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At least 181 records · Page 10

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NASA NTRS1993

Two-Beam multiplexed laser-induced fluorescence measurements of an argon arcjet plume

We describe a multiplexed, laser-induced fluorescence (LIF) technique with which radial and axial profiles of vector velocities of excited propellant species were obtained in the exhaust plume from a 300-W argon arcjet. Although the arcjet is a prototype, and although argon is not an interesting propellant from a propulsion perspective, the technique clearly demonstrates how a narrowband, frequency-stabilized ring-dye laser can be used to obtain simultaneous measurements of two velocity components in an arcjet plume and how a third signal from an optogalvanic cell can be used as a frequency reference. We also show that much information on the flow can be obtained by analyzing the Doppler widths and fluorescence intensities of the LIF data. Specifically, the data identify a boundary layer in the radial direction of the plume and a shock in the downstream region of the flow. Also, some flow anisotropy is observed, consistent with the assumption that the magnitude of the mean flow velocity fluctuates. The peak velocity on centerline remains roughly constant at 3 km/s throughout the expansion.

Ruyten, Wilhelmus M.↗

NASA NTRS2002

Interface Conditions for Wave Propagation Through Mesh Refinement Boundaries

We study the propagation of waves across fixed mesh refinement boundaries in linear and nonlinear model equations in 1-D and 2-D, and in the 3-D Einstein equations of general relativity. We demonstrate that using linear interpolation to set the data in guard cells leads to the production of reflected waves at the refinement boundaries. Implementing quadratic interpolation to fill the guard cells eliminates these spurious signals.

Choi, Dae-II↗

NASA NTRS2004

Structural Basis for the Catalytic Activity of Human Serine/Threonine Protein Phosphatase-5

Serinehhreonine protein phosphatase-5 (PP5) affects many signaling networks that regulate cell growth and cellular responses to stress. Here we report the crystal structure of the PP5 catalytic domain (PP5c) at a resolution of 1.6 A. From this structure we resolved the mechanism for PP5-mediated hydrolysis of phosphoprotein substrates, which requires the precise positioning of two metal ions within a con served Aspn-271-M(sub 1):M(sub 2)-W(sup 1)-His-427-His-304-Asp-274 catalytic motif. The structure of PPSc provides a structural basis for explaining the exceptional catalytic proficiency of protein phosphatases, which are among the most powerful known catalysts. Resolution of the entire C-terminus revealed a novel subdomain, and the structure of the PP5c should also aid development of type-specific inhibitors.

Swingle, M. R.↗

NASA NTRS2004

Structural Basis for the Catalytic Activity of Human SER/THR Protein Phosphatase-5

Serinekhreonine protein phosphatase-5 (PP5) affects many signaling networks that regulate cell growth. Here we report the 1.6 Angstrom resolution crystal structure of PP5 catalytic domain with metal and phosphate ions in the active site. The structure reveals a mechanism for PPS-mediated catalysis that requires the precise positioning of two metal ions within a conserved Asp(sup 271)-M(sub 1),-M(sub 2)-His(sup 427)-W(sup 2)-His(sup 304)-Asp(sup 274) catalytic motif, and provides a structural basis for the exceptional catalytic proficiency of protein phosphatases placing them among the most powerful catalysts. Resolution of the entire C-terminus revealed a novel subdomain, and the structure of PP5 should aid development of specific inhibitors.

Swingle, M. R.↗

NASA NTRS2003

Gravity-regulated differential auxin transport from columella to lateral root cap cells

Gravity-induced root curvature has long been considered to be regulated by differential distribution of the plant hormone auxin. However, the cells establishing these gradients, and the transport mechanisms involved, remain to be identified. Here, we describe a GFP-based auxin biosensor to monitor auxin during Arabidopsis root gravitropism at cellular resolution. We identify elevated auxin levels at the root apex in columella cells, the site of gravity perception, and an asymmetric auxin flux from these cells to the lateral root cap (LRC) and toward the elongation zone after gravistimulation. We differentiate between an efflux-dependent lateral auxin transport from columella to LRC cells, and an efflux- and influx-dependent basipetal transport from the LRC to the elongation zone. We further demonstrate that endogenous gravitropic auxin gradients develop even in the presence of an exogenous source of auxin. Live-cell auxin imaging provides unprecedented insights into gravity-regulated auxin flux at cellular resolution, and strongly suggests that this flux is a prerequisite for root gravitropism.

