIN and the LD-coat protein LDAP to facilitate LD formation in Arabidopsis thaliana. Heterologous expression in insect cells demonstrated that LDAP is required for the targeting of LDIP to the LD surface, and both proteins are required for the production of normal numbers and sizes of LDs in plant cells. LDIP also interacts with SEIPIN via a conserved hydrophobic helix in SEIPIN and LDIP functions together with SEIPIN to modulate LD numbers and sizes in plants. Further, the co-expression of both proteins is required to restore normal LD production in SEIPIN-deficient yeast cells. These data, combined with the analogous function of LDIP to a mammalian protein called LD Assembly Factor 1, are discussed in the context of a new model for LD biogenesis in plant cells with evolutionary connections to LD biogenesis in other eukaryotes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Lipid droplet-associated proteins in alcohol-associated fatty liver disease: A proteomic approach

The earliest manifestation of alcohol-associated liver disease (ALD) is steatosis characterized by deposition of fat in specialized organelles called lipid droplets (LDs). While alcohol administration causes a rise in LD numbers in the hepatocytes, little is known regarding their characteristics that allow their accumulation and size to increase. The aim of the present study is to gain insights into underlying pathophysiological mechanisms by investigating the ethanol-induced changes in hepatic LD proteome as a function of LD size. Adult male Wistar rats (180–200 g BW) were fed with ethanol liquid diet for 6 weeks. At sacrifice, large-, medium-, and small-sized hepatic LD subpopulations (LD1, LD2, and LD3, respectively) were isolated and subjected to morphological and proteomic analyses. Morphological analysis of LD1-LD3 fractions of ethanol-fed rats clearly demonstrated that LD1 contained larger LDs compared with LD2 and LD3 fractions. Our preliminary results from principal component analysis showed that the proteome of different-sized hepatic LD fractions was distinctly different. Proteomic data analysis identified over 2000 proteins in each LD fraction with significant alterations in protein abundance among the three LD fractions. Among the altered proteins, several were related to fat metabolism, including synthesis, incorporation of fatty acid, and lipolysis. Ingenuity pathway analysis revealed increased fatty acid synthesis, fatty acid incorporation, LD fusion, and reduced lipolysis in LD1 compared to LD3. Overall, the proteomic findings indicate that the increased level of protein that facilitates fusion of LDs combined with an increased association of negative regulators of lipolysis dictates the generation of large-sized LDs during the development of alcohol-associated hepatic steatosis. Several significantly altered proteins were identified in different-sized LDs isolated from livers of ethanol-fed rats. Ethanol-induced increases in specific proteins that hinder LD lipid metabolism led to the accumulation and persistence of large-sized LDs in the liver.

60 APPLIED LIFE SCIENCES↗
NASA NTRSDate not supplied

Hazards of Lunar Surface Exploration: Determining the Immunogenicity/Allergenicity of Lunar Dust

There are multiple Apollo program reports of lunar dust (LD) exposure leading to significant upper respiratory symptoms in select crewmembers. Possible mechanisms include particulate irritation, oxidization and release of noxious gas, or legitimate adaptive immune-mediated response. Although sterile non-protein matter would not be expected to be an allergen, one Apollo flight surgeon reported increasing symptoms upon repeated exposure, with associated eosinophilia indicative of allergy (*Acta Astronautica. 2008 63 (7–10): 980–987). Many ISS crews display a pattern of persistent immune system dysregulation and latent virus reactivation (NPJ Microgravity. 2015 Sep 3; 1:15013; NPJ Microgravity. 2017 Apr 12; 3:11). Some ISS crews manifest atypical respiratory and/or dermatitis symptoms which could have an allergic pathogenesis (J Allergy Clin. Immunol. Pract. 2016 Jul-Aug; 4(4):759-762.e8). It is logical to anticipate crew immune dysregulation would worsen during prolonged deep space missions. Planetary surface hazards will only complicate crew health risks. This study hypothesizes that LD exposure can alter susceptible individuals’ immune responses such that repeated exposure will elicit an IgE mediated allergic response either to the LD itself or concomitant antigen exposure during spaceflight. This will adversely increase clinical and operational impacts for long-duration lunar astronauts and affect countermeasure requirements for surface vehicles. Specific aims for this study are (1) Does in vitro LD exposure result in increased histamine from human peripheral blood basophils? (2) Can LD impact the capacity of CD4+ helper and/or CD19+ B-cell mediated IgE production? To address these questions, a set of in-vitro cell culture experiments will be employed (short and long term) using human peripheral blood mononuclear cells (PBMC) and basophils from both atopic and non-atopic individuals, as well as established human basophil and mast cell lines. Cells will be co-cultured with cellular mitogens, common recall antigens (tetanus, Der p1), nickel (as a possible allergenic component of LD), with or without graded amounts of LD, to study whether LD exposure for varying time intervals will alter the generation of selective immune responses associated with clinical allergic reactions. Measured outputs include supernatant-derived IgE, tryptase, histamine and selected cytokine levels. Cellular activation will be monitored by assessing activation markers via flow cytometry. EM/x-ray analysis will be used to determine cellular interactions with dust particles. The minimal amount of LD (Apollo 14 dust) and controls/simulants have been requested. This study, originally planned as an FY20/21 activity, was delayed due to the COVID pandemic. It is now scheduled to be performed during FY22.

