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All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Supramolecular Motion Enables Chondrogenic Bioactivity of a Cyclic Peptide Mimetic of Transforming Growth Factor-β1

Transforming growth factor (TGF)-β1 is a multifunctional protein that is essential in many cellular processes that include fibrosis, inflammation, chondrogenesis, and cartilage repair. In particular, cartilage repair is important to avoid physical disability since this tissue does not have the inherent capacity to regenerate beyond full development. We report here on supramolecular coassemblies of two peptide amphiphile molecules, one containing a TGF-β1 mimetic peptide, and another which is one of two constitutional isomers lacking bioactivity. Using human articular chondrocytes, we investigated the bioactivity of the supramolecular copolymers of each isomer displaying either the previously reported linear form of the mimetic peptide or a novel cyclic analogue. Based on fluorescence depolarization and 1 H NMR spin–lattice relaxation times, we found that coassemblies containing the cyclic compound and the most dynamic isomer exhibited the highest intracellular TGF-β1 signaling and gene expression of cartilage extracellular matrix components. Here, we conclude that control of supramolecular motion is emerging as an important factor in the binding of synthetic molecules to receptors that can be tuned through chemical structure.

Antigens↗
DOE OSTI2024

First Time-Resolved Leader Spectra Associated With a Downward Terrestrial Gamma-Ray Flash Detected at the Telescope Array Surface Detector

Optical emissions associated with Terrestrial Gamma ray Flashes (TGFs) have recently become important subjects in space-based and ground-based observations as they can help us understand how TGFs are produced during thunderstorms. In this paper, we present the first time-resolved leader spectra of the optical component associated with a downward TGF. The TGF was observed by the Telescope Array Surface Detector (TASD) simultaneously with other lightning detectors, including a Lightning Mapping Array (LMA), an INTerFerometer (INTF), a Fast Antenna (FA), and a spectroscopic system. The spectroscopic system recorded leader spectra at 29,900 frames per second (33.44 μs time resolution), covering a spectral range from 400 to 900 nm, with 2.1 nm per pixel. The recordings of the leader spectra began 11.7 ms before the -18 kA return stroke and at a height of 2.37 km above the ground. These spectra reveal that optical emissions of singly ionized nitrogen and oxygen occur between 167 μs before and 267 μs after the TGF detection, while optical emissions of neutrals (H I, 656 nm; N I, 744 nm, and O I, 777 nm) occur right at the moment of the detection. The time-dependent spectra reveal differences in the optical emissions of lightning leaders with and without downward TGFs.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
NASA NTRS1999

Gravity and Skeletal Growth

Two simultaneous experiments were performed using 5-week-old male Sprague Dawley rats; in one study, the rats were flown in low earth orbit; in the other study, the hindlimbs of the growing rats were elevated to prevent weight bearing. Following 9 d of unloading, weight bearing was restored for 4, 28, and 76 hrs. Afterwards, additional hindlimb unloading experiments were performed to evaluate the skeletal response to 0, 2, 4, 6, 8, 10, 12, 16, and 24 hrs of restored weight bearing following 7 d of unloading. Cancellous and cortical bone histomorphometry were evaluated in the left tibia at the proximal metaphysis and in the left femur at mid-diaphysis, respectively. Steady-state mRNA levels for bone matrix proteins and skeletal signaling peptides were determined in total cellular RNA extracted from trabeculae from the right proximal tibiametaphysis and periosteum from the right femur. Spaceflight and hindlimb unloading each resulted in cancellous osteopenia, as well as a tendency towards decreased periosteal bone formation. Both models for skeletal unloading resulted in site specific reductions in mRNA levels for transforming growth factor-beta (sub 1) (TGF-beta) osteocalcin (OC), and prepro-alpha (I) subunit of type 1 collagen (collagen) and little or no changes in mRNA levels for glyceraldehyde-3-phosphate dehydrogenase (GAP) and insulin-like growth factor I (IGF-I). Restoration of normal weight bearing resulted in transient increases in mRNA levels for the bone matrix proteins and TGF-beta in the proximal metaphysis and periosteum and no changes in either GAP or IGF-I mRNA levels. The timecourse for the response differed between the two skeletal compartments; the tibial metaphysis responded much more quickly to reloading. These results suggest that the skeletal adaptation to acute physiological changes in mechanical usage are mediated, in part, by changes in mRNA levels for bone matrix proteins and TGF-beta.

