Aortic wave reflection and input impedance as a function of posture in a chronic primate model
No abstract available
NASA Discipline Cardiopulmonary↗
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From Parasite Encounter to Infection: Multiple-Scale Drivers of Parasite Richness in a Wild Social Primate Population
Host parasite diversity plays a fundamental role in ecological and evolutionary processes, yet the factors that drive it are still poorly understood. A variety of processes, operating across a range of spatial scales, are likely to influence both the probability of parasite encounter and subsequent infection. Here, we explored eight possible determinants of parasite richness, comprising rainfall and temperature at the population level, ranging behavior and home range productivity at the group level, and age, sex, body condition, and social rank at the individual level. We used a unique dataset describing gastrointestinal parasites in a terrestrial subtropical vertebrate (chacma baboons, Papio ursinus), comprising 662 faecal samples from 86 individuals representing all age-sex classes across two groups over two dry seasons in a desert population. Three mixed models were used to identify the most important factor at each of the three spatial scales (population, group, individual); these were then standardised and combined in a single, global, mixed model. Individual age had the strongest influence on parasite richness, in a convex relationship. Parasite richness was also higher in females and animals in poor condition, albeit at a lower order of magnitude than age. Finally, with a further halving of effect size, parasite richness was positively correlated to day range and temperature. These findings indicate that a range of factors influence host parasite richness through both encounter and infection probabilities, but that individual-level processes may be more important than those at the group or population level.
Benavides J. A.↗
Evolution of neuronal cell classes and types in the vertebrate retina
The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs1. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.
59 BASIC BIOLOGICAL SCIENCES↗
Squirrel Monkey Requirements for Chronic Acceleration
This study examined: (1) the ability of a small non-human primate to tolerate chronic centrifugation on a centrifuge with a radius of 0.9 m, and (2) the influence of centrifuge radius on the response of primates to hyperdynamic fields. Eight adult male squirrel monkeys were exposed to 1.5 g via centrifugation at two different radii (0.9 m and 3.0 m). Body temperature, activity, feeding and drinking were monitored. These primates did tolerate and adapt to 1.5G via centrifugation on either radius centrifuge. The results show, however, that centrifuge radius does have an effect on the responses of the primate to the hyperdynamic environment. Adaptation to the hyperdynamic environment occurred more quickly on the larger centrifuge. This study demonstrates that a small, non-human primate model, such as the squirrel monkey, could be used on a 0.9 m radius centrifuge such as is being considered by the NASA Space Station Program.
Fuller, Charles A.↗
Structure of the Receptor Binding Domain of EnvP(b)1, an Endogenous Retroviral Envelope Protein Expressed in Human Tissues
EnvP(b)1 is an endogenous retroviral envelope gene found in human and other primate genomes. We report EnvP(b)1 sequences in primate genomes consistent with an integration event between 40 and 71 million years ago. Using a highly specific polyclonal antiserum raised against the putative receptor binding domain (RBD) of human EnvP(b)1, we detected expression in human placenta, ovaries, and thymus. We found that EnvP(b)1 is proteolytically processed, and using cell-cell fusion assays in multiple primate cell lines, we demonstrated that extant EnvP(b)1 proteins from a variety of primate genomes are fusogenic. This work supports the idea that EnvP(b)1 is under purifying selection and its fusogenic activity has been maintained for over 40 million years. We determined the structure of the RBD of human EnvP(b)1, which defines structural similarities with extant leukemia viruses, despite little sequence conservation. This structure highlights a common scaffold from which novel receptor binding specificities likely evolved. The evolutionary plasticity of this domain may underlie the diversity of related Envs in circulating viruses.
59 BASIC BIOLOGICAL SCIENCES↗
Reduced meiotic recombination in rhesus macaques and the origin of the human recombination landscape
Characterizing meiotic recombination rates across the genomes of nonhuman primates is important for understanding the genetics of primate populations, performing genetic analyses of phenotypic variation and reconstructing the evolution of human recombination. Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primates in biomedical research. We constructed a high-resolution genetic map of the rhesus genome based on whole genome sequence data from Indian-origin rhesus macaques. The genetic markers used were approximately 18 million SNPs, with marker density 6.93 per kb across the autosomes. We report that the genome-wide recombination rate in rhesus macaques is significantly lower than rates observed in apes or humans, while the distribution of recombination across the macaque genome is more uniform. These observations provide new comparative information regarding the evolution of recombination in primates.
59 BASIC BIOLOGICAL SCIENCES↗
Small Particle Aerosol Exposure of African Green Monkeys to MERS-CoV as a Model for Highly Pathogenic Coronavirus Infection
Emerging coronaviruses are a global public health threat because of the potential for person-to-person transmission and high mortality rates. Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012, causing lethal respiratory disease in $\gg$35% of cases. Primate models of coronavirus disease are needed to support development of therapeutics, but few models exist that recapitulate severe disease. For initial development of a MERS-CoV primate model, 12 African green monkeys were exposed to 10 3 , 10 4 , or 10 5 PFU target doses of aerosolized MERS-CoV. We observed a dose-dependent increase of respiratory disease signs, although all 12 monkeys survived for the 28-day duration of the study. This study describes dosedependent effects of MERS-CoV infection of primates and uses a route of infection with potential relevance to MERSCoV transmission. Aerosol exposure of African green monkeys might provide a platform approach for the development of primate models of novel coronavirus diseases.
59 BASIC BIOLOGICAL SCIENCES↗
Accuracy optimized neural networks do not effectively model optic flow tuning in brain area MSTd
Accuracy-optimized convolutional neural networks (CNNs) have emerged as highly effective models at predicting neural responses in brain areas along the primate ventral stream, but it is largely unknown whether they effectively model neurons in the complementary primate dorsal stream. We explored how well CNNs model the optic flow tuning properties of neurons in dorsal area MSTd and we compared our results with the Non-Negative Matrix Factorization (NNMF) model, which successfully models many tuning properties of MSTd neurons. To better understand the role of computational properties in the NNMF model that give rise to optic flow tuning that resembles that of MSTd neurons, we created additional CNN model variants that implement key NNMF constraints – non-negative weights and sparse coding of optic flow. While the CNNs and NNMF models both accurately estimate the observer's self-motion from purely translational or rotational optic flow, NNMF and the CNNs with nonnegative weights yield substantially less accurate estimates than the other CNNs when tested on more complex optic flow that combines observer translation and rotation. Despite its poor accuracy, NNMF gives rise to tuning properties that align more closely with those observed in primate MSTd than any of the accuracy-optimized CNNs. This work offers a step toward a deeper understanding of the computational properties and constraints that describe the optic flow tuning of primate area MSTd.
60 APPLIED LIFE SCIENCES↗
The Language Research Center's Computerized Test System for environmental enrichment and psychological assessment
In the spring of 1987, we undertook to provide environmental enrichment to nonhuman primate subjects in ways that would complement and even contribute to the bio-behaviorial science that justified the monkeys' captivity. Of course, the psychological well-being of captive primates--and indeed all research species-- has been an area of intense research activity since the 1985 amendment of the Animal Welfare Act. This mandate for researchers to ensure the psychological, as well as physical, fitness of experimental animals catalyzed the humane and scientific interests of the research community. The contemporary literature is replete with proposed means both of assaying and of providing enrichment and well-being. Notwithstanding, consensus on either assessment or intervention has yet to be reached. The paradigm we employed was modelled after successful efforts with chimpanzees. An automated test system was constructed in which subjects responded to computer tasks by manipulating a joystick. The tasks, interactive game-like versions of many of the classic testing paradigms of cognitive and comparative psychology, permitted the controlled presentation of stimuli and demands without the required presence of a human experimenter. Despite significant barriers to the success, rhesus monkeys (Macaca mulatta) and a variety of other primate species (including, of course, humans) have mastered the skills necessary for testing in this paradigm. Previous experiments have illustrated the utility of the test system for addressing questions of learning, memory, attention, perception, and motivation. Additional data have been reported to support the contention that the Language Research Center's Computerized Test System (LRC-CTS) serves its other raison d'etre--providing environmental enrichment and assessing psychological well-being. This paper is designed to augment previous descriptions of the technology and the paradigm for scientists and caretakers interested in environmental enrichment and performance assessment with primates.
