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At least 1,315 records · Page 73

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NASA NTRS1999

CCAAT/enhancer-binding protein delta is a critical regulator of insulin-like growth factor-I gene transcription in osteoblasts

Insulin-like growth factor-I (IGF-I) plays a major role in promoting skeletal growth by stimulating bone cell replication and differentiation. Prostaglandin E2 and other agents that induce cAMP production enhance IGF-I gene transcription in cultured rat osteoblasts through a DNA element termed HS3D, located in the proximal part of the major rat IGF-I promoter. We previously determined that CCAAT/enhancer-binding protein delta (C/EBPdelta) is the key cAMP-stimulated regulator of IGF-I transcription in these cells and showed that it transactivates the rat IGF-I promoter through the HS3D site. We now have defined the physical-chemical properties and functional consequences of the interactions between C/EBPdelta and HS3D. C/EBPdelta, expressed in COS-7 cells or purified as a recombinant protein from Escherichia coli, bound to HS3D with an affinity at least equivalent to that of the albumin D-site, a known high affinity C/EBP binding sequence, and both DNA elements competed equally for C/EBPdelta. C/EBPdelta bound to HS3D as a dimer, with protein-DNA contact points located on guanine residues on both DNA strands within and just adjacent to the core C/EBP half-site, GCAAT, as determined by methylation interference footprinting. C/EBPdelta also formed protein-protein dimers in the absence of interactions with its DNA binding site, as indicated by results of glutaraldehyde cross-linking studies. As established by competition gel-mobility shift experiments, the conserved HS3D sequence from rat, human, and chicken also bound C/EBPdelta with similar affinity. We also found that prostaglandin E2-induced expression of reporter genes containing human IGF-I promoter 1 or four tandem copies of the human HS3D element fused to a minimal promoter and show that these effects were enhanced by a co-transfected C/EBPdelta expression plasmid. Taken together, our results provide evidence that C/EBPdelta is a critical activator of IGF-I gene transcription in osteoblasts and potentially in other cell types and species.

NASA Discipline Musculoskeletal↗

NASA NTRS2012

Reverberant Acoustic Testing and Direct Field Acoustic Testing Acoustic Standing Waves and their Impact on Structural Responses

The aerospace industry has been using two methods of acoustic testing to qualify flight hardware: (1) Reverberant Acoustic Test (RAT), (2) Direct Field Acoustic Test (DFAT). The acoustic field obtained by RAT is generally understood and assumed to be diffuse, expect below Schroeder cut-of frequencies. DFAT method of testing has some distinct advantages over RAT, however the acoustic field characteristics can be strongly affected by test setup such as the speaker layouts, number and location of control microphones and control schemes. In this paper the following are discussed based on DEMO tests performed at APL and JPL: (1) Acoustic wave interference patterns and acoustic standing waves, (2) The structural responses in RAT and DFAT.

vibro-acoustics↗

DOE OSTI2021

Neuroprotectin D1 Attenuates Blast Overpressure Induced Reactive Microglial Cells in the Cochlea

Objective/Hypothesis We examined a neuroinflammatory response associated with glial activation in the cochlea exposed to blast overpressure and evaluated the potential therapeutic efficacy of specialized pro‐resolving mediators such as neuroprotectin D1, NPD1; (10R, 17S‐dihydroxy‐4Z, 7Z, 11E, 13E, 15Z, 19Z‐docosahexaenoic acid) in a rodent blast‐induced auditory injury model. Study Design Animal Research. Methods A compressed‐air driven shock tube was used to expose anesthetized adult male Long‐Evan rats to shock waves simulating an open‐field blast exposure. Approximately 30 minutes after blast exposure, rats were treated with NPD1 (100 ng/kg body wt.) or vehicle delivered intravenously via tail vein injection. Rats were then euthanized 48 hours after blast exposure. Unexposed rats were included as controls. Tissue sections containing both middle and inner ear were prepared with hematoxylin–eosin staining to elucidate histopathological changes associated with blast exposure. Cochlear tissues were evaluated for relative expression of ionized calcium‐binding adaptor 1 (Iba1), as an indicator of microglial activation by immunohistochemistry and western blot analyses. Results Our animal model resulted in an acute injury mechanism manifested by damage to the tympanic membrane, hemorrhage, infiltration of inflammatory cells, and increased expression of Iba1 protein. Moreover, therapeutic intervention with NPD1 significantly reduced Iba1 expression in the cochlea, suggesting a reduction of a neuroinflammatory response caused by blast overpressure. Conclusions Blast overpressure resulted in an increased expression of proteins involved in gliosis within the auditory system, which were reduced by NPD1. Treatment of NPD1 suggests an effective strategy to reduce or halt auditory microglial cell activation due to primary blast exposure. Level of Evidence NA Laryngoscope , 131:E2018–E2025, 2021