Brian Crucian↗
DOE OSTI2014

SU-F-18C-06: Prospective Patient Evaluation of Iterative Reconstruction in Radiation Oncology

Purpose: This work incorporates iterative reconstruction (IR) into a dose reduction study to characterize image quality metrics, delineation, and dosimetric assessment, with the goal of reducing imaging dose in Radiation Oncology. Methods: Three-dimensional noise power spectrum (NPS) analysis characterized noise magnitude/texture (120 kVp, 50–200 mAs, IR levels 1–6 yielding noise reduction of 0.89–0.55 compared to filtered backprojection (FBP)). Task-specific Modulation Transfer Functions (MTFtask) were characterized across varied subject contrasts. A prospective dose reduction study (500 to 150 mAs) was conducted for 12 patients (43 inter-fraction CTs) for high-dose rate brachytherapy. Three physicians performed qualitative image assessment between full-dose FBP (FD-FBP, 500 mAs), low-dose FBP (LD-FBP, 150–250 mAs), and low-dose IRL5-6 (LD-IR) scans for image noise, cuff/bladder interface detectability, spatial resolution, texture, and segmentation confidence. Comparisons between LD-FBP and LD-IR were conducted for the following metrics: delineation (bladder and rectum evaluated via overlap indices (OI) and Dice similarity coefficients (DSC)), noise, boundary changes, dose calculation, and digitally reconstructed radiographs (DRRs). Results: NPS showed ∼50% reduction in noise magnitude and ∼0.1 1/mm spatial frequency shift with IRL6. The largest MTFtask decrease between FBP and IR was 0.08 A.U. Qualitative patient image evaluation revealed LD-IR was equivalent or slightly worse than FD-FBP, and superior to LD-FBP for all metrics except low contrast interface and texture. The largest CT number discrepancy from FBP occurred at a bone/tissue interface using IRL6 (−1.2 ± 4.9 HU (range: −17.6 – 12.5 HU)). No significant contour differences (OIs and DSCs = 0.85 – 0.95) and dose calculation discrepancy (<0.02%) were observed. DRRs preserved anatomical detail and demonstrated <2% difference in intensity between LD-FBP and LD-IRL6. Conclusion: While phantom analysis showed slight noise texture differences with IR, patient results revealed that image quality, contouring ability, and dosimetric parameters were not adversely affected, thus support integrating IR into treatment planning. Research supported in part by a grant from Philips HealthCare.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-CD-207A-02: Implementation of Live EPID-Based Inspiration Level Assessment (LEILA) for Deepinspiration Breath-Hold (DIBH) Monitoring Using MV Fluoroscopy