Morey-Holton, Emily↗
NASA NTRS2003

Inhibition of HSP70 and a Collagen-Specific Molecular Chaperone (HSP47) Expression in Rat Osteoblasts by Microgravity

Rat osteoblasts were cultured aboard a space shuttle for 4 or 5 days. Cells were exposed to 1alpha, 25 dihydroxyvitamin D(3) during the last 20 h and then solubilized by guanidine solution. The mRNA levels for molecular chaperones were analyzed by semi-quantitative RT-PCR. ELISA was used to quantify TGF-beta1 in the conditioned medium. The HSP70 mRNA levels in the flight cultures were almost completely suppressed, as compared to the ground (1 x g) controls. The inducible HSP70 is known as the major heat shock protein that prevents stress-induced apoptosis. The mean mRNA levels for the constitutive HSC73 in the flight cultures were reduced to 69%, approximately 60% of the ground controls. HSC73 is reported to prevent the pathological state that is induced by disruption of microtubule network. The mean HSP47 mRNA levels in the flight cultures were decreased to 50% and 19% of the ground controls on the 4th and 5th days. Concomitantly, the concentration of TGF-beta1 in the conditioned medium of the flight cultures was reduced to 37% and 19% of the ground controls on the 4th and 5th days. HSP47 is the collagen-specific molecular chaperone that controls collagen processing and quality and is regulated by TGF-beta1. Microgravity differentially modulated the expression of molecular chaperones in osteoblasts, which might be involved in induction and/or prevention of osteopenia in space.

Animals↗
NASA NTRS2010

Fermi GBM Observations of Terrestrial Gamma Flashes

In its first two years of operation, the Fermi Gamma Ray Burst Monitor (GBM) has observed more than 77 Terrestrial Gamma Flashes (TGFs). The thick Bismuth Germanate (BGO) detectors are excellent for TGF spectroscopy, having a high probability of recording the full energy of an incident photon, spanning a broad energy range from 150 keV to 40 MeV, and recording a large number of photons per TGF. Correlations between GBM TGF triggers and lightning sferics detected with the World-Wide Lightning Location Network indicate that TGFs and lightning are simultaneous to within tens of microseconds. The energy spectra of some TGFs have strong 511 keV positron annihilation lines, indicating that these TGFs contain a large fraction of positrons

Wilson-Hodge, Colleen A.↗
NASA NTRS2010

Fermi GBM Observations of Terrestrial Gamma Flashes

In its first two years of operation, the Fermi Gamma Ray Burst Monitor (GBM) has observed 79 Terrestrial Gamma Flashes (TGFs). The thick Bismuth Germanate (BGO) detectors are excellent for TGF spectroscopy, having a high probability of recording the full energy of an incident photon, spanning a broad energy range from 150 keV to 40 MeV, and recording a large number of photons per TGF. Correlations between GBM TGF triggers and lightning sferics detected with the World-Wide Lightning Location Network indicate that TGFs and lightning are simultaneous to within tens of microseconds.

Wilson-Hodge, Colleen A.↗
NASA NTRS2010

GBM Observations of Terrestrial Gamma-Ray Flashes

The TGF detection rate of Gamma-ray Burst Monitor (GBM) has been increased twice since launch. The most recent improvement is from a new operating mode in which data for individual photons are down-linked for selected portions of the orbit, enabling a more sensitive ground-based search for TGFs. The new search has increased the TGF detection rate and is finding TGFs more than five times fainter than the TGFs of the previous GBM sample. We summarize the properties of the original GBM TGF sample and compare to the less intense TGFs now being detected. In addition to gamma-ray TGFs, GBM is observing distant TGFs from the propagation of charged particles along geomagnetic field lines. Strong 511 keV annihilation lines have been observed, demonstrating that both electrons and positrons are present in the particle beams. Spectral fits to these electron/positron TGFs will be shown.