Non-NASA Center↗

NASA NTRS2000

Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K(+) channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional CaR

The existence in osteoblasts of the G-protein-coupled extracellular calcium (Ca(o)(2+))-sensing receptor (CaR) that was originally cloned from parathyroid and kidney remains controversial. In our recent studies, we utilized multiple detection methods to demonstrate the expression of CaR transcripts and protein in several osteoblastic cell lines, including murine MC3T3-E1 cells. Although we and others have shown that high Ca(o)(2+) and other polycationic CaR agonists modulate the function of MC3T3-E1 cells, none of these actions has been unequivocally shown to be mediated by the CaR. Previous investigations using neurons and lens epithelial cells have shown that activation of the CaR stimulates Ca(2+)-activated K(+) channels. Because osteoblastic cells express a similar type of channel, we have examined the effects of specific "calcimimetic" CaR activators on the activity of a Ca(2+)-activated K(+) channel in MC3T3-E1 cells as a way of showing that the CaR is not only expressed in those cells but is functionally active. Patch-clamp analysis in the cell-attached mode showed that raising Ca(o)(2+) from 0.75 to 2.75 mmol/L elicited about a fourfold increase in the open state probability (P(o)) of an outward K(+) channel with a conductance of approximately 92 pS. The selective calcimimetic CaR activator, NPS R-467 (0.5 micromol/L), evoked a similar activation of the channel, while its less active stereoisomer, NPSS-467 (0.5 micromol/L), did not. Thus, the CaR is not only expressed in MC3T3-E1 cells, but is also functionally coupled to the activity of a Ca(2+)-activated K(+) channel. This receptor, therefore, could transduce local or systemic changes in Ca(o)(2+) into changes in the activity of this ion channel and related physiological processes in these and perhaps other osteoblastic cells.

NASA Discipline Musculoskeletal↗

NASA NTRS1998

Neural learning rules for the vestibulo-ocular reflex

Mechanisms for the induction of motor learning in the vestibulo-ocular reflex (VOR) were evaluated by recording the patterns of neural activity elicited in the cerebellum by a range of stimuli that induce learning. Patterns of climbing-fiber, vestibular, and Purkinje cell simple-spike signals were examined during sinusoidal head movement paired with visual image movement at stimulus frequencies from 0.5 to 10 Hz. A comparison of simple-spike and vestibular signals contained the information required to guide learning only at low stimulus frequencies, and a comparison of climbing-fiber and simple-spike signals contained the information required to guide learning only at high stimulus frequencies. Learning could be guided by comparison of climbing-fiber and vestibular signals at all stimulus frequencies tested, but only if climbing fiber responses were compared with the vestibular signals present 100 msec earlier. Computational analysis demonstrated that this conclusion is valid even if there is a broad range of vestibular signals at the site of plasticity. Simulations also indicated that the comparison of vestibular and climbing-fiber signals across the 100 msec delay must be implemented by a subcellular "eligibility" trace rather than by neural circuits that delay the vestibular inputs to the site of plasticity. The results suggest two alternative accounts of learning in the VOR. Either there are multiple mechanisms of learning that use different combinations of neural signals to drive plasticity, or there is a single mechanism tuned to climbing-fiber activity that follows activity in vestibular pathways by approximately 100 msec.

NASA Discipline Neuroscience↗

NASA NTRS1995

Probing transmembrane mechanical coupling and cytomechanics using magnetic twisting cytometry

We recently developed a magnetic twisting cytometry technique that allows us to apply controlled mechanical stresses to specific cell surface receptors using ligand-coated ferromagnetic microbeads and to simultaneously measure the mechanical response in living cells. Using this technique, we have previously shown the following: (i) beta 1 integrin receptors mediate mechanical force transfer across the cell surface and to the cytoskeleton, whereas other transmembrane receptors (e.g., scavenger receptors) do not; (ii) cytoskeletal stiffness increases in direct proportion to the level of stress applied to integrins; and (iii) the slope of this linear stiffening response differs depending on the shape of the cell. We now show that different integrins (beta 1, alpha V beta 3, alpha V, alpha 5, alpha 2) and other transmembrane receptors (scavenger receptor, platelet endothelial cell adhesion molecule) differ in their ability to mediate force transfer across the cell surface. In addition, the linear stiffening behavior previously observed in endothelial cells was found to be shared by other cell types. Finally, we demonstrate that dynamic changes in cell shape that occur during both cell spreading and retraction are accompanied by coordinate changes in cytoskeletal stiffness. Taken together, these results suggest that the magnetic twisting cytometry technique may be a powerful and versatile tool for studies analyzing the molecular basis of transmembrane mechanical coupling to the cytoskeleton as well as dynamic relations between changes in cytoskeletal structure and alterations in cell form and function.

