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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 163 records · Page 9
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection

Abstract Topoisomerase II alpha and beta (TOP2A and TOP2B) isoenzymes perform essential and non-redundant cellular functions. Anthracyclines induce their potent anti-cancer effects primarily via TOP2A, but at the same time they induce a dose limiting cardiotoxicity through TOP2B. Here we describe the development of theobexclass of TOP2 inhibitors that bind to a previously unidentified druggable pocket in the TOP2 ATPase domain to act as allosteric catalytic inhibitors by locking the ATPase domain conformation with the capability of isoform-selective inhibition. Through rational drug design we have developed topobexin, which interacts with residues that differ between TOP2A and TOP2B to provide inhibition that is both selective for TOP2B and superior to dexrazoxane. Topobexin is a potent protectant against chronic anthracycline cardiotoxicity in an animal model. This demonstration of TOP2 isoform-specific inhibition underscores the broader potential to improve drug specificity and minimize adverse effects in various medical treatments.

Science & Technology - Other Topics↗
DOE OSTI2024

Safety and efficacy of C. muridarum vaccines adjuvanted with CpG-1826 and four concentrations of Montanide-ISA-720-VG

It is recommended that the adjuvant Montanide ISA 720 VG be used at a concentration of 70% v/v. At this concentration, Montanide causes at the site of immunization a local granuloma that can last for several weeks. To determine the safety and protective efficacy of a Chlamydia muridarum MOMP vaccine, formulated with CpG-1826 and four different concentrations of Montanide (70%, 50%, 30% and 10%), BALB/c (H-2 d ) female mice were immunized twice intramuscularly. Local reactogenicity was significant for vaccines formulated with 70% or 50% Montanide but not for those inoculated with 30% or 10% Montanide. Robust humoral and cell mediated memory immune responses were elicited by the 70%, 50% and 30% Montanide formulations. Mice were challenged intranasally with 10 4 C. muridarum inclusion forming units (IFU). Based on changes in body weight, lungs’s weight and number of IFU recovered, mice vaccinated with the 70%, 50% and 30% Montanide formulations were significantly protected, but not mice receiving 10% Montanide. To conclude, we recommend the 30% Montanide concentration to be tested in humans and animal models to determine its safety and efficacy, in comparison to the 70% Montanide concentration currently used. The 30% Montanide formulation could significantly facilitate licensing of this adjuvant for human use.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles

Broad immune responses are needed to mitigate viral evolution and escape. To induce antibodies against conserved receptor-binding domain (RBD) regions of SARS-like betacoronavirus (sarbecovirus) spike proteins that recognize SARS-CoV-2 variants of concern and zoonotic sarbecoviruses, we developed mosaic-8b RBD nanoparticles presenting eight sarbecovirus RBDs arranged randomly on a 60-mer nanoparticle. Mosaic-8b immunizations protected animals from challenges from viruses whose RBDs were matched or mismatched to those on nanoparticles. Here, we describe neutralizing mAbs isolated from mosaic-8b-immunized rabbits, some on par with Pemgarda, the only currently FDA-approved therapeutic mAb. Deep mutational scanning, in vitro selection of spike resistance mutations, and single-particle cryo-electron microscopy structures of spike–antibody complexes demonstrated targeting of conserved RBD epitopes. Rabbit mAbs included critical D-gene segment RBD-recognizing features in common with human anti-RBD mAbs, despite rabbit genomes lacking an equivalent human D-gene segment, thus demonstrating that the immune systems of humans and other mammals can utilize different antibody gene segments to arrive at similar modes of antigen recognition. These results suggest that animal models can be used to elicit anti-RBD mAbs with similar properties to those raised in humans, which can then be humanized for therapeutic use, and that mosaic RBD nanoparticle immunization coupled with multiplexed screening represents an efficient way to generate and select broadly cross-reactive therapeutic pan-sarbecovirus and pan-SARS-CoV-2 variant mAbs.

Science & Technology - Other Topics↗
DOE OSTI2025

A protective and broadly binding antibody class engages the influenza virus hemagglutinin head at its stem interface

ABSTRACT Influenza infection and vaccination impart strain-specific immunity that protects against neither seasonal antigenic variants nor the next pandemic. However, antibodies directed to conserved sites can confer broad protection. Here, we identify and characterize a class of human antibodies that engage a previously undescribed, conserved epitope on the influenza hemagglutinin (HA) protein. Prototype antibody S8V1-157 binds at the normally occluded interface between the HA head and stem. Antibodies to this HA head–stem interface epitope are non-neutralizingin vitrobut protect against lethal influenza infection in mice. These antibodies bind to most influenza A subtypes and seasonal human variants, and are present at low frequencies in the memory B cell populations of multiple human donors. Vaccines designed to elicit these antibodies might contribute to “universal” influenza immunity. IMPORTANCE Antibodies to the influenza virus hemagglutinin (HA) protein confer the strongest protection against infection. Human antibodies elicited by infection and/or vaccination fail to protect against antigenically novel animal, pandemic, or human seasonal viruses. Improved vaccines are needed. We identify a novel class of antibodies that bind most divergent HA subtypes and all seasonal human HA antigenic variants tested. These antibodies confer protection from lethal influenza challenge in animal models. The corresponding epitope on the HA head is occluded by its interaction with the stem and is inaccessible in the well-resolved prefusion state. The immunogenicity of this head–stem interface indicates that poorly understood conformations of HA presenting widely conserved surfaces are explored in biochemical, cell-based, andin vivoassays. Head–stem interface antibodies warrant further investigation as an avenue to improve influenza vaccines and therapeutics.

Microbiology↗
DOE OSTI2024

Molecular profiles of blood from numerous species that differ in sensitivity to acute inflammation

Abstract Vertebrates differ over 100,000-fold in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation. This may inform better selection of species for pre-clinical models and could lead to new therapeutic strategies that mimic mechanisms in inflammation-resilient species to limit inflammation without causing immunosuppression.

Biochemistry & Molecular Biology↗
NASA NTRS1977

The chimpanzee as a flight candidate

Some of the characteristics that make the chimpanzee an attractive animal model (anatomy, size, intelligence, and durability) also create some very unique problems. The universally recognized problems of availability and expensive maintenance, combined with the often underestimated problems associated with routine housing, husbandry, restraint, and medical management, severely limit the availabe avenues of approach. Problems involved in using implantable, multichannel radiotelemetry systems to monitor cardiodynamics in chimpanzees are discussed.

Source record↗
NASA NTRS1982

Changes in blood volume and response to vaso-active drugs in horizontally casted primates

Experiments were performed on horizontally casted primates (male rhesus monkeys) in order to note changes in blood volume caused by horizontal restraint, to compare orthostatic tolerance before and after casting using the responses to upright tilting, to begin to uncover the cardiovascular and neural mechanisms involved in deconditioning, and to compare the data with that obtained from bed-rested human subjects and from humans exposed to weightlessness. Bolus injections of norepinephrine of 2.0 microgram/kg, phenylephrine of 4.0 microgram/kg, and nitroprusside of 2.0 microgram/kg were administered; and aortic pressure and heart rate were recorded during the injections. The results indicate that the horizontally casted primate is a valid animal model for studying the effects of simulated zero-G on the human cardiovascular system.

Dickey, D. T.↗
NASA NTRS1983

A study of stress-free living bone and its application to space flight

Observations of animals and human subjects in weightless space flight (Skylab and COSMOS) document altered bone metabolism. Bone metabolism is affected by a number of local and systemic factors. The calcification and growth of transplanted bone is independent of local muscle, nervous, and mechanical forces; therefore, transplanted bone would provide data on the role of local vs. systematic factors. Bone metabolism in living transplanted bone, devoid of stress, was investigated as a possible tool for the investigation of countermeasures against disuse bone loss. An animal model using Sprague-Dawley rats was developed for transplantation of femur bone tissue on a nutrient vascular pedicel. The long term course of these implants was assessed through the measure of regional and total bone mineral, blood flow, and methylene diphosphonate (MDP) uptake. Clomid, an estrogen agonist/antagonist, was shown to protect bone from disuse loss of minerals by retarding trabecular and cortical resorption.

Leblanc, A.↗
NASA NTRS1983

Spacelab mission 4 - The first dedicated life sciences mission

Plans for the first Spacelab-4 mission dedicated entirely to the life sciences, are reviewed. The thrust of the scientific mission scheduled for late 1985 will be to study the acute effects of weightlessness on living systems, particularly humans. The payload of the Spacelab compartment will contain 24 experiments of which approximately half will involve humans. Among the major areas of interest are cardiovascular and pulmonary function, vestibular function, renal and endocrine physiology, hematology, nitrogen balance, immunological function, the gravitational biology of plants, inflight fertilization of frogs' eggs and the effects of zero gravity on monkeys and rats. In selecting the array of experiments an effort was made to combine investigations with complementary scientific objectives to develop animal models of human biological problems.

Perry, T. W.↗
NASA NTRS1984

Alterations in bone forming cells due to reduced weight bearing

A reduction in new bone formation occurred as a result of space flight (Cosmos 1129) and in the suspended animal model of Morey-Holton (1979, 1980). The results indicate that alkaline phosphatase activity of the bone-forming cells is also reduced under these conditions, and the cells in the diaphysis are more affected than those in the metaphyseal region. In addition, these cells show (1) reduced proline incorporation into bone matrix, and (2) increased intracellular lysosomal activity. A change in the cytoskeleton could be the common factor in explaining these results. This suggestion is futher supported by the previous observations that colchicine injections result in decreased osteoblastic function.

