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At least 37 records · Page 2

Homeostasis in Primates in the Hyperdynamic Environment

The influence of chronic centrifugation upon the homestatic regulation of the circadian timekeeping system was examined. The interactions of body temperature regulation and the behavioral state of arousal were studied by evaluating the influence of cephalic fluid shifts induced by lower body positive air pressure (LBPP), upon these systems. The small diurnal squirrel monkey (Saimiri sciureus) was used as the non-human primate model. Results show that the circadian timekeeping system of these primates is functional in the hyperdynamic environment, however, some of its components appear to be regulated at different homeostatic levels. The LBPP resulted in an approximate 0.7 C decrease in DBT (p 0.01). However, although on video some animals appeared drowsy during LBPP, sleep recording revealed no significant changes in state of arousal. Thus, the physiological mechanisms underlying this lowering of body temperature can be independent of the arousal state.

Fuller, C. A.↗

The effect of head-down tilt and water immersion on intracranial pressure in nonhuman primates

Intracranial pressure (ICP) is investigated in primates during and after -6-deg head-down tilt (HDT) and immersion in water to examine the effects of the headward fluid shift related to spaceflight. Following the HDT the primates are subjected to head-out thermoneutral water immersion, and the ICP is subsequently measured. ICP is found to increase from 3.8 +/- 1.1 to 5.3 +/- 1.3 mm Hg during the horizontal control period. ICP stabilizes at -6.3 +/- 1.3 mm Hg and then increases to -2.2 +/- 1.9 mm Hg during partial immersion, and ICP subsequently returns to preimmersion levels after immersion. These data indicate that exposure to HDT or water immersion lead to an early sharp increase in ICP, and water immersion alone leads to higher ICP levels. A significant conclusion of the work is that the ICP did not approach pathological levels, and this finding is relevant to human spaceflight research.

Keil, Lanny C.↗

Learning about primates' learning, language, and cognition

Results are presented of many years of research on the methods of teaching primates the language and cognitive skills which were long considered to be unteachable to particular species of primates. It was found that chimpanzee subjects could not only learn a number of 'stock sentences' but to use them in variations and several combinations for the purpose of solving various problems. Apes placed in different rooms could be taught to communicate via computer, and collaborate with each other on doing specific tasks. Contrary to expectations, young rhesus monkeys proved to be able to learn as much as the chimpanzee species.

Rumbaugh, Duane M.↗

Evaluation of Flow Biosensor Technology in a Chronically-Instrumented Non-Human Primate Model

The Physiology Research Branch of Brooks AFB conducts both human and non-human primate experiments to determine the effects of microgravity and hypergravity on the cardiovascular system and to indentify the particular mechanisms that invoke these responses. Primary investigative research efforts in a non-human primate model require the calculation of total peripheral resistance (TPR), systemic arterial compliance (SAC), and pressure-volume loop characteristics. These calculations require beat-to-beat measurement of aortic flow. We have evaluated commercially available electromagnetic (EMF) and transit-time flow measurement techniques. In vivo and in vitro experiments demonstrated that the average error of these techniques is less than 25 percent for EMF and less than 10 percent for transit-time.

