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Sample records for non-human primate bac

  1. A non-human primate BAC resource to study interchromosomal segmental duplications.

    PubMed

    Kirsch, S; Hodler, C; Schempp, W

    2009-01-01

    Segmental duplications (SDs) are involved in the reshaping and evolutionary development of primate genome architecture. Their intrinsic property to promote genomic instability facilitates genome rearrangements, thereby contributing to karyotype diversity in primates. However, comparative analyses of SDs based on whole-genome shotgun assemblies of primate genomes may lead to a distorted view of their evolutionary dynamics as this method will incorrectly assemble or simply not represent these regions. Therefore high-quality sequences of chromosomally assigned SDs are indispensable for unraveling the amplification and dispersal pattern of SDs during primate evolution. Here, we use an updated version of the ancestral duplicon state of the non-palindromic SDs of all 4 human Y-chromosome euchromatin/heterochromatin transition regions to perform a survey of duplicons genome-wide across 7 primate species. By adjusting experimental conditions to the mean nucleotide sequence divergence to human we identified 11,075 BAC clones carrying primate orthologs or paralogs of human Y chromosome-derived duplicons. Preliminary results indicate lineage-specific amplification of duplicons in prosimians and gibbons. This BAC-based framework represents the first complete set of a defined number of duplicons over 60 million years of primate evolution. Comparative sequence analysis of this genetic resource can contribute to our deeper understanding of the impact of segmental duplications on primate genome evolution. (c) 2009 S. Karger AG, Basel.

  2. [Ecotourism disturbances to non-human primates].

    PubMed

    Fan, Peng-Lai; Xiang, Zuo-Fu

    2013-02-01

    In tandem with economic growth and rising living conditions, ecotourism has increasingly gained popularity among the Chinese public. Non-human primates, as charismatic animals and the closest relatives of human beings, have shown a strong affinity in attracting the general public and raising money, and for that reason a variety of monkey parks, valleys, and islands are becoming increasingly popular in China. Though successful in raising a substantial sum of money for the managing agency of a nature reserve, there may be negative impacts on monkey groups used in ecotourism. Here, to establish effective guards for non-human primates involved in ecotourism, we present a review on tourism disturbance and summarize the negative impacts on behavioral patterns, reproduction, and health condition of animals.

  3. Non-Human Primate Models of Tuberculosis.

    PubMