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All sourcesNASA NTRSDOE OSTI
NASA NTRS2002

Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency

Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH. Copyright 2002 Wiley-Liss, Inc.

Case Reports↗
NASA NTRS2002

Stability of Pseudobrookite-Type Titanium Oxides

Orthorhombic, (Bbmm), (Al, Fe, Cr, Ti)(sub 2) TiO5-(Mg, Fe)Ti2O5 solid solutions (pseudobrookites, s.l.) are found either as an oxidation product of ilmenite and/or spinel or a primary crystallizing phase in igneous and metamorphic rocks on Earth (e.g., basalt flows, crustal and mantle xenoliths, hornfels), and basaltic rocks on the Moon. Moreover, orthorhombic oxides are often part of the crystalline matrix in glass/ceramics with useful applications, and play a major role in the industrial production of TiO2. To fully exploit the potential of these compounds as petrogenetic indicators and/or useful materials we need to quantitatively understand the factors controlling their properties and stability, and thus, to extrapolate beyond the calibrating experiments. For that purpose, we need to combine thermochemistry, phase equilibrium, and in situ P-V-T-cation disorder experimental data that presently either are incomplete or lacking. Perhaps, the most complete data set is that for MgTi2O5 (karrooite) which allows the calibration of models for the Gibbs free energy of the MgTi2O5 as a function of pressure, temperature, and the Mg2+-Ti4+ distribution between the two nonequivalent octahedral sites. Consequently, the effect of cation disorder on MgTi2O5 stability, and the phase relations among MgTi2O5, other titanium oxides, and silicate minerals can be examined. Calculated phase relations in the Mg-Ti-Si-O system and phase equilibrium experiments in Fe-bearing compositions suggest that pseudobrookite-type oxides may be a more common in rocks than previously realized. However, homogeneous and heterogeneous equilibria, and crystallization paths likely affect their stability. For example, isobaric increases in temperature favor disordering and thus entropy-stabilization, in contrast, isothermal increases in pressure have the opposite effect. Although, currently, the potential effect of composition to cation disorder cannot be fully explored, it appears that enrichment in trivalent cations probably enhances entropy-stabilization and thus may increase the stability of (Al, Fe, Cr, Ti)-rich pseudobrookites relative to that of (Mg, Fe)-rich ones. In addition, high-temperature, nearly isothermal, decompression paths of olivine+orthopyroxene+oxide assemblages may favor pseudobrookites (s.l.) over rutile and/or ilmenite, in contrast, cooling at low pressures seems to favor ilmenite and/or rutile. In the case of crustal and mantle xenoliths, the presence or absence of orthorhombic oxides is probably controlled by reactions with olivine, orthopyroxene, ilmenite, and rutile. In oceanic mantle xenoliths such reactions may also involve a TiO2-enriched but not SiO2-enriched melt/fluid, because pseudobrookites (s.l.) would react with the SiO2-enriched melt/fluid to form orthopyroxene and rutile. Parenthetically, experiments and model calculations in the Mg-Ti-Si-O system suggest that low degree partial melting of low-TiO2 bulk compositions may produce Ti-enriched liquids in equilibrium with olivine, orthopyroxen ad=nd MgTi2O5, rutile or ilmenite.

Xirouchakis, Dimistrios↗
NASA NTRS1982

Chemical and physical studies of type 3 chondrites. I - Metamorphism related studies of Antarctic and other type 3 ordinary chondrites

New thermoluminescence (TL) sensitivity measurements on 17 finds and one fall are presented, and petrologic assignments are made on the basis of TL sensitivity and silicate heterogeneity. The correlation that exists between TL sensitivity and glow curve shape is discussed, with the difference in the glow curve shapes of meteorite types 3.4 and less and type 3.5 and greater being tentatively attributed to an order-disorder transition in plagioclase, the TL phosphor. A correlation between TL sensitivity and heteogeneity of the silicate composition is found, but it tends to break down in the most heterogeneous meteorites. For Antarctic meteorites, the TL data show a much more restricted range in TL sensitivity than in silicate heterogeneity. The Quinyambie meteorite is the only one not consistent with the observed trend. Several explanations are offered, none of them totally satisfactory.

Sears, D. W.↗
NASA NTRS1997

Psychosocial value of space simulation for extended spaceflight

There have been over 60 studies of Earth-bound activities that can be viewed as simulations of manned spaceflight. These analogs have involved Antarctic and Arctic expeditions, submarines and submersible simulators, land-based simulators, and hypodynamia environments. None of these analogs has accounted for all the variables related to extended spaceflight (e.g., microgravity, long-duration, heterogeneous crews), and some of the stimulation conditions have been found to be more representative of space conditions than others. A number of psychosocial factors have emerged from the simulation literature that correspond to important issues that have been reported from space. Psychological factors include sleep disorders, alterations in time sense, transcendent experiences, demographic issues, career motivation, homesickness, and increased perceptual sensitivities. Psychiatric factors include anxiety, depression, psychosis, psychosomatic symptoms, emotional reactions related to mission stage, asthenia, and postflight personality, and marital problems. Finally, interpersonal factors include tension resulting from crew heterogeneity, decreased cohesion over time, need for privacy, and issues involving leadership roles and lines of authority. Since future space missions will usually involve heterogeneous crews working on complicated objectives over long periods of time, these features require further study. Socio-cultural factors affecting confined crews (e.g., language and dialect, cultural differences, gender biases) should be explored in order to minimize tension and sustain performance. Career motivation also needs to be examined for the purpose of improving crew cohesion and preventing subgrouping, scapegoating, and territorial behavior. Periods of monotony and reduced activity should be addressed in order to maintain morale, provide meaningful use of leisure time, and prevent negative consequences of low stimulation, such as asthenia and crew member withdrawal. Leadership roles and lines of authority need to be studied further to understand the factors leading to status leveling, leadership competition, and role confusion. Finally, the relationship between crews and ground personnel should be characterized in order to minimize the displacement of anger and tension to the outside, to counter the effects of inter-group miscommunications, and to develop support strategies that can help to counter in-group/out-group conflicts. Ground-based space simulations still have a role to play in terms of understanding the impact of these factors and ways of dealing with them. In particular, issues involving language, cultural differences, gender biases, career motivation, monotonous conditions, use of free time, leadership, lines of authority, and the relationship between crews and outside monitoring personnel need to be further characterized and examined under controlled conditions. Until such time as these factors can be studied directly in space, simulations provide an opportunity to learn more about these psychosocial issues and to plan ways of minimizing their negative consequences during actual space missions.

NASA Discipline Number 00-00↗
NASA NTRS2010

Space Radiation Heart Disease Risk Estimates for Lunar and Mars Missions

The NASA Space Radiation Program performs research on the risks of late effects from space radiation for cancer, neurological disorders, cataracts, and heart disease. For mortality risks, an aggregate over all risks should be considered as well as projection of the life loss per radiation induced death. We report on a triple detriment life-table approach to combine cancer and heart disease risks. Epidemiology results show extensive heterogeneity between populations for distinct components of the overall heart disease risks including hypertension, ischaemic heart disease, stroke, and cerebrovascular diseases. We report on an update to our previous heart disease estimates for Heart disease (ICD9 390-429) and Stroke (ICD9 430-438), and other sub-groups using recent meta-analysis results for various exposed radiation cohorts to low LET radiation. Results for multiplicative and additive risk transfer models are considered using baseline rates for US males and female. Uncertainty analysis indicated heart mortality risks as low as zero, assuming a threshold dose for deterministic effects, and projections approaching one-third of the overall cancer risk. Medan life-loss per death estimates were significantly less than that of solid cancer and leukemias. Critical research questions to improve risks estimates for heart disease are distinctions in mechanisms at high doses (>2 Gy) and low to moderate doses (<2 Gy), and data and basic understanding of radiation doserate and quality effects, and individual sensitivity.

Cucinotta, Francis A.↗
NASA NTRS2021

Micromechanics-based Modeling of Laminated SiC/SiC Ceramic Matrix Composites

The behavior and response of ceramic matrix composites (CMCs), in particular silicon carbide fiber reinforced silicon carbide matrix (SiC/SiC), is affected by many factors such as variation of fiber volume fraction, residual stresses resulting from processing of the composites at high temperature, random microstructures, and the presence of matrix flaws (e.g., voids, pores, cracks etc.) as well as general material nonlinearity and heterogeneity that occurs randomly in a composite. Residual stresses arising from the phase change of constituents are evaluated in this paper and it is shown that they do influence composite strength and need to be properly accounted for. Additionally, the microstructures (location of fiber centers, coating thickness etc.) of advanced CMCs are usually disordered (or random) and fiber diameter and strength typically have a distribution. They rarely resemble the ordered fiber packing (square, rectangular, or hexagonal) that is generally assumed in micromechanics-based models with periodic boundary conditions for computational expediency. These issues raise the question of how should one model such systems effectively? Can an ordered hexagonal packed repeating unit cell (RUC) accurately represent the random microstructure behavior? How many fibers need to be included to enable accurate representation? Clearly, the number of fibers within an RUC must be limited to insure a balance between accuracy and efficiency. NASA’s in-house micromechanics-based code MAC/GMC provides a framework to analyze such RUCs for the overall composite behavior and the FEAMAC computer code provides linkage of MAC/GMC to the commercial FEA code, ABAQUS. The appropriate level of discretization of the RUC as well as the analysis method employed, i.e., Generalized Method of Cells (GMC) or High Fidelity Generalized Method of Cells (HFGMC), is investigated in this paper in the context of a unidirectional as well as a cross-ply laminated CMC. Results including effective composite properties, proportional limit stress (an important design parameter) and fatigue are shown utilizing both GMC as well as HFGMC. Finally, a few multiscale analyses are performed on smooth bar test coupons as well as test coupons with features such as open-hole and double notches using FEAMAC. Best practices and guidance are provided to take these phenomena into account and keep a proper balance between fidelity (accuracy) and efficiency. Following these guidelines can account for important physics of the problem and provide significant advantages when performing large multiscale composite structural analyses.

Ceramic Matrix Composites↗
NASA NTRS2000

Growth of Megaspherulites In a Rhyolitic Vitrophyre

Megaspherulites occur in the middle zone of a thick sequence of rhyolitic vitrophyre that occupies a small, late Eocene to early Oligocene volcanic-tectonic basin near Silver Cliff, Custer County, Colorado. Diameters of the megaspherulites range from 0.3 m to over 3.66 m, including a clay envelope. The megaspherulites are compound spherulites. consisting of an extremely large number (3.8 x 10(exp 9) to 9.9 x 10(exp 9)) of individual growth cones averaging 3 mm long by 1.25 mm wide at their termination. They are holocrystalline, very fine- to fine-grained, composed of disordered to ordered sanidine (orthoclase) and quartz, and surrounded by a thin K-feldspar, quartz rich rind, an inner clay layer with mordenite, and an outer clay layer composed wholly of 15 A montmorillonite. Whole rock analyses of the megaspherulites show a restricted composition from their core to their outer edge, with an average analyses of 76.3% SiO2, 0.34% CaO, 2.17% Na2O, 6.92% K2O, 0.83% H2O+ compared to the rhyolitic vitrophyre from which they crystallize with 71.07% SiO2, 0.57% CaO, 4.06% Na2O,4.l0% K2O, and 6.40% H2O+. The remaining oxides of Fe2O3 (total Fe), A12O3, MnO,MgO, TiO2, P2O5, Cr2O3, and trace elements show uniform distribution between the megaspherulites and the rhyolitic vitrophyre. Megaspherulite crystallization began soon after the rhyolitic lava ceased to flow as the result of sparse heterogeneous nucleation, under nonequilibrium conditions, due to a high degree of undercooling, delta T. The crystals grow with a fibrous habit which is favored by a large delta T ranging between 245 C and 295 C, despite lowered viscosity, and enhanced diffusion due to the high H2O content, ranging between 5% and 7%. Therefore, megaspherulite growth proceeded in a diffusion controlled manner, where the diffusion, rate lags behind the crystal growth rate at the crystal-liquid interface, restricting fibril lengths and diameters to the 10 micron to 15 micron and 3 micron and 8 micron ranges respectively. Once diffusion reestablishes itself at the crystallization front, a new nucleation event occurs at the terminated tips of the fibril cones and a new cone begins to develop with a similar orientation (small angle branching) to the earlier cones. During crystallization, these fibril cones impinge upon each other, resulting in fibril cone-free areas. These cone-free areas consist of coarser, fine-grained phases, dominated by quartz, which crystallized from the melt as it accumulated between the crystallizing K-feldspar fibrils of the cones. The anhydrous nature of the disordered to ordered sanidine (orthoclase) and quartz, suggests that water in the vitrophyre moved ahead of the crystallization front, resulting in a water rich fluid being enriched in Si, K, Na, Mg, Ca, Sr, Ba, and Y. The clay layers associated with the megaspherulites are therefore, the result of the deuteric alteration between the fractionated water and the vitrophyre, as indicated by the presence of the minerals mordenite and montmorillonite. This silica rich fluid also resulted in the total silicification of the megaspherulites within the upper 3 m of the vitrophyre.