SC Koenig↗

Microgravity Flight - Accommodating Non-Human Primates

Spacelab Life Sciences-3 (SLS-3) was scheduled to be the first United States man-tended microgravity flight containing Rhesus monkeys. The goal of this flight as in the five untended Russian COSMOS Bion flights and an earlier American Biosatellite flight, was to understand the biomedical and biological effects of a microgravity environment using the non-human primate as human surrogate. The SLS-3/Rhesus Project and COSMOS Primate-BIOS flights all utilized the rhesus monkey Macaca mulatta. The ultimate objective of all flights with an animal surrogate has been to evaluate and understand biological mechanisms at both the system and cellular level, thus enabling rational effective countermeasures for future long duration human activity under microgravity conditions and enabling technical application to correction of common human physiological problems within earth's gravity, e.g., muscle strength and reloading, osteoporosis, immune deficiency diseases. Hardware developed for the SLS-3/Rhesus Project was the result of a joint effort with the French Centre National d'Etudes Spatiales (CNES) and the United States National Aeronautics and Space Administration (NASA) extending over the last decade. The flight hardware design and development required implementation of sufficient automation to insure flight crew and animal bio-isolation and maintenance with minimal impact to crew activities. A variety of hardware of varying functional capabilities was developed to support the scientific objectives of the original 22 combined French and American experiments, along with 5 Russian co-investigations, including musculoskeletal, metabolic, and behavioral studies. Unique elements of the Rhesus Research Facility (RRF) included separation of waste for daily delivery of urine and fecal samples for metabolic studies and a psychomotor test system for behavioral studies along with monitored food measurement. As in untended flights, telemetry measurements would allow monitoring of thermoregulation, muscular, and cardiac responses to weightlessness. In contrast, the five completed Cosmos/Bion flights, lacked the metabolic samples and behavioral task monitoring, but did facilitate studies of the neurovestibular system during several of the flights. The RRF accommodated two adult 8-11 kg rhesus monkeys, while the Russian experiments and hardware were configured for a younger animal in the 44 kg range. Both the American and Russian hardware maintained a controlled environmental system, specifically temperature, humidity, a timed lighting cycle, and had means for providing food and fluids to the animal(s). Crew availability during a Shuttle mission was to be an optimal condition for retrieval and refrigeration of the animal urine samples along with a manual calcein injection which could lead to greater understanding of bone calcium incorporation. A special portable bioisolation glove box was under development to support this aspect of the experiment profile along with the capability of any contingency human intervention. As a result of recent U.S./Russian negotiations, funding for Space Station, and a series of other events, the SLS-3 mission was cancelled and applicable Rhesus Project experiments incorporated into the Russian Bion 11 and 12 missions. A presentation of the RRF and COSMOS/Bion rhesus hardware is presented along with current plans for the hardware.

Dalton, Bonnie P.↗

Microgravity Flight: Accommodating Non-Human Primates

Spacelab Life Sciences-3 (SLS-3) was scheduled to be the first United States man-tended microgravity flight containing Rhesus monkeys. The goal of this flight as in the five untended Russian COSMOS Bion flights and an earlier American Biosatellite flight, was to understand the biomedical and biological effects of a microgravity environment using the non-human primate as human surrogate. The SLS-3/Rhesus Project and COSMOS Primate-BIOS flights all utilized the rhesus monkey, Macaca mulatta. The ultimate objective of all flights with an animal surrogate has been to evaluate and understand biological mechanisms at both the system and cellular level, thus enabling rational effective countermeasures for future long duration human activity under microgravity conditions and enabling technical application to correction of common human physiological problems within earth's gravity, e.g., muscle strength and reloading, osteoporosis, immune deficiency diseases. Hardware developed for the SLS-3/Rhesus Project was the result of a joint effort with the French Centre National d'Etudes Spatiales (CNES) and the United States National Aeronautics and Space Administration (NASA) extending over the last decade. The flight hardware design and development required implementation of sufficient automation to insure flight crew and animal bio-isolation and maintenance with minimal impact to crew activities. A variety of hardware of varying functional capabilities was developed to support the scientific objectives of the original 22 combined French and American experiments, along with 5 Russian co-investigations, including musculoskeletal, metabolic, and behavioral studies. Unique elements of the Rhesus Research Facility (RRF) included separation of waste for daily delivery of urine and fecal samples for metabolic studies and a psychomotor test system for behavioral studies along with monitored food measurement. As in untended flights, telemetry measurements would allow monitoring of thermoregulation, muscular, and cardiac responses to weightlessness. In contrast, the five completed Cosmos/Bion flights, lacked the metabolic samples and behavioral task monitoring, but did facilitate studies of the neurovestibular system during several of the flights. The RRF accommodated two adult 8-11 kg rhesus monkeys, while the Russian experiments and hardware were configured for a younger animal in the 44 kg range. Both the American and Russian hardware maintained a controlled environmental system, specifically temperature, humidity, a timed lighting cycle, and had means for providing food and fluids to the animal(s). Crew availability during a Shuttle mission was to be an optimal condition for retrieval and refrigeration of the animal urine samples along with a manual calcein injection which could lead to greater understanding of bone calcium incorporation. A special portable bioisolation glove box was under development to support this aspect of the experiment profile along with the capability of any contingency human intervention. As a result of recent U.S./Russian negotiations, funding for Space Station, and a series of other events, the SLS-3 mission was cancelled and applicable Rhesus Project experiments incorporated into the Russian Bion 11 and 12 missions. A presentation of the RRF and COSMOS/Bion rhesus hardware is presented along with current plans for the hardware.

Dalton, Bonnie P.↗

Microgravity Flight - Accommodating Non-Human Primates

Spacelab Life Sciences-3 (SLS-3) was scheduled to be the first United States man-tended microgravity flight containing Rhesus monkeys. The goal of this flight as in the five untended Russian COSMOS Bion flights and an earlier American Biosatellite flight, was to understand the biomedical and biological effects of a microgravity environment using the non-human primate as human surrogate. The SLS-3/Rhesus Project and COSMOS Primate-BIOS flights all utilized the rhesus monkey, Macaca mulatta. The ultimate objective of all flights with an animal surrogate has been to evaluate and understand biological mechanisms at both the system and cellular level, thus enabling rational effective countermeasures for future long duration human activity under microgravity conditions and enabling technical application to correction of common human physiological problems within earth's gravity, e.g., muscle strength and reloading, osteoporosis, immune deficiency diseases. Hardware developed for the SLS-3/Rhesus Project was the result of a joint effort with the French Centre National d'Etudes Spatiales (CNES) and the United States National Aeronautics and Space Administration (NASA) extending over the last decade. The flight hardware design and development required implementation of sufficient automation to insure flight crew and animal bio-isolation and maintenance with minimal impact to crew activities. A variety of hardware of varying functional capabilities was developed to support the scientific objectives of the original 22 combined French and American experiments, along with 5 Russian co-investigations, including musculoskeletal, metabolic, and behavioral studies. Unique elements of the Rhesus Research Facility (RRF) included separation of waste for daily delivery of urine and fecal samples for metabolic studies and a psychomotor test system for behavioral studies along with monitored food measurement. As in untended flights, telemetry measurements would allow monitoring of thermoregulation, muscular, and cardiac responses to weightlessness. In contrast, the five completed Cosmos/Bion flights, lacked the metabolic samples and behavioral task monitoring, but did facilitate studies of the neurovestibular system during several of the flights.

Dalton, Bonnie P.↗

Visually induced adaptation in three-dimensional organization of primate vestibuloocular reflex

The adaptive plasticity of the spatial organization of the vestibuloocular reflex (VOR) has been investigated in intact and canal-plugged primates using 2-h exposure to conflicting visual (optokinetic, OKN) and vestibular rotational stimuli about mutually orthogonal axes (generating torsional VOR + vertical OKN, torsional VOR + horizontal OKN, vertical VOR + horizontal OKN, and horizontal VOR + vertical OKN). Adaptation protocols with 0.5-Hz (+/-18 degrees ) head movements about either an earth-vertical or an earth-horizontal axis induced orthogonal response components as high as 40-70% of those required for ideal adaptation. Orthogonal response gains were highest at the adapting frequency with phase leads present at lower and phase lags present at higher frequencies. Furthermore, the time course of adaptation, as well as orthogonal response dynamics were similar and relatively independent of the particular visual/vestibular stimulus combination. Low-frequency (0. 05 Hz, vestibular stimulus: +/-60 degrees ; optokinetic stimulus: +/-180 degrees ) adaptation protocols with head movements about an earth-vertical axis induced smaller orthogonal response components that did not exceed 20-40% of the head velocity stimulus (i.e., approximately 10% of that required for ideal adaptation). At the same frequency, adaptation with head movements about an earth-horizontal axis generated large orthogonal responses that reached values as high as 100-120% of head velocity after 2 h of adaptation (i.e., approximately 40% of ideal adaptation gains). The particular spatial and temporal response characteristics after low-frequency, earth-horizontal axis adaptation in both intact and canal-plugged animals strongly suggests that the orienting (and perhaps translational) but not inertial (velocity storage) components of the primate otolith-ocular system exhibit spatial adaptability. Due to the particular nested arrangement of the visual and vestibular stimuli, the optic flow pattern exhibited a significant component about the third spatial axis (i.e., orthogonal to the axes of rotation of the head and visual surround) at twice the oscillation frequency. Accordingly, the adapted VOR was characterized consistently by a third response component (orthogonal to both the axes of head and optokinetic drum rotation) at twice the oscillation frequency after earth-horizontal but not after earth-vertical axis 0.05-Hz adaptation. This suggests that the otolith-ocular (but not the semicircular canal-ocular) system can adaptively change its spatial organization at frequencies different from those of the head movement.