Ríos, José David↗

NASA NTRS1972

Continuous animal exposure to dichloromethane

Continuous exposures of dogs, monkeys, rats and mice to 5000 ppm and 1000 ppm of dichloromethane vapor (CH2Cl2) produced severe toxic effects on dogs, rats and mice. Dogs died after 3 weeks exposure to 1000 ppm and after 6 weeks exposure to 5000 ppm. Thirty percent of the mice also succumbed during four weeks exposure to 5000 ppm CH2Cl2. Although rats survived 14 weeks exposure to 5000 ppm, they experienced subnormal weight gains. Significant gross and histopathological hepatic lesions were noted in all 3 species at death or experimental termination in 14 weeks. In addition, rats showed abnormal kidney histopathology. Fat stains disclosed mild fatty increase in monkey livers after 14 weeks exposure to 1000 ppm CH2Cl2.

Macewen, J. D.↗

NASA NTRS1977

Effect of altered gravity on temperature regulation in mammals: Investigation of gravity effect on temperature regulation in mammals

Male, Long-Evans hooded rats were instrumented for monitoring core and hypothalamic temperatures as well as shivering and nonshivering thermogenesis in response to decreased ambient temperature in order to characterize the nature of the neural controller of temperature in rats at 1G and evaluate chronic implantation techniques for the monitoring of appropriate parameters at hypergravic fields. The thermoregulatory responses of cold-exposed rats at 2G were compared to those at 1G. A computer model was developed to simulate the thermoregulatory system in the rat. Observations at 1 and 2G were extended to acceleration fields of 1.5, 3.0 and 4.0G and the computer model was modified for application to altered gravity conditions. Changes in the acceleration field resulted in inadequate heat generation rather than increased heat loss. Acceleration appears to impair the ability of the neurocontroller to appropriately integrate input signals for body temperature maintenance.

Horwitz, B. A.↗

NASA NTRS1980

Model for antiorthostatic hypokinesia - Head-down tilt effects on water and salt excretion

Water and electrolyte excretion was investigated in antiorthostatic hypokinetic and orthostatic hypokinetic and control rats in metabolic cages. Significant (t test, P less than 0.05) diuresis, natriuresis, and kaliuresis occurred in the antiorthostatic hypokinetic subjects but did not occur in either the orthostatic hypokinetic or controls. Recovery from antiorthostatic hypokinesia was characterized by retention of water, sodium, and potassium. Patterns of changes in body weight and food and water consumption were virtually identical in antiorthostatic and orthostatic hypokinetic rats and thus could not account for the differences in renal handling of water and electrolytes. Also, differences in ingestion of food and water in controls could not account for differences in excretion of water and electrolytes between these and antiorthostatic hypokinetic rats. It was concluded that the antiorthostatic position was responsible for the diuresis and natriuresis and that the antiorthostatic hypokinetic rat appears to be a good model for the study of water and elecrolyte excretion during conditions such as bed rest, water immersion, and exposure to weightlessness.

Deavers, D. R.↗

NASA NTRS1982

Knee-ligament loading properties as influenced by gravity. I - Junction with bone of 3-G rodents

The effect of 3-G conditions on the bone-to-ligament junctions of the knee is studied in rats. Results following chronic 3-G centrifugation of rats show that their bone-to-ligament junctions exhibited a force-sustaining capacity (F) which was 95 + or - 12% of the value for the control group. However, F was actually 29 + or - 5% greater for centrifuged rats than for control rats of comparable size, as the experimental animals grew to smaller body mass. It is concluded that gravity determines part of the magnitude of F, and therefore this value will probably be weaker after development in a weightless environment.