Non-NASA Center↗
Naphthalene-DNA Adduct Formation in a Lung Airway Explant Model: The Role of Bioactivation and Naphthalene Metabolites
Humans are widely exposed to naphthalene. Once inhaled or ingested, naphthalene is metabolized by cytochrome P450 and other enzymes to form toxic metabolites known to harm lung epithelial cells. Naphthalene metabolites circulate in the blood. Chronic naphthalene inhalation promotes lesions in the epithelium of the mouse lung and rat nose. Oral naphthalene exposure leads to DNA adduct formation in mouse lung, but the contributions of different enzymatic pathways and the metabolites they generate are not fully understood. This study explores the influence of naphthalene metabolites on DNA adduct formation in the lungs of two species (mice and primates). To isolate the lung response, conducting airway explants containing Club cells, a target for pulmonary naphthalene toxicity, were microdissected from live lung tissue and incubated with 14 C-naphthalene or its metabolites: 14 C-1,2-naphthoquinone or 14 C-naphthalene-1,2-dihydrodiol. Explants were incubated for 1 h, then processed immediately (T1), or were transferred to clean media for the remainder of the 24 h (T24), to monitor 14 C in DNA over time. Accelerator mass spectrometry analysis revealed the formation of DNA adducts by all three radiolabeled compounds by T24. Our results support the notion that P450 enzymes of the Cyp2abfgs subfamily contribute to naphthalene-induced DNA adduct formation (approximately 4-fold reduction in male mice lacking the Cyp2abfgs genes, P < 0.01). The finding that naphthalene-1,2-dihydrodiol, a stable metabolite, formed DNA adducts (102–117 adducts/10 8 nucleotides) at 24 h following addition to the culture media validates the concern that circulating naphthalene metabolites can contribute to DNA adduct formation in the lung. DNA adducts persisted to 24 h after exposure in both mouse and primate airways and at comparable levels between species (77.8 vs 129 adducts/10 8 nucleotides, respectively). Together, these results support the importance of a potential genotoxic mechanism of naphthalene and its metabolites in vivo in both mice and nonhuman primates, and possibly also in humans.
Biological and medical sciences↗
Computational simulation of coupled material degradation processes for probabilistic lifetime strength of aerospace materials
The research included ongoing development of methodology that provides probabilistic lifetime strength of aerospace materials via computational simulation. A probabilistic material strength degradation model, in the form of a randomized multifactor interaction equation, is postulated for strength degradation of structural components of aerospace propulsion systems subjected to a number of effects or primative variables. These primative variable may include high temperature, fatigue or creep. In most cases, strength is reduced as a result of the action of a variable. This multifactor interaction strength degradation equation has been randomized and is included in the computer program, PROMISS. Also included in the research is the development of methodology to calibrate the above described constitutive equation using actual experimental materials data together with linear regression of that data, thereby predicting values for the empirical material constraints for each effect or primative variable. This regression methodology is included in the computer program, PROMISC. Actual experimental materials data were obtained from the open literature for materials typically of interest to those studying aerospace propulsion system components. Material data for Inconel 718 was analyzed using the developed methodology.
Boyce, Lola↗
Pursuit Eye Movements
When viewing objects, primates use a combination of saccadic and pursuit eye movements to stabilize the retinal image of the object of regard within the high-acuity region near the fovea. Although these movements involve widespread regions of the nervous system, they mix seamlessly in normal behavior. Saccades are discrete movements that quickly direct the eyes toward a visual target, thereby translating the image of the target from an eccentric retinal location to the fovea. In contrast, pursuit is a continuous movement that slowly rotates the eyes to compensate for the motion of the visual target, minimizing the blur that can compromise visual acuity. While other mammalian species can generate smooth optokinetic eye movements - which track the motion of the entire visual surround - only primates can smoothly pursue a single small element within a complex visual scene, regardless of the motion elsewhere on the retina. This ability likely reflects the greater ability of primates to segment the visual scene, to identify individual visual objects, and to select a target of interest.
Krauzlis, Rich↗
Noninvasive markers of bone metabolism in the rhesus monkey: normal effects of age and gender
Measurement of bone turnover in conditions such as osteoporosis has been limited by the need for invasive iliac bone biopsy to reliably determine parameters of bone metabolism. Recent advances in the area of serum and urinary markers of bone metabolism have raised the possibility for noninvasive measurements; however, little nonhuman primate data exist for these parameters. The purpose of this experiment was to define the normal range and variability of several of the newer noninvasive bone markers which are currently under investigation in humans. The primary intent was to determine age and gender variability, as well as provide some normative data for future experiments in nonhuman primates. Twenty-four rhesus macaques were divided into equal groups of male and female according to the following age groupings: 3 years, 5-10 years, 15-20 years, and > 25 years. Urine was collected three times daily for a four-day period and measured for several markers of bone turnoverm including pyridinoline (PYD), deoxypyrodinoline (DPD), hydroxyproline, and creatinine. Bone mineral density measurements of the lumbar spine were performed at the beginning and end of the study period. Serum was also obtained at the time of bone densitometry for measurement of osteocalcin levels by radioimmunoassay. There were no significant differences in bone mineral density, urine PYD, or urine DPD based on gender. Bone density was lowest in the youngest animals, peaked in the 15-20-year group, but again decreased in the oldest animals. The osteocalcin, PYD, and DPD levels followed an inversely related pattern to bone density. The most important result was the relative age insensitivity of the ratio of PYD:DPD in monkeys up to age 20 years. Since bone density changes take months or years to become measurable and iliac biopsies are invasive, the PYD/DPD marker ratio may have important implications for rapid noninvasive measurement of the effects of potential treatments for osteoporosis in the non-human primate model.