NASA Discipline Number 40-20↗

NASA NTRS1995

Human osteoblast-like cells respond to mechanical strain with increased bone matrix protein production independent of hormonal regulation

Exposure of osteosarcoma cell lines to chronic intermittent strain increases the activity of mechano-sensitive cation (SA-cat) channels. The impact of mechano-transduction on osteoblast function has not been well studied. We analyzed the expression and production of bone matrix proteins in human osteoblast-like osteosarcoma cells, OHS-4, in response to chronic intermittent mechanical strain. The OHS-4 cells exhibit type I collagen production, 1,25-Dihydroxyvitamin D-inducible osteocalcin, and mineralization of the extracellular matrix. The matrix protein message level was determined from total RNA isolated from cells exposed to 1-4 days of chronic intermittent strain. Northern analysis for type I collagen indicated that strain increased collagen message after 48 h. Immunofluorescent labeling of type I collagen demonstrated that secretion was also enhanced with mechanical strain. Osteopontin message levels were increased several-fold by the application of mechanical load in the absence of vitamin D, and the two stimuli together produced an additive effect. Osteocalcin secretion was also increased with cyclic strain. Osteocalcin levels were not detectable in vitamin D-untreated control cells. However, after 4 days of induced load, significant levels of osteocalcin were observed in the medium. With vitamin D present, osteocalcin levels were 4 times higher in the medium of strained cells compared to nonstrained controls. We conclude that mechanical strain of osteoblast-like cells is sufficient to increase the transcription and secretion of matrix proteins via mechano-transduction without hormonal induction.

NASA Discipline Number 40-40↗

NASA NTRS2009

Simulation of TGF-Beta Activation by Low-Dose HZE Radiation in a Cell Culture

High charge (Z) and energy (E) (HZE) nuclei comprised in the galactic cosmic rays are main contributors to space radiation risk. They induce many lesions in living matter such as non-specific oxidative damage and the double-strand breaks (DSBs), which are considered key precursors of early and late effects of radiation. There is increasing evidence that cells respond collectively rather than individually to radiation, suggesting the importance of cell signaling1. The transforming growth factor (TGF ) is a signaling peptide that is expressed in nearly all cell type and regulates a large array of cellular processes2. TGF have been shown to mediate cellular response to DNA damage3 and to induce apoptosis in non-irradiated cells cocultured with irradiated cells4. TFG molecules are secreted by cells in an inactive complex known as the latency-associated peptide (LAP). TGF is released from the LAP by a conformational change triggered by proteases, thrombospondin-1, integrins, acidic conditions and .OH radical5. TGF then binds to cells receptors and activates a cascade of events mediated by Smad proteins6, which might interfere with the repair of DNA. Meanwhile, increasingly sophisticated Brownian Dynamics (BD) algorithms have appeared recently in the literature7 and can be applied to study the interaction of molecules with receptors. These BD computer models have contributed to the elucidation of signal transduction, ligand accumulation and autocrine loops in the epidermal growth factor (EGF) and its receptor (EFGR) system8. To investigate the possible roles of TGF in an irradiated cell culture, our Monte-Carlo simulation codes of the radiation track structure9 will be used to calculate the activation of TFG triggered by .OH produced by low doses of HZE ions. The TGF molecules will then be followed by a BD algorithm in a medium representative of a cell culture to estimate the number of activated receptors.

Plante, Ianik↗

NASA NTRS2000

Shape-dependent control of cell growth, differentiation, and apoptosis: switching between attractors in cell regulatory networks

Development of characteristic tissue patterns requires that individual cells be switched locally between different phenotypes or "fates;" while one cell may proliferate, its neighbors may differentiate or die. Recent studies have revealed that local switching between these different gene programs is controlled through interplay between soluble growth factors, insoluble extracellular matrix molecules, and mechanical forces which produce cell shape distortion. Although the precise molecular basis remains unknown, shape-dependent control of cell growth and function appears to be mediated by tension-dependent changes in the actin cytoskeleton. However, the question remains: how can a generalized physical stimulus, such as cell distortion, activate the same set of genes and signaling proteins that are triggered by molecules which bind to specific cell surface receptors. In this article, we use computer simulations based on dynamic Boolean networks to show that the different cell fates that a particular cell can exhibit may represent a preprogrammed set of common end programs or "attractors" which self-organize within the cell's regulatory networks. In this type of dynamic network model of information processing, generalized stimuli (e.g., mechanical forces) and specific molecular cues elicit signals which follow different trajectories, but eventually converge onto one of a small set of common end programs (growth, quiescence, differentiation, apoptosis, etc.). In other words, if cells use this type of information processing system, then control of cell function would involve selection of preexisting (latent) behavioral modes of the cell, rather than instruction by specific binding molecules. Importantly, the results of the computer simulation closely mimic experimental data obtained with living endothelial cells. The major implication of this finding is that current methods used for analysis of cell function that rely on characterization of linear signaling pathways or clusters of genes with common activity profiles may overlook the most critical features of cellular information processing which normally determine how signal specificity is established and maintained in living cells. Copyright 2000 Academic Press.