Wunder, C. C.↗

NASA NTRS1984

Mammalian gravity receptors: Structure and metabolism

High performance liquid chromatography (HPLC) instrumentation was used for amino acid analysis of rat otoconial complexes. The amino acids of otoconial complexes pooled by origin from only 10 rats were analyzed. It is indicated that it should be possible to analyze complexes from only three rats, and perhaps fewer, which means that the method should be applicable to material from space flow rats. It is suggested that the organic otoconial phase is comparable in its complement of acidic amino acids to other calcium carbonate containing materials such as fish otoliths and certain mollusk shells. The organic material is high in acidic amino acids; and the relative proportions of aspirate, glutamate, threonine and serine appear to be similar to those found in neogastropod shells. Its significance to the evolution of biomineralization processes occurring in the animal kingdom is emphasized.

Ross, M.↗

NASA NTRS1984

Set-point changes in hierarchically-arranged thermogenic systems

Rats acclimated to either 23 or 5 C were concurrently exposed to cold and hypergravic fields to test the proposal that mammals have parallel controllers for thermoregulation. The two groups of rats were used to evaluate the different relative contributions of shivering and nonshivering thermogenesis to the increased oxygen consumption of the cold-exposed rats in hypergravic fields. The lower magnitude of the cold-induced oxygen consumption observed when cold-exposed rats are moved from 1 G to hypergravic fields is probably due to an inactivation of shivering rather than nonshivering thermogenesis. The observation that shivering, but not nonshivering thermogenesis, appears to be impaired by hypergravic fields is consistent with the representation of central thermoregulation by multiple controllers.

Horowitz, J. M.↗

NASA NTRS1985

Structural Development and Gravity

Major research projects designed to elucidate the mechanisms by which gravity loading and/or fluid distribution alter bone formation and/or resorption in rat bone are reported. Projects completed include: (1) analysis of bone parameters in rats from 6 weeks to 68 weeks of age; (2) restricted access area in which rats on the model were not allowed to touch any side of the cage; and (3) the effect of dietary calcium levels on bone formation and resorption rates in controls and head-down rats.

Holton, E. M.↗

NASA NTRS1985

Role of Glucocorticoids in the Response to Unloading of Muscle Protein and Amino Acid Metabolism

Intact control (weight bearing) and suspended rats gained weight at a similar rate during a 6 day period. Adrenaectomized (adx) weight bearing rats gained less weight during this period while adrenalectomized suspended rats showed no significant weight gain. Cortisol treatment of both of these groups of animals caused a loss of body weight. Results from these studies show several important findings: (1) Metabolic changes in the extensor digitorum longus muscle of suspended rats are due primarily to increased circulating gluccorticoids; (2) Metabolic changes in the soleus due to higher steroid levels are probably potentiated by greater numbers of receptors; and (3) Not all metabolic responses in the unloaded soleus muscle are due to direct action of elevated glucocorticoids or increased sensitivity to these hormones.

Tischler, M. E.↗

NASA NTRS1985

Changes in skeletal muscle properties following hindlimb suspension

Changes in AChE regulation, the functions of the sarcoplasmic reticulum (SR), and muscle fiber-type population in the extensor digitorium longus (EDL) and soleus of male rats suspended in a nonweight-bearing position are studied. Muscle weight, AChE activity, protein content, SR calcium loading rates, and muscle types in the suspended and control rats are evaluated and compared. It is observed that following 1-4 weeks of suspension the EDL is unaffected; however, the soleus muscle weight, and protein content decrease and the AChE activity increases. The SR calcium loading rates of EDL decrease 10 percent and the soleus increase 50 percent in the suspended rats. The data reveal that the population of muscle type 1 (slow fibers) decreases and type 2 (fast fibers) increases for the soleus, and the distribution is unchanged for the EDL of the suspended rats. It is detected that a nonweight-bearing position affects the soleus (a fast-twitch muscle), but not the EDL (a slow-twitch muscle).