Briggs, M. S.↗
NASA NTRS2011

Modularized TGFbeta-Smad Signaling Pathway

The Transforming Growth Factor beta (TGFbeta) signaling pathway is a prominent regulatory signaling pathway controlling various important cellular processes. It can be induced by several factors, including ionizing radiation. It is regulated by Smads in a negative feedback loop through promoting increases in the regulatory Smads in the cell nucleus, and subsequent expression of inhibitory Smad, Smad7 to form a ubiquitin ligase with Smurf targeting active TGF receptors for degradation. In this work, we proposed a mathematical model to study the radiation-induced Smad-regulated TGF signaling pathway. By modularization, we are able to analyze each module (subsystem) and recover the nonlinear dynamics of the entire network system. Meanwhile the excitability, a common feature observed in the biological systems, along the TGF signaling pathway is discussed by mathematical analysis and numerical simulation.

Li, Yongfeng↗
NASA NTRS2011

High-Energy Radiation from Thunderstorms with ADELE: TGFs, Steps, and Glows

The biggest challenge in the study of high-energy processes in thunderstorms is getting a detector to the vicinity of the electrically active regions of a storm. The Airborne Detector for Energetic Lightning Emissions (ADELE) has been used to detect gamma rays from aircraft above storms and from a storm-chasing van on the ground. In August 2009, ADELE flew above Florida storms in a Gulfstream V jet, detecting the first terrestrial gamma-ray flash (TGF) seen from a plane and continuous glows of high-energy emission above thunderclouds. The presence of these glows suggests that a gradual process of relativistic runaway and feedback may help limit the total amount of charging in thunderstorms, in contrast to the traditional view that only lightning discharges compete with the charging process. The upper limits on TGF emission from intracloud and cloud-to-ground lightning from the ADELE flights demonstrated conclusively that a TGF of the sort seen from space is not associated with most lightning and not necessary to trigger it. In August 2010, observations from a van detected stepped-leader x-ray emission from at least four lightning strikes in ten days of operations. This mode of operation is therefore promising for future observations of the stepping process, although a more varied suite of instrumentation, in particular a flash-distance detector, would be useful. We will report on these results and on future possibilities for ADELE campaigns.

Smith, David M.↗
NASA NTRS2017

Terrestrial Gamma Ray Flashes due to Particle Acceleration in Tropical Storm Systems

Terrestrial gamma ray flashes (TGFs) are submillisecond flashes of energetic radiation that are believed to emanate from intracloud lightning inside thunderstorms. This emission can be detected hundreds of kilometers from the source by space-based observatories such as the Fermi Gamma-ray Space Telescope (Fermi). The location of the TGF-producing storms can be determined using very low frequency (VLF) radio measurements made simultaneously with the Fermi detection, allowing additional insight into the mechanisms which produce these phenomena. In this paper, we report 37 TGFs originating from tropical storm systems for the first time. Previous studies to gain insight into how tropical cyclones formed and how destructive they can be include the investigation of lightning flash rates and their dependence on storm evolution. We find TGFs to emanate from a broad range of distances from the storm centers. In hurricanes and severe tropical cyclones, the TGFs are observed to occur predominately from the outer rainbands. A majority of our sample also show TGFs occurring during the strengthening phase of the encompassing storm system. These results verify that TGF production closely follows when and where lightning predominately occurs in cyclones. The intrinsic characteristics of these TGFs were not found to differ from other TGFs reported in larger samples. We also find that some TGF-producing storm cells in tropical storm systems far removed from land have a low number of WWLLN sferics. Although not unique to tropical cyclones, this TGF/sferic ratio may imply a high efficiency for the lightning in these storms to generate TGFs.