Review↗

NASA NTRS2001

Battery Cell By-Pass Circuit

The invention is a circuit and method of limiting the charging current voltage from a power supply net work applied to an individual cell of a plurality of cells making up a battery being charged in series. It is particularly designed for use with batteries that can be damaged by overcharging, such as Lithium-ion type batteries. In detail. the method includes the following steps: 1) sensing the actual voltage level of the individual cell; 2) comparing the actual voltage level of the individual cell with a reference value and providing an error signal representative thereof; and 3) by-passing the charging current around individual cell necessary to keep the individual cell voltage level generally equal a specific voltage level while continuing to charge the remaining cells. Preferably this is accomplished by by-passing the charging current around the individual cell if said actual voltage level is above the specific voltage level and allowing the charging current to the individual cell if the actual voltage level is equal or less than the specific voltage level. In the step of bypassing the charging current, the by-passed current is transferred at a proper voltage level to the power supply. The by-pass circuit a voltage comparison circuit is used to compare the actual voltage level of the individual cell with a reference value and to provide an error signal representative thereof. A third circuit, designed to be responsive to the error signal, is provided for maintaining the individual cell voltage level generally equal to the specific voltage level. Circuitry is provided in the third circuit for bypassing charging current around the individual cell if the actual voltage level is above the specific voltage level and transfers the excess charging current to the power supply net work. The circuitry also allows charging of the individual cell if the actual voltage level is equal or less than the specific voltage level.

Evers, Jeffrey↗

NASA NTRS2001

Battery Cell By-Pass Circuit

Susan J Mumaw↗

NASA NTRS1996

Mechanisms of Bone Mineralization and Effects of Mechanical Loading

The data suggest that PTH and PKC inhibit nodule formation, and that alternative energy sources are utilized by osteoblasts in the process of mineralization. The conditions and techniques to grow, fix, photograph, and measure bone mineralization in vitro were defined. The results are presently in preliminary form and require further assessment as follows; quantitate the surface area of nodules + treatments via computer-aided image analysis; use PTH + inhibitors of signaling pathways to determine the mechanism of nodule formation; determine how protein kinase C is involved as a promotor of nodule formation; cell proliferation vs. cell death affected by modulation of signal transduction (i.e., PTH, enzyme inhibitors and activators); identify mRNA induced or decreased in response to PTH and signaling modulators that encode proteins that regulate cell morphology, proliferation, and nodule formation. Therefore, several follow-up studies between the laboratories at NASA-Ames Research Center and my laboratory at the University of Illinois have been initiated.

Babich, Michael↗

NASA NTRS2015

Cellular Response to Bleomycin-Induced DNA Damage in Human Fibroblast Cells in Space

Living organisms are constantly exposed to space radiation that consists of energetic protons and other heavier charged particles. Whether spaceflight factors, microgravity in particular, affects on the cellular response to DNA damage induced by exposures to radiation or other toxic chemicals will have an impact on the radiation risks for the astronauts, as well as on the mutation rate in microorganisms, is still an open question. Although the possible synergistic effects of space radiation and other spaceflight factors have been investigated since the early days of the human space program, the published results were mostly conflicting and inconsistent. To investigate the effects of spaceflight on the cellular response to DNA damages, human fibroblast cells flown to the International Space Station (ISS) were treated with bleomycin for three hours in the true microgravity environment, which induces DNA damages including the double strand breaks (DSB) similar to the ionizing radiation. Damage in the DNA was measured by the phosphorylation of a histone protein H2AX (-H2AX), which showed slightly more foci in the cells on ISS than in the ground control. The expression of genes involved in the DNA damage response was also analyzed using the PCR array. Although a number of the genes, including CDKN1A and PCNA, were significantly altered in the cells after bleomycin treatment, no significant difference in the expression profile of DNA damage response genes was found between the flight and ground samples. At the time of the bleomycin treatment, the cells on the ISS were found to be proliferating faster than the ground control as measured by the percentage of cells containing positive Ti-67 signals. Our results suggested that the difference in -H2AX between flight and ground was due to the faster growth rate of the cells in space, but spaceflight did not affect the response of the DNA damage response genes to bleomycin treatment.