NASA Discipline Musculoskeletal↗
An improved dataset for predicting mammal infecting viruses from genetic sequence information
There have been several attempts to develop machine learning (ML) models to identify human infecting viruses from their genomic sequences, with varying degrees of success. Direct comparison between models is problematic, because these models are typically trained and evaluated on different datasets with alternative data splitting schemes, features, and model performance metrics. In this paper we present a standardized dataset of mammal infecting and non-infecting viral pathogens, refined from the previous work of Mollentze et al. to include the latest literature evidence, roughly doubling the number of curated host-virus records available to the community, and new host target labels, primate and mammal. The new host labels were included for several reasons, including previous reports that classification performance is better at broader taxonomic ranks and the idea that there may be more data for primate infection that might serve as a suitable proxy for zoonotic potential and avoidance of false positives for human infection due to absence of evidence. On this dataset, we report the performance of eight machine learning models for predicting mammal-infecting viruses from their genomic sequences. We find that randomly assigning cases in our improved dataset to training/testing sets, when compared to the original assignments into training/testing in Mollentze et al., increases the overall average ROC AUC of prediction of human infection from 0.663 ± 0.070 to 0.784 ± 0.013, consistent with the reduction in phylogenetic distance between train and test sets (relative entropy change from 3.00 to 0.08). The broadest host category of mammal infection can be predicted most reliably at 0.850 ± 0.020. We share our improved dataset and code to enable standardized comparisons of machine learning methods to predict human host infections. Overall, we have presented preliminary evidence that classification of virus host infection is more tractable at higher taxonomic ranks, that unsurprisingly reducing the phylogenetic distance between training and test sets can improve predictive performance, that peptide kmer features appear to be harmful to out of sample model performance, and we are left with the question of whether models for virus host prediction can reasonably be expected to perform well in out of sample scenarios given the likelihood that viruses do not share a common ancestor. Consistent with this concern, when the data is resampled such that there is no overlap between viral families in training and test sets (relative entropy > 24), models perform no better than random chance at prediction of human infection regardless of whether kmers are included (ROC AUC 0.50 ± 0.08) or not (ROC AUC 0.50 ± 0.04).
59 BASIC BIOLOGICAL SCIENCES↗
The phylogenetic roots of addiction: compulsive drug seeking, natural and drug-sensitive reward, and the acquisition of learned habits
Our rational faculties permit us humans to maximize the utility of our actions. We perform a fundamental type of cost-benefit analysis in which we frame a problem, assign values to the different paths, and then choose from among a set of available options, the course that promises the most favorable outcome. So why then does addiction appear to be so impervious to the associated costs, so unaffected by undesired consequences, and ultimately so resistant to cognitive oversight? The answer may likely be found in the fact that the drivers for compulsive drug seeking and drug taking are located in affective brain circuits, circuits that are structured and patterned by learning with repeated activation. These deep processes exhibit significant resistance to control by our cognitive faculties. The general consensus is that addiction arises from mechanisms that overvalue the magnitude of reward, discount the associated risks, and thereby bias individuals towards compulsive pursuit of addictive drugs. Behavioral disruption and dependence appear to arise at the intersection of a number of connected but separate phenomena: expectations for the occurrence of specific events, behaviors that seek encounters with them, the ability to notice and learn nonrandom, co-occurring conditions, the prediction and valuation of consequences, the forming of enduring memories, and the drivers of focused behavior through compulsion, habits, and acquired routines. It is important to recognize that each one of these individual faculties are present and well developed across the entire phylogenetic tree of bilateral metazoans. The goal of this special volume is dedicated to exploring the degree to which inherent elements can account for addiction and addiction-associated phenomena. In much of the literature on addiction, the underlying processes are often viewed as distinctly mammalian, arising, in part, from the strong cognitive capacities of this taxon. Some phenomena may even be regarded to exist only in primates, or even solely in humans. This supposition arises from the fact that