Roberts, O. S.↗
NASA NTRS1999

The Effects of Orbital Spaceflight on Human Osteoblastic Cell Physiology and Gene Expression

The purpose of the proposed study is to establish whether changes in gravitational loading have a direct effect on osteoblasts to regulate TGF-6 expression. The effects of spaceflight and reloading on TGF-B MRNA and peptide levels will be studied in a newly developed line of immortalized human fetal osteoblasts (HFOB) transfected with an SV-40 temperature dependent mutant to generate proliferating, undifferentiated hFOB cells at 33-34 C and a non-proliferating, differentiated HFOB cells at 37-39'C. Unlike previous cell culture models, HFOB cells have unlimited proliferative capacity yet can be precisely regulated to differentiate into mature cells which express mature osteoblast function. If isolated osteoblasts respond to changes in mechanical loading in a manner similar to their response in animals, the cell system could provide a powerful model to investigate the signal transduction pathway for gravitational loading.

Turner, R. T.↗
NASA NTRS2001

Physical and biological studies with protons and HZE particles in a NASA supported research center in radiation health

NASA has established and supports a specialized center for research and training (NSCORT) to specifically address the potential deleterious effects of HZE particles on human health. The NSCORT in radiation health is a joint effort between Lawrence Berkeley National Laboratory (LBNL) and Colorado State University (CSU). The overall scope of research encompasses a broad range of subjects from microdosimetric studies to cellular and tissue responses to initial damage produced by highly energetic protons and heavy charged particles of the type found in galactic cosmic rays (GCR) spectrum. The objectives of the microdosimetry studies are to determine the response of Tissue Equivalent Proportional Counter (TEPC) to cosmic rays using ground based accelerators. This includes evaluation of energy loss due to the escape of high-energy delta rays and increased energy deposition due to the enhanced delta ray production in the wall of the detector. In this report major results are presented for 56Fe at 1000, 740, 600 and 400 MeV/nucleon. An assessment of DNA repair and early development of related chromosomal changes is extremely important to our overall understanding of enhanced biological effectiveness of high LET particle radiation. Results are presented with respect to the fidelity of the rejoining of double strand breaks and the implications of misrejoining. The relationship between molecular and cytogenetic measurements is presented by studying damage processing in highly heterochromatic supernumerary (correction of sypernumerary) X chromosomes and the active X-chromosome. One of the important consequences of cell's inability to handle DNA damage can be evaluated through mutation studies. Part of our goal is the assessment of potential radioprotectors to reduce the mutation yield following HZE exposures, and some promising results are presented on one compound. A second goal is the integration of DNA repair and mutation studies. Results are presented on a direct comparison of initial double strand breaks induction, the time course and fidelity of double strand break rejoining, cell killing and mutation induction in the same human model system. In order to understand the carcinogenic potential of protons and HZE particles, the role of damaged microenvironment in this process must be understood. In this project it has been postulated that radiation affects the microenvironment, which then modifies cell interactions in a manner conducive to neoplastic progression. Both TGF-beta and FGF-2 are important components of microenvironment. A recent result on the assessment of the role of FGF-2 and its cross-talk with TGF-beta as a function of radiation quality is presented. Theoretical modeling has so far played a central role in analyzing and integrating experimental data on repair and mutation studies and predicting new phenomena. The integrated NSCORT program also provides a broad training experience for students and postdoctoral fellows in space radiation health.