Non-NASA Center↗

Evaluation of transit-time and electromagnetic flow measurement in a chronically instrumented nonhuman primate model

The Physiology Research Branch at Brooks AFB conducts both human and nonhuman primate experiments to determine the effects of microgravity and hypergravity on the cardiovascular system and to identify the particular mechanisms that invoke these responses. Primary investigative efforts in our nonhuman primate model require the determination of total peripheral resistance, systemic arterial compliance, and pressure-volume loop characteristics. These calculations require beat-to-beat measurement of aortic flow. This study evaluated accuracy, linearity, biocompatability, and anatomical features of commercially available electromagnetic (EMF) and transit-time flow measurement techniques. Five rhesus monkeys were instrumented with either EMF (3 subjects) or transit-time (2 subjects) flow sensors encircling the proximal ascending aorta. Cardiac outputs computed from these transducers taken over ranges of 0.5 to 2.0 L/min were compared to values obtained using thermodilution. In vivo experiments demonstrated that the EMF probe produced an average error of 15% (r = .896) and 8.6% average linearity per reading, and the transit-time flow probe produced an average error of 6% (r = .955) and 5.3% average linearity per reading. Postoperative performance and biocompatability of the probes were maintained throughout the study. The transit-time sensors provided the advantages of greater accuracy, smaller size, and lighter weight than the EMF probes. In conclusion, the characteristic features and performance of the transit-time sensors were superior to those of the EMF sensors in this study.

Non-NASA Center↗

Effect of upright tilt on ventricular/vascular coupling in chronically instrumented primates

Studies of the hydraulic loading conditions on the heart in humans, especially pulsatile load, have primarily been limited to the supine state. Therefore, we have chosen a nonhuman primate model, the baboon, to assess left ventricular/vascular coupling in both supine and upright positions. Primate subjects were studied by catheterization under sedation and then after surgical implantation of transducers. This allowed the evaluation of postural stress in the chronically instrumented conscious baboon and then after light dissociative doses of ketamine. Basic hemodynamic variables were evaluated for baboons in supine and upright positions. Fourier analysis was applied to aortic pressure and flow to obtain input and characteristic impedance and the ratio of pulsatile (Wp) to total (Wt) left ventricular power (Wp/Wt). The aortic reflected, or backward, pressure was also calculated. Peripheral resistance increased (P = 0.01) and reflected pressure decreased (17.74 +/- 1.50 vs. 15.21 +/- 2 mmHg; P < 0.01) in upright subjects. Characteristic impedance and Wp/Wt were unchanged. Postoperatively, peripheral resistance increased (2,651 +/- 311 vs. 3,667 +/- 276; P < 0.05) and mean power and Wt decreased (P < 0.01) without changes in reflected pressure. All variables were unchanged after light dissociative doses of ketamine. Thus there is no significant change in efficiency of left ventricular/vascular coupling formulated in terms of Wp/Wt or input impedance with postural stress.

NASA Program Space Physiology and Countermeasures↗

Clinicopathologic and Transcriptomic Analysis of Radiation-Induced Lung Injury in Nonhuman Primates

Radiation-induced lung injury (RILI) is a progressive condition with an early phase (radiation pneumonitis) and a late phase (lung fibrosis). RILI may occur after partial-body ionizing radiation exposures or internal radioisotope exposure, with wide individual variability in timing and extent of lung injury. This study aimed to provide new insights into the pathogenesis and progression of RILI in the nonhuman primate (NHP) rhesus macaque model.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Multidrug-resistant Shigella flexneri outbreak affecting humans and non-human primates in New Mexico, USA

Shigellosis is a gastrointestinal infection caused by species of Shigella . A large outbreak of Shigella flexneri serotype 2a occurred in Albuquerque, New Mexico between May 2021 and November 2023 that involved humans and non-human primates (NHP) from a local zoo. We analyzed the genomes of 202 New Mexican isolates as well as 15 closely related isolates from other states, and four from NHP. The outbreak was initially detected within men who have sex with men but then predominantly affected people experiencing homelessness. Nearly 70% of cases were hospitalized and there was one human death. The outbreak extended into Albuquerque’s BioPark Zoo, causing high morbidity and six deaths in NHPs. All isolates were multidrug-resistant, including towards fluoroquinolones, a first line treatment option which led to treatment failures in human and NHP populations. We show the circulation of the same S. flexneri strain in humans and NHPs, causing fatalities in both populations. This study demonstrates the threat of antimicrobial resistant organisms to vulnerable human and NHP populations and emphasizes the value of genomic surveillance within a One Health framework.

59 BASIC BIOLOGICAL SCIENCES↗

Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates

Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 μg of the mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs after SARS-CoV-2 challenge in vaccinated animals and most strongly correlated with levels of anti–S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway. Passive transfer of mRNA-1273–induced immunoglobulin G to naïve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine–induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs.