Purpose: As prior work has shown that current DIBH monitoring approaches using surrogate measures (marker block on chest) do not always correspond with the clinical quantity of interest (lung depth, LD), a software tool and workflow are introduced to use MV fluoroscopy during treatment for real-time / Live EPID-based Inspiration Level Assessment (LEILA). Methods: A prototype software tool calculates and displays the LD during the treatment of left sided breast cancer. Calculations are based on MV cine images which are acquired with the treatment beam thereby not incurring any additional imaging dose. Image capture and processing are implemented using a dedicated frame grabber computer. The calculation engine automatically detects image orientation and includes provisions for large treatment fields that exceed the size of the EPID panel. LD is measured along a line profile in the middle of the field. LEILA’s interface displays the current MV image, a reference image (DRR), the current LD, as well as a trace of LD over treatment time. The display includes patient specific LD tolerances. Tolerances are specified for each field and loaded before the treatment. A visual warning is generated when the tolerance is exceeded. LEILA is initially run in parallel with current DIBH techniques. When later run by itself DIBH setup will be done using skin marks and room laser. Results: Offline tests of LEILA confirmed accurate automatic LD measurement for a variety of patient geometries. Deployment of the EPID during all left sided breast treatments was well tolerated by patients and staff during a multi-month pilot. The frame grabber provides 11 frames-per-second; the MATLAB based LEILA prototype software can analyze five frames-per-second standalone on standard desktop hardware. Conclusion: LEILA provides an automated approach to quantitatively monitor LD on MV images during DIBH treatment. Future improvements include a database and further speed optimization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Arabidopsis thaliana EARLY RESPONSIVE TO DEHYDRATION 7 Localizes to Lipid Droplets via Its Senescence Domain

Lipid droplets (LDs) are neutral-lipid-containing organelles found in all kingdoms of life and are coated with proteins that carry out a vast array of functions. Compared to mammals and yeast, relatively few LD proteins have been identified in plants, particularly those associated with LDs in vegetative (non-seed) cell types. Thus, to better understand the cellular roles of LDs in plants, a more comprehensive inventory and characterization of LD proteins is required. Here, we performed a proteomics analysis of LDs isolated from drought-stressed Arabidopsis leaves and identified EARLY RESPONSIVE TO DEHYDRATION 7 (ERD7) as a putative LD protein. mCherry-tagged ERD7 localized to both LDs and the cytosol when ectopically expressed in plant cells, and the protein’s C-terminal senescence domain (SD) was both necessary and sufficient for LD targeting. Phylogenetic analysis revealed that ERD7 belongs to a six-member family in Arabidopsis that, along with homologs in other plant species, is separated into two distinct subfamilies. Notably, the SDs of proteins from each subfamily conferred targeting to either LDs or mitochondria. Further, the SD from the ERD7 homolog in humans, spartin, localized to LDs in plant cells, similar to its localization in mammals; although, in mammalian cells, spartin also conditionally localizes to other subcellular compartments, including mitochondria. Disruption of ERD7 gene expression in Arabidopsis revealed no obvious changes in LD numbers or morphology under normal growth conditions, although this does not preclude a role for ERD7 in stress-induced LD dynamics. Consistent with this possibility, a yeast two-hybrid screen using ERD7 as bait identified numerous proteins involved in stress responses, including some that have been identified in other LD proteomes. Collectively, these observations provide new insight to ERD7 and the SD-containing family of proteins in plants and suggest that ERD7 may be involved in functional aspects of plant stress response that also include localization to the LD surface.

54 ENVIRONMENTAL SCIENCES↗
NASA NTRSDate not supplied

Increased Rates of Hip and Spine Fractures in Astronauts are Associated with Longer Spaceflight Durations

Given the accelerated declines in bone mineral density reported in US astronauts serving on the International Space Station, there is a possibility that a prolonged exposure to spaceflight could put astronauts at increased fracture risk during subsequent planetary explorations or after return to Earth. To date, there have been no fractures in astronauts during spaceflight. Recently-reported data from a flight study suggested that intake of the bisphosphonate alendronate combined with resistive exercise (on the Advanced Resistive Exercise Device – ARED) preserved more astronauts at their preflight skeletal status after a ~6-mos spaceflight than with ARED exercise alone. However, there is low acceptance of alendronate, or the recommended zoledronic acid, to suppress in-flight bone loss largely due to concern for unintended medication side effects and a perceived absence of astronaut fractures that can be directly attributable to spaceflight exposure. Hence, a recent survey of all astronaut fractures was analyzed to assess whether the rate of postflight fractures could be associated with extended spaceflight exposures. The fracture survey was of 262 astronauts across 8433.6 person-years (PY) and grouped according to previous exposure to a “Long Duration (LD)” spaceflight (3 mos or greater, but typically 6-mos). The number of fractures was modeled using count regression adjusting for i) the repeated measures within individuals across the groups, ii) the differing length of surveillance for each individual and iii) age at start of surveillance for each of the groups. Astronaut Group by Spaceflight Exposure #Individuals PY Covered No Exposure to Spaceflight 262 1882.7 No Exposure to LD spaceflight “Non-LD” 232 6121.3 Exposure to LD spaceflight 42 429.6 Analysis revealed an increased rate of hip and spine fractures for surveillance periods compared between LD Exposure and Non-LD Exposure: Hip – Relative Rate: 3.4 (95%CI: 1.0, 12.0); Spine– Relative Rate: 3.4 (95%CI: 1.0, 11.6). For all other skeletal sites, rates of fracture were similar for LD and Non-LD exposures. Data comparisons were conducted between groups of astronauts to preclude the interpretation of greater physical activity in astronauts as a contributing factor to fracture rates. This analysis of fracture data is the first report associating postflight hip and spine fractures in astronauts with exposure to extended duration spaceflights. Further analyses integrating co-morbidities for bone loss are planned.