NASA Discipline Radiation Health↗
NASA NTRS2000

Effects of orbital spaceflight on human osteoblastic cell physiology and gene expression

During long-term spaceflight, astronauts lose bone, in part due to a reduction in bone formation. It is not clear, however, whether the force imparted by gravity has direct effects on bone cells. To examine the response of bone forming cells to weightlessness, human fetal osteoblastic (hFOB) cells were cultured during the 17 day STS-80 space shuttle mission. Fractions of conditioned media were collected during flight and shortly after landing for analyses of glucose utilization and accumulation of type I collagen and prostaglandin E(2) (PGE(2)). Total cellular RNA was isolated from flight and ground control cultures after landing. Measurement of glucose levels in conditioned media indicated that glucose utilization occurred at a similar rate in flight and ground control cultures. Furthermore, the levels of type I collagen and PGE(2) accumulation in the flight and control conditioned media were indistinguishable. The steady-state levels of osteonectin, alkaline phosphatase, and osteocalcin messenger RNA (mRNA) were not significantly changed following spaceflight. Gene-specific reductions in mRNA levels for cytokines and skeletal growth factors were detected in the flight cultures using RNase protection assays. Steady-state mRNA levels for interleukin (IL)-1alpha and IL-6 were decreased 8 h following the flight and returned to control levels at 24 h postflight. Also, transforming growth factor (TGF)-beta(2) and TGF-beta(1) message levels were modestly reduced at 8 h and 24 h postflight, although the change was not statistically significant at 8 h. These data suggest that spaceflight did not significantly affect hFOB cell proliferation, expression of type I collagen, or PGE(2) production, further suggesting that the removal of osteoblastic cells from the context of the bone tissue results in a reduced ability to respond to weightlessness. However, spaceflight followed by return to earth significantly impacted the expression of cytokines and skeletal growth factors, which have been implicated as mediators of the bone remodeling cycle. It is not yet clear whether these latter changes were due to weightlessness or to the transient increase in loading resulting from reentry.

Non-NASA Center↗
NASA NTRS2009

Terrestrial Gamma-ray Flash (TGFs) Above Thunderstorms

Terrestrial gamma-ray flashes (TGFs) are being observed with the Gamma-ray Burst Monitor (GBM) detectors on Fermi about once every four weeks. These intense millisecond flashes of MeV photons have been observed with four space-borne experiments since their initial discovery by the BATSE-CGRO experiment in the early 1990s. TGFs have extremely hard spectra (harder than GRBs) and photons are seen to extend to over 30 MeV. The GBM-Fermi observations have the highest temporal resolution of any previous TGF observations and time-resolved coarse spectra can be derived. These features will be crucial for testing the leading current model of TGF production: relativistic run-away electron cascades formed in the intense electric fields within thunderstorms.

Fishman, Gerald J.↗
NASA NTRS2010

Intense Gamma-Ray Flashes Above Thunderstorms on the Earth and Other Planets

Intense millisecond flashes of MeV photons have been observed with space-borne detectors in Earth orbit. They are expected to be present on other planets that exhibit lightning. The terrestrial gamma-ray flashes (TGFs) were discovered with the Burst and Transient Source Experiment (BATSE) aboard the Compton Gamma-Ray Observatory (CGRO) in the early 1990s. They are now being observed with several other instruments, including the Gamma-ray Burst Monitor (GBM) detectors on the Fermi Gamma-ray Space Telescope. Although Fermi- GBM was designed and optimized for the observation of cosmic gamma-ray bursts (GRBs), it has unprecedented capabilities for TGF observations. The TGFs usually have extremely hard continuous spectra, typical of highly- Comptonized bremsstrahlung radiation. These spectral are harder than those of GRBs, with photons extending to over 40 MeV. The most likely origin of these high-energy photons is bremsstrahlung radiation produced by a relativistic "runaway avalanche" electron beam. Such a beam is expected to be produced in an extended, intense electric field in or above thunderstorm regions. The altitude of origin and beaming characteristics of the radiation are quite uncertain. They have generated considerable observational and theoretical interest in recent years. This talk will give an overview of the all of the space-borne observations of TGFs that have been made thus far. Instruments are being designed specifically for TGF observations from new spacecraft as well as from airborne platforms