60 APPLIED LIFE SCIENCES↗

CpG ODN D35 improves the response to abbreviated low-dose pentavalent antimonial treatment in non-human primate model of cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) affects the lives of 0.7–1 million people every year causing lesions that take months to heal. These lesions can result in disfiguring scars with psychological, social and economic consequences. Antimonials are the first line of therapy for CL, however the treatment is lengthy and linked to significant toxicities; further, its efficacy is variable and resistant parasites are emerging. Shorter or lower dose antimonial treatment regimens, which would decrease the risk of adverse events and improve patient compliance, have shown reduced efficacy and further increase the risk emergence of antimonial-resistant strains. The progression of lesions in CL is partly determined by the immune response it elicits, and previous studies showed that administration of immunomodulatory type D CpG ODNs, magnifies the immune response to Leishmania and reduces lesion severity in nonhuman primates (NHP) challenged with Leishmania major or Leishmania amazonensis. Here we explored whether the addition of a single dose of immunomodulating CpG ODN D35 augments the efficacy of a short-course, low-dose pentavalent antimonial treatment regimen. Results show that macaques treated with D35 plus 5mg/kg sodium stibogluconate (SbV ) for 10 days had smaller lesions and reduced time to re-epithelization after infection with Leishmania major. No toxicities were evident during the studies, even at doses of D35 10 times higher than those used in treatment. Critically, pentavalent antimonial treatment did not modify the ability of D35 to induce type I IFNs. The findings support the efficacy of D35 as adjuvant therapy for shorter, low dose pentavalent antimonial treatment.

59 BASIC BIOLOGICAL SCIENCES↗

Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates

The induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several human-derived broadly neutralizing antibodies.

59 BASIC BIOLOGICAL SCIENCES↗

Broadly neutralizing humanized SARS-CoV-2 antibody binds to a conserved epitope on Spike and provides antiviral protection through inhalation-based delivery in non-human primates

The COVID-19 pandemic represents a global challenge that has impacted and is expected to continue to impact the lives and health of people across the world for the foreseeable future. The rollout of vaccines has provided highly anticipated relief, but effective therapeutics are required to further reduce the risk and severity of infections. Monoclonal antibodies have been shown to be effective as therapeutics for SARS-CoV-2, but as new variants of concern (VoC) continue to emerge, their utility and use have waned due to limited or no efficacy against these variants. Furthermore, cumbersome systemic administration limits easy and broad access to such drugs. As well, concentrations of systemically administered antibodies in the mucosal epithelium, a primary site of initial infection, are dependent on neonatal Fc receptor mediated transport and require high drug concentrations. To reduce the viral load more effectively in the lung, we developed an inhalable formulation of a SARS-CoV-2 neutralizing antibody binding to a conserved epitope on the Spike protein, ensuring pan-neutralizing properties. Administration of this antibody via a vibrating mesh nebulization device retained antibody integrity and resulted in effective distribution of the antibody in the upper and lower respiratory tract of non-human primates (NHP). In comparison with intravenous administration, significantly higher antibody concentrations can be obtained in the lung, resulting in highly effective reduction in viral load post SARS-CoV-2 challenge. This approach may reduce the barriers of access and uptake of antibody therapeutics in real-world clinical settings and provide a more effective blueprint for targeting existing and potentially emerging respiratory tract viruses.

60 APPLIED LIFE SCIENCES↗

Factorized visual representations in the primate visual system and deep neural networks

Object classification has been proposed as a principal objective of the primate ventral visual stream and has been used as an optimization target for deep neural network models (DNNs) of the visual system. However, visual brain areas represent many different types of information, and optimizing for classification of object identity alone does not constrain how other information may be encoded in visual representations. Information about different scene parameters may be discarded altogether (‘invariance’), represented in non-interfering subspaces of population activity (‘factorization’) or encoded in an entangled fashion. In this work, we provide evidence that factorization is a normative principle of biological visual representations. In the monkey ventral visual hierarchy, we found that factorization of object pose and background information from object identity increased in higher-level regions and strongly contributed to improving object identity decoding performance. We then conducted a large-scale analysis of factorization of individual scene parameters – lighting, background, camera viewpoint, and object pose – in a diverse library of DNN models of the visual system. Models which best matched neural, fMRI, and behavioral data from both monkeys and humans across 12 datasets tended to be those which factorized scene parameters most strongly. Notably, invariance to these parameters was not as consistently associated with matches to neural and behavioral data, suggesting that maintaining non-class information in factorized activity subspaces is often preferred to dropping it altogether. Thus, we propose that factorization of visual scene information is a widely used strategy in brains and DNN models thereof.

59 BASIC BIOLOGICAL SCIENCES↗