skeleton↗
NASA NTRS2003

The Effects of Spaceflight on the Rat Circadian Timing System

Two fundamental environmental influences that have shaped the evolution of life on Earth are gravity and the cyclic changes occurring over the 24-hour day. Light levels, temperature, and humidity fluctuate over the course of a day, and organisms have adapted to cope with these variations. The primary adaptation has been the evolution of a biological timing system. Previous studies have suggested that this system, named the circadian (circa - about; dies - a day) timing system (CTS), may be sensitive to changes in gravity. The NASA Neurolab spaceflight provided a unique opportunity to evaluate the effects of microgravity on the mammalian CTS. Our experiment tested the hypotheses that microgravity would affect the period, phasing, and light sensitivity of the CTS. Twenty-four Fisher 344 rats were exposed to 16 days of microgravity on the Neurolab STS-90 mission, and 24 Fisher 344 rats were also studied on Earth as one-G controls. Rats were equipped with biotelemetry transmitters to record body temperature (T(sub b)) and heart rate (HR) continuously while the rats moved freely. In each group, 18 rats were exposed to a 24-hour light-dark (LD 12:12) cycle, and six rats were exposed to constant dim red-light (LL). The ability of light to induce a neuronal activity marker (c-fos) in the circadian pacemaker of the brain, the suprachiasmatic nucleus (SCN), was examined in rats studied on flight days two (FD2) and 14 (FD14), and postflight days two (R+1) and 14 (R+13). The flight rats in LD remained synchronized with the LD cycle. However, their T(sub b), rhythm was markedly phase-delayed relative to the LD cycle. The LD flight rats also had a decreased T(sub b) and a change in the waveform of the T(sub b) rhythm compared to controls. Rats in LL exhibited free-running rhythms of T(sub b), and HR; however, the periods were longer in microgravity. Circadian period returned to preflight values after landing. The internal phase angle between rhythms was different in flight than in one-G. Compared with control rats, the flight rats exhibited no change in HR. Finally, the LD FD2 flight rats demonstrated a reduced sensitivity to light as shown by significantly reduced c-fos expression in the SCN in comparison with controls. These findings constitute the first demonstration that microgravity affects the fundamental properties of the mammalian circadian timing system, specifically by influencing the clock's period, and its ability to maintain temporal organization and phase angle of synchronization to an external LD cycle.

Fuller, Charles A.↗
DOE OSTI2019

Multiscale method based on coupled lattice‐Boltzmann and Langevin‐dynamics for direct simulation of nanoscale particle/polymer suspensions in complex flows

Summary A hybrid computational method coupling the lattice‐Boltzmann (LB) method and a Langevin‐dynamics (LD) method is developed to simulate nanoscale particle and polymer (NPP) suspensions in the presence of both thermal fluctuation and long‐range many‐body hydrodynamic interactions (HIs). Brownian motion of the NPP is explicitly captured by a stochastic forcing term in the LD method. The LD method is two‐way coupled to the nonfluctuating LB fluid through a discrete LB forcing source distribution to capture the long‐range HI. To ensure intrinsically linear scalability with respect to the number of particles, a Eulerian‐host algorithm for short‐distance particle neighbor search and interaction is developed and embedded to LB‐LD framework. The validity and accuracy of the LB‐LD approach are demonstrated through several sample problems. The simulation results show good agreements with theory and experiment. The LB‐LD approach can be favorably incorporated into complex multiscale computational frameworks for efficiently simulating multiscale multicomponent particulate suspension systems such as complex blood suspensions.

Liu, Zixiang↗