Patterson, G. T.↗

NASA NTRS1990

Experiment K-6-08. Biochemical and histochemical observations of vastus medialis

Muscles of the hindlimb in the rat have been used to demonstrate the effects of unloading in weightlessness and in animal models used to mimic weightlessness. The vastus medialis (VM) is discussed here. Samples were obtained from rats exposed to weightlessness for 12 days in Cosmos 1887 (Experiment K-6-08, coordinated by Dr. V.S. Oganov). The principal objective of this study was to ascertain if the vastus medialis responded to 12 days of microgravity exposure. The loss in muscle mass is greatest, -43 percent, when comparing F vs B, and least, -13 percent, when comparing F vs. V. Taken at face value these differences may be misleading. Due to the variability of the muscle weight in the basal group, these muscle mass losses may be exaggerated. In terms of percent water, there were no differences between the flight and the control groups. In spite of the limited sample, researchers conclude that muscle mass changes in the VM are not significant. Although some of the morphological parameters suggest a small degree of atrophy in the vastus medialis, the biochemical analyses (protein, RNA and DNA) suggest that these may be minimal and functionally nonsignificant. The relatively similar CS and LDH activities of VM from F and various control groups, as well as the lack of difference in LPL activity between F and S rats, suggests that there is little or no effect on the oxidative or glycolytic function of this muscle. Since the VM is chiefly a mixed fast twitch muscle, these metabolic indices of energy production are relatively unchanged. The results of VM studies are in agreement with previous observations of another type II fast twitch muscle, the EDL, from SL-3 rats which did not respond markedly to weightlessness and whole body suspension.

Musacchia, X. J.↗

NASA NTRS1992

Alterations in glucose and protein metabolism in animals subjected to simulated microgravity

Reduction of physical activity due to disease or environmental restraints, such as total bed rest or exposure to spaceflight, leads to atrophy of skeletal muscle and is frequently accompanied by alterations in food intake and the concentration of metabolic regulatory hormones such as insulin. Hindlimb suspension of laboratory rats, as a model for microgravity, also shows marked atrophy of gravity-dependent muscles along with a reduced gain in body weight. Suspended rats exhibit enhanced sensitivity to insulin-induced glucose uptake when compared with normal control rats and resistance to insulin action when compared with control rats matched similarly for reduced body weight gain. These changes are accompanied by decreased insulin binding and tyrosine kinase activity in soleus but not plantaris muscle, unchanged glucose uptake by perfused hindlimb and decreased sensitivity but not responsiveness to insulin-induced suppression of net proteolysis in hindlimb skeletal muscle. These findings suggest that loss of insulin sensitivity during muscle atrophy is associated with decreased insulin binding and tyrosine kinase activity in atrophied soleus muscle along with decreased sensitivity to the effects of insulin on suppressing net protein breakdown but not on enhancing glucose uptake by perfused hindlimb.

Mondon, C. E.↗

NASA NTRS1991

Microgravity and the lung

Results are presented from studies of the effect of microgravity on the lungs of rats flown on the Cosmos 2044 mission, and from relevant laboratory experiments. The effects of microgravity fall into five categories: topographical structure and function, the lung volumes and mechanics, the intrathoracic blood pressures and volumes, the pulmonary deposition of aerosol, and denitrogenaton during EVA. The ultrastructure of the left lungs of rats flown for 14 days on the Cosmos 2044 spacecraft and that of some tail-suspended rats disclosed presence of red blood cells in the alveolar spaces, indicating that pulmonary hemorrhage and pulmonary edema occurred in these rats. Possible causes for this phenomenon are discussed.