Doty, S. B.↗
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 NTRS1990

Changes in geometrical and biomechanical properties of immature male and female rat tibia

The differences in the geometry and mechanical properties of immature male and female rat tibiae were detailed in order to provide comparative data for spaceflight, exercise, or disease experiments that use immature rats as an animal model. The experiment focuses on the particularly rapid period of growth that occurs in the Sprague-Dawley rat between 40 and 60 d of age. Tibial length and middiaphysical cross-sectional data were analyzed for eight different groups of rats according to age and sex, and tibial mechanical properties were obtained via three-point bending tests to failure. Results indicate that, during the 15 d period of rapid growth, changes in rat tibial geometry are more important than changes in bone material properties for influencing the mechanical properties of the tibia. Male tibiae changed primarily in structural properties, while in the female rats major changes in mechanical properties of the tibia were only attributable to changes in the structural properties of the bone.

Zernicke, Ronald F.↗
NASA NTRS1991

Humans in Earth Orbit and Planetary Exploration Missions; IAA Man in Space Symposium, 8th, Tashkent, Uzbek SSR, Sept. 29-Oct. 3, 1990, Selection of Papers

The present conference on findings from space life science investigations relevant to long-term earth orbit and planetary exploration missions, as well as considerations for future research projects on these issues, discusses the cardiovascular system and countermeasures against its deterioration in the microgravity environment, cerebral and sensorimotor functions, findings to date in endocrinology and immunology, the musculoskeletal system, and health maintenance and medical care. Also discussed are radiation hazards and protective systems, life-support and habitability factors, and such methodologies and equipment for long space mission research as the use of animal models, novel noninvasive techniques for space crew health monitoring, and an integrated international aerospace medical information system.

Grigor'ev, A. I.↗
NASA NTRS1992

Improving survival after tissue vaporization (Ebullism)

Exposure of unprotected humans to altitudes above 63,000 ft results in ebullism. Ebullism occurs when the vapor pressure of tissues is less than the ambient pressure and the tissues spontaneously 'boil'. This may result in rapid unconsciousness, cardiac vaporlock, pulmonary collapse, cerebral anoxia, and sometimes even death. Potential places for this include EVA accidents in space, aircraft experiencing rapid decompression at high altitudes with cabin or pressure suit failure, and accidents during pressure suit training exercises. The pathophysiology of ebullism was studied in the 40's to 60's using animal models. There is one report of a prolonged, unprotected human exposure and several anecdotal of unprotected short term exposures to near vacuum. In addition to pulmonary and neurologic concerns, unprotected exposure of the head may result in freezing of the corneal surface of the eye. Surface eye freezing may impair vision and significantly impact mission completion. At this time, little data are available on the effectiveness of conventional treatment protocols, such as hyperbaric oxygen, for ebullism induced injuries. Research is needed to assess the efficacy of other adjunctive therapies such as high frequency ventilation and cerebral protective drugs that are still under development.

Stegmann, Barbara J.↗
NASA NTRS1991

A study of lens opacification for a Mars mission

A method based on risk-related cross sections is used to estimate risks of 'stationary' cataracts caused by radiation exposures during extended missions in deep space. Estimates of the even more important risk of late degenerative cataractogenesis are made on the basis of the limited data available. Data on lenticular opacification in the New Zealand white rabbit, an animal model from which such results can be extrapolated to humans, are analyzed by the Langley cosmic ray shielding code (HZETRN) to generate estimates of stationary cataract formation resulting from a Mars mission. The effects of the composition of shielding material and the relationship between risk and LET are given, and the effects of target fragmentation on the risk coefficients are evaluated explicitly.

Shinn, J. L.↗
NASA NTRS1992

Spacelab Life Sciences 1 results

Results are presented from the experiments conducted by the first Shuttle/Spacelab mission dedicated entirely to the life sciences, the Spacelab Life Sciences 1, launched on June 5, 1991. The experiments carried out during the 9-day flight included investigations of changes in the human cardiovascular, pulmonary, renal/endocrine, blood, and vestibular systems that were brought about by microgravity. Results were also obtained from the preflight and postflight complementary experiments performed on rats, which assessed the suitability of rodents as animal models for humans. Most results verified, or expanded on, the accepted theories of adaptation to zero gravity.

Seddon, Rhea↗
NASA NTRS1993

Animal surgery in microgravity

Prototype hardware and procedures which could be applied to a surgical support system on SSF are realistically evaluated in microgravity using an animal model. Particular attention is given to the behavior of bleeding in a surgical scenario and techniques for hemostasis and fluid management.

Campbell, Mark R.↗
NASA NTRS1991

Self-Motion Perception and Motion Sickness

Motion sickness typically is considered a bothersome artifact of exposure to passive motion in vehicles of conveyance. This condition seldom has significant impact on the health of individuals because it is of brief duration, it usually can be prevented by simply avoiding the eliciting condition and, when the conditions that produce it are unavoidable, sickness dissipates with continued exposure. The studies conducted examined several aspects of motion sickness in animal models. A principle objective of these studies was to investigate the neuroanatomy that is important in motion sickness with the objectives of examining both the utility of putative models and defining neural mechanisms that are important in motion sickness.

Robert A Fox↗