studies are conducted almost exclusively in mammals and primates, while evolutionary antecedents of the behavior are rarely considered. A more comprehensive perspective that examines drug reward and reinforcement in a wider range of organisms demonstrates that many of the component traits are actually well developed across the greater metazoan lineage, and they may well predate the emergence of a mammalian clade by a wide margin. The collection of papers assembled here supports the notion that the capacity to associate cues and quences has not arisen in mammals de novo. Rather, the neural mechanisms for detecting contingencies and for predicting future outcomes are very deeply rooted across broad phylogenetic divisions. Our understanding of an ability to associate paired events has been enriched by work in invertebrate preparations in both classical and operant conditioning scenarios [Cook and Carew, 1986, 1989a, 1989b]. The ability to learn allows us to connect cues and behavioral actions to their associated consequences. Pavlovian conditioning enriches surrounding cues with predictive value. Outcomes with positive valence generate appetitive responses and approach to the associated cues, while those perceived as aversive bring cue avoidance and withdrawal. Humans are not the only life forms capable of such short- and long-term modulations of behavior
59 BASIC BIOLOGICAL SCIENCES↗
Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation
Mycobacterium tuberculosis (Mtb) infection causes tuberculosis (TB), a disease characterized by development of granulomas. Granulomas consist of activated immune cells that cluster together to limit bacterial growth and restrict dissemination. Control of the TB epidemic has been limited by lengthy drug regimens, antibiotic resistance, and lack of a robustly efficacious vaccine. Fibrosis commonly occurs during treatment and is associated with both positive and negative disease outcomes in TB but little is known about the processes that initiate fibrosis in granulomas. Human and nonhuman primate granulomas undergoing fibrosis can have spindle-shaped macrophages with fibroblast-like morphologies suggesting a relationship between macrophages, fibroblasts, and granuloma fibrosis. This relationship has been difficult to investigate because of the limited availability of human pathology samples, the time scale involved in human TB, and overlap between fibroblast and myeloid cell markers in tissues. To better understand the origins of fibrosis in TB, we used a computational model of TB granuloma biology to identify factors that drive fibrosis over the course of local disease progression. We validated the model with granulomas from nonhuman primates to delineate myeloid cells and lung-resident fibroblasts. Our results suggest that peripheral granuloma fibrosis, which is commonly observed, can arise through macrophage-to-myofibroblast transformation (MMT). Further, we hypothesize that MMT is induced in M1 macrophages through a sequential combination of inflammatory and anti-inflammatory signaling in granuloma macrophages. We predict that MMT may be a mechanism underlying granuloma-associated fibrosis and warrants further investigation into myeloid cells as drivers of fibrotic disease.
59 BASIC BIOLOGICAL SCIENCES↗
Zika virus dynamics: Effects of inoculum dose, the innate immune response and viral interference
Experimental Zika virus infection in non-human primates results in acute viral load dynamics that can be well-described by mathematical models. The inoculum dose that would be received in a natural infection setting is likely lower than the experimental infections and how this difference affects the viral dynamics and immune response is unclear. Here we study a dataset of experimental infection of non-human primates with a range of doses of Zika virus. We develop new models of infection incorporating both an innate immune response and viral interference with that response. We find that such a model explains the data better than models with no interaction between virus and the immune response. We also find that larger inoculum doses lead to faster dynamics of infection, but approximately the same total amount of viral production.
59 BASIC BIOLOGICAL SCIENCES↗
The squirrel monkey as a candidate for space flight
Because of its size and other unique diurnal-primate characteristics, the squirrel monkey is used in: (1) actual bioflight missions, (2) in laboratory tests designed to clarify the risks to man during launch and recovery as well as in hazardous spaceflight environments; and (3) in the acquisition of data on unknown risks encountered in long duration space exploration. Pertinent data concerning samiri sciureus as described in published and unpublished reports are summarized. Topics include: taxonomy, ethology, life history, sensory-learning-motor capabilities in primate perspective, anatomy and physiology (including homeostatic adaptation to stress), susceptibility to environmental hazards, reproduction, care and clinical management, and previous use in aerospace biomedical research.
Brizzee, K. R.↗