West, John B.↗

NASA NTRS1992

Spaceflight and age affect tibial epiphyseal growth plate histomorphometry

Growth plate histomorphometry of rats flown aboard the Soviet biosatellite Cosmos 2044, a 14-day spaceflight, was compared with that of control groups. In growth plates of flight animals, there was a significant increase in cell number per column and height of the proliferative zone and a reduction in height and cell number in the hypertrophy/calcification zone. No significant differences were found in matrix organization at the ultrastructural level of flight animals, indicating that although spacefligfht continues to affect bone growth of 15-wk-old rats, extracellular matrix is not altered in the same manner as seen previously in younger animals. All groups showed growth plate characteristics attributed to aging: lack of calcification zone, reduced hypertrophy zone, and unraveling of collagen fibrils. Tail-suspended controls did not differ from other controls in any of the parameters measured. The results suggest that growth plates of older rats are less responsive to unloading by spaceflight or suspension than those of younger rats and provide new evidence about the modifying effect of spaceflight on the growth plate.

Montufar-Solis, Dina↗

NASA NTRS1992

Ventral horn cell responses to spaceflight and hindlimb suspension

Ventral horn cells of the lumbosacral enlargement of the spinal cord were studied focusing on the succinate dehydrogenase (SDH) activity and cross-sectional area of the soma of ventral horn cells which were measured using a computer-aided image-processing system. The relationships between the soma size and SDH activities of lumber ventral horn cells after 14 days of spaceflight (Cosmos 2044) or of hindlimb suspension are considered. Three groups of rats under consideration include control, 14-day spaceflight, and 14-day hindlimb suspension. Data obtained indicate that, compared to the control group, the population distribution of SDH activities in the flight rats shifted toward higher activities, whereas in the suspended rats the distribution shifted toward lower activities. The interactive effects within individual cells showed that there was a higher percentage of small cells with high SDH activities in the flight than in the control or suspended rats. It is suggested that changes in ventral horn cells were due to factors other than simply the absence of weight support.

Jiang, Bian↗

NASA NTRS1994

Physiological Anatomical Rodent Experiment (PARE) .04 feasibility test 2

The objective of this feasibility study was to subject pregnant rats of the same age, strain, and size that will be utilized in a shuttle flight experiment to all flight conditions except the unique microgravity of space flight and determine the feasibility of the proposed experimental design to meet the experimental objectives. The study utilized facilities at NASA, Ames Research Center, Moffett Field, CA to subject the rats to the gravitational stresses of a simulated shuttle launch and simulated shuttle landing. One hundred pregnant rats were received on gestation day (G) 2 (day 1 = day of vaginal sperm) and on G7, eighty rats were laparotomized to determine the condition of pregnancy and allow assignment to test groups. The five test groups (N=10 each group) were as follows: Group 1, Nominal Flight; Group 2, Laparotomy Control; Group 3, Hysterectomy Control; Group 4, Vivarium Control; Group 5, Delayed Recovery. On G9, animals in groups 1,2,3, and 5 were subjected to a shuttle launch simulation. On G18, groups 1,2, and 3 were subjected to a shuttle landing simulation and on this same day groups 1 and 2 were subjected to unilateral hysterectomy to obtain fetuses and placentas for evaluation. Fetal crown-rump length and fetal weight of the Nominal Flight group was significantly less than the Laparotomy Control group, but placentas were similar. On G20, group 5 was subjected to a shuttle landing simulation and on this day this group received a unilateral hysterectomy and fetuses and placentas were weighed. Animals in all groups were allowed to go to term and all animals delivered between 06:00 hours G22 and 18:00 hours G23. After delivery, a blood sample was taken from each experimental dam, and they were euthanized and the thymus and adrenal glands weighed. The thymus weight from all experimental group dams was decreased relative to the Vivarium Control group but adrenal glands and hormone values in dam plasma was similar in all groups. Pups from experimental groups were tattooed for identification, the anogenital distance of male pups was measured, and all pups placed with foster dams and litter sizes were standardized to 10. There was no difference in anogenital distances between male pups from different test groups. Pups delivered from Delayed Recovery animals were smaller than pups delivered from Nominal Flight animals. On neonatal day 7, all pups were euthanized and pup adrenal glands and thymus weighed. There was no difference in weights of thymus and adrenal glands in pups euthanized at neonatal day 7. Collectively, these data confirm the feasibility of the experimental design to meet objectives of the studies proposed for shuttle flight.

Burden, Hubert W.↗