Smith, Robert K.↗
NASA NTRS2017

Flexible Proteins at the Origin of Life

Almost all modern proteins possess well-defined, relatively rigid scaffolds that provide structural preorganization for desired functions. Such scaffolds require the sufficient length of a polypeptide chain and extensive evolutionary optimization. How ancestral proteins attained functionality, even though they were most likely markedly smaller than their contemporary descendants, remains a major, unresolved question in the origin of life. On the basis of evidence from experiments and computer simulations, we argue that at least some of the earliest water-soluble and membrane proteins were markedly more flexible than their modern counterparts. As an example, we consider a small, evolved in vitro ligase, based on a novel architecture that may be the archetype of primordial enzymes. The protein does not contain a hydrophobic core or conventional elements of the secondary structure characteristic of modern water-soluble proteins, but instead is built of a flexible, catalytic loop supported by a small hydrophilic core containing zinc atoms. It appears that disorder in the polypeptide chain imparts robustness to mutations in the protein core. Simple ion channels, likely the earliest membrane protein assemblies, could also be quite flexible, but still retain their functionality, again in contrast to their modern descendants. This is demonstrated in the example of antiamoebin, which can serve as a useful model of small peptides forming ancestral ion channels. Common features of the earliest, functional protein architectures discussed here include not only their flexibility, but also a low level of evolutionary optimization and heterogeneity in amino acid composition and, possibly, the type of peptide bonds in the protein backbone.

Flexible protein↗
NASA NTRS1995

Neurochemical phenotype of corticocortical connections in the macaque monkey: quantitative analysis of a subset of neurofilament protein-immunoreactive projection neurons in frontal, parietal, temporal, and cingulate cortices

The neurochemical characteristics of the neuronal subsets that furnish different types of corticocortical connections have been only partially determined. In recent years, several cytoskeletal proteins have emerged as reliable markers to distinguish subsets of pyramidal neurons in the cerebral cortex of primates. In particular, previous studies using an antibody to nonphosphorylated neurofilament protein (SMI-32) have revealed a consistent degree of regional and laminar specificity in the distribution of a subpopulation of pyramidal cells in the primate cerebral cortex. The density of neurofilament protein-immunoreactive neurons was shown to vary across corticocortical pathways in macaque monkeys. In the present study, we have used the antibody SMI-32 to examine further and to quantify the distribution of a subset of corticocortically projecting neurons in a series of long ipsilateral corticocortical pathways in comparison to short corticocortical, commissural, and limbic connections. The results demonstrate that the long association pathways interconnecting the frontal, parietal, and temporal neocortex have a high representation of neurofilament protein-enriched pyramidal neurons (45-90%), whereas short corticocortical, callosal, and limbic pathways are characterized by much lower numbers of such neurons (4-35%). These data suggest that different types of corticocortical connections have differential representation of highly specific neuronal subsets that share common neurochemical characteristics, thereby determining regional and laminar cortical patterns of morphological and molecular heterogeneity. These differences in neuronal neurochemical phenotype among corticocortical circuits may have considerable influence on cortical processing and may be directly related to the type of integrative function subserved by each cortical pathway. Finally, it is worth noting that neurofilament protein-immunoreactive neurons are dramatically affected in the course of Alzheimer's disease. The present results support the hypothesis that neurofilament protein may be crucially linked to the development of selective neuronal vulnerability and subsequent disruption of corticocortical pathways that lead to the severe impairment of cognitive function commonly observed in age-related dementing disorders.

Non-NASA Center↗
NASA NTRS2002

Coordinate late expression of trefoil peptide genes (pS2/TFF1 and ITF/TFF3) in human breast, colon, and gastric tumor cells exposed to X-rays

The trefoil factors (TFFs) are pleiotropic factors involved in organization and homeostasis of the gastrointestinal tract, estrogen responsiveness, inflammatory disorders, and carcinogenesis. In an earlier study using cDNA array technologies to identify new genes expressed in irradiated cell survivors, we isolated a cDNA clone corresponding to the reported human TFF1 gene (E. K. Balcer-Kubiczek et al., Int. J. Radiat. Biol., 75: 529-541, 1999). To determine whether expression of other TFFs is altered by ionizing radiation, we quantified changes in expression of TFF3 as well as TFF1 in RNA samples obtained from irradiated and control human tumor breast, colon, and gastric tumor cells and examined expression kinetics up to 2 weeks after irradiation. X-ray-induced TFF1 and TFF3 expression profiles were compared with those induced by hydrogen peroxide (H2O2) or 17beta-estradiol (ES). The results revealed that TFF1 and TFF3 mRNA are coinduced by X-irradiation in a subset of the lines, but substantial heterogeneity in their responses was observed in cells derived from a single cell type. TFF1 and TFF3 transcriptional response to X-irradiation differed from that to H2O2 or ES in the timing of their induction as well as tissue-type dependence, i.e., their induction pattern after X-irradiation was late and sustained, whereas their induction by H2O2 or ES was early and transient. TFF1 mRNA, protein production in the cytoplasm, and secretion in the culture supernatant were coordinately regulated after X-irradiation. There was no requirement for TP53 in this induction. These results demonstrate the existence of a novel class of radiation-responsive genes that might be involved in bystander effects.

Non-NASA Center↗