Lu, Tao↗

NASA NTRS2001

Ongoing cell death and immune influences on regeneration in the vestibular sensory organs

Hair cells in the vestibular organs of birds have a relatively short life span. Mature hair cells appear to die spontaneously and are then quickly replaced by new hair cells that arise from the division of epithelial supporting cells. A similar regenerative mechanism also results in hair cell replacement after ototoxic damage. The cellular basis of hair cell turnover in the avian ear is not understood. We are investigating the signaling pathways that lead to hair cell death and the relationship between ongoing cell death and cell production. In addition, work from our lab and others has demonstrated that the avian inner ear contains a resident population of macrophages and that enhanced numbers of macrophages are recruited to sites of hair cells lesions. Those observations suggest that macrophages and their secretory products (cytokines) may be involved in hair cell regeneration. Consistent with that suggestion, we have found that treatment with the anti-inflammatory drug dexamethasone reduces regenerative cell proliferation in the avian ear, and that certain macrophage-secreted cytokines can influence the proliferation of vestibular supporting cells and the survival of statoacoustic neurons. Those results suggest a role for the immune system in the process of sensory regeneration in the inner ear.

Non-NASA Center↗

NASA NTRS2000

Cell movement is guided by the rigidity of the substrate

Directional cell locomotion is critical in many physiological processes, including morphogenesis, the immune response, and wound healing. It is well known that in these processes cell movements can be guided by gradients of various chemical signals. In this study, we demonstrate that cell movement can also be guided by purely physical interactions at the cell-substrate interface. We cultured National Institutes of Health 3T3 fibroblasts on flexible polyacrylamide sheets coated with type I collagen. A transition in rigidity was introduced in the central region of the sheet by a discontinuity in the concentration of the bis-acrylamide cross-linker. Cells approaching the transition region from the soft side could easily migrate across the boundary, with a concurrent increase in spreading area and traction forces. In contrast, cells migrating from the stiff side turned around or retracted as they reached the boundary. We call this apparent preference for a stiff substrate "durotaxis." In addition to substrate rigidity, we discovered that cell movement could also be guided by manipulating the flexible substrate to produce mechanical strains in the front or rear of a polarized cell. We conclude that changes in tissue rigidity and strain could play an important controlling role in a number of normal and pathological processes involving cell locomotion.

NASA Discipline Cell Biology↗

NASA NTRS2009

Development of a GCR Event-based Risk Model

A goal at NASA is to develop event-based systems biology models of space radiation risks that will replace the current dose-based empirical models. Complex and varied biochemical signaling processes transmit the initial DNA and oxidative damage from space radiation into cellular and tissue responses. Mis-repaired damage or aberrant signals can lead to genomic instability, persistent oxidative stress or inflammation, which are causative of cancer and CNS risks. Protective signaling through adaptive responses or cell repopulation is also possible. We are developing a computational simulation approach to galactic cosmic ray (GCR) effects that is based on biological events rather than average quantities such as dose, fluence, or dose equivalent. The goal of the GCR Event-based Risk Model (GERMcode) is to provide a simulation tool to describe and integrate physical and biological events into stochastic models of space radiation risks. We used the quantum multiple scattering model of heavy ion fragmentation (QMSFRG) and well known energy loss processes to develop a stochastic Monte-Carlo based model of GCR transport in spacecraft shielding and tissue. We validated the accuracy of the model by comparing to physical data from the NASA Space Radiation Laboratory (NSRL). Our simulation approach allows us to time-tag each GCR proton or heavy ion interaction in tissue including correlated secondary ions often of high multiplicity. Conventional space radiation risk assessment employs average quantities, and assumes linearity and additivity of responses over the complete range of GCR charge and energies. To investigate possible deviations from these assumptions, we studied several biological response pathway models of varying induction and relaxation times including the ATM, TGF -Smad, and WNT signaling pathways. We then considered small volumes of interacting cells and the time-dependent biophysical events that the GCR would produce within these tissue volumes to estimate how GCR event rates mapped to biological signaling induction and relaxation times. We considered several hypotheses related to signaling and cancer risk, and then performed simulations for conditions where aberrant or adaptive signaling would occur on long-duration space mission. Our results do not support the conventional assumptions of dose, linearity and additivity. A discussion on how event-based systems biology models, which focus on biological signaling as the mechanism to propagate damage or adaptation, can be further developed for cancer and CNS space radiation risk projections is given.

Cucinotta, Francis A.↗