Fishman, Gerald J.↗
NASA NTRS2010

Space-Borne Observations of Intense Gamma-Ray Flashes (TGFs) Above Thunderstorms

Intense millisecond flashes of MeV photons are being observed with space-borne detectors. These terrestrial gamma-ray flashes (TGFs) were discovered with the Burst and Transient Source Experiment (BATSE) aboard the Compton Gamma-Ray Observatory (CGRO) in the early 1990s. They are now being observed with several other instruments, including the Gamma-ray Burst Monitor (GBM) detectors on the Fermi Gamma-ray Space Telescope. Although Fermi-GBM was designed and optimized for the observation of cosmic gamma-ray bursts (GRBs), it has unprecedented capabilities for TGF observations. The TGFs usually have extremely hard continuous spectra, typical of highly-Comptonized bremsstrahlung radiation. These spectral are harder than those of GRBs, with photons extending to over 40 MeV. The most likely origin of these high-energy photons is bremsstrahlung radiation produced by a relativistic runaway avalanche electron beam. Such a beam is expected to be produced in an extended, intense electric field in or above thunderstorm regions. The altitude of origin and beaming characteristics of the radiation are quite uncertain. These TGFs may produce an appreciable radiation dose to passengers and crew in nearby aircraft. They have generated considerable observational and theoretical interest in recent years. Instruments are being designed specifically for TGF observations from new spacecraft as well as from airborne platforms.

Fishman, Gerald J.↗
NASA NTRS2010

Fermi GBM Observations of Terrestrial Gamma-Ray Flashes

This slide presentation explores the relationship between Terrestrial Gamma-Ray Flashes (TGF) and lightning. Using data from the World-Wide Lightning Location Network (WWLLN), and the gamma ray observations from Fermi's Gamma-ray Burst Monitor (GBM), the study reviews any causal relationship between TGFs and lightning. The conclusion of the study is that the TGF and lightning are simultaneous with out a causal relationship.

Wilson-Hodge, Colleen A.↗
NASA NTRS2017

Systemic Response to Microgravity: Utilizing GeneLab Datasets to Identify Molecular Targets for Future Hypotheses-Driven Spaceflight Studies

Biological risks associated with microgravity are a major concern for long-term space travel. Although determination of risk has been a focus for NASA research, data examining systemic (i.e., multi- or pan-tissue) responses to space flight are sparse. To perform our analysis, we utilized the NASA GeneLab database which is a publicly available repository containing a wide array of omics results from experiments conducted with: i) with different flight conditions (space shuttle (STS) missions vs. International Space Station (ISS); ii) a variety of tissues; and 3) assays that measure epigenetic, transcriptional, and protein expression changes. Meta-analysis of the transcriptomic data from 7 different murine and rat data sets, examining tissues such as liver, kidney, adrenal gland, thymus, mammary gland, skin, and skeletal muscle (soleus, extensor digitorum longus, tibialis anterior, quadriceps, and gastrocnemius) revealed for the first time, the existence of potential master regulators coordinating systemic responses to microgravity in rodents. We identified p53, TGF(beta)1 and immune related pathways as the highly prevalent pan-tissue signaling pathways that are affected by microgravity. Some variability in the degree of change in their expression across species, strain and time of flight was also observed. Interestingly, while certain skeletal muscle (gastrocnemius and soleus) exhibited an overall down-regulation of these genes, some other muscle types such as the extensor digitorum longus, tibialis anterior and quadriceps, showed an up-regulated expression, indicative of potential compensatory mechanisms to prevent microgravity-induced atrophy. Key genes isolated by unbiased systems analyses displayed a major overlap between tissue types and flight conditions and established TGF(beta)1 to be the most connected gene across all data sets. Finally, a set of microgravity responsive miRNA signature was identified and based on their predicted functional state and subsequent impact on health, a theoretical health risk score was calculated. The genes and miRNAs identified from our analyses can be targeted for future research involving efficient countermeasure design. Our study thus exemplifies the utility of GeneLab data repository to aid in the process of performing novel hypothesis based spaceflight research aimed at elucidating the global impact of environmental stressors at multiple biological scales.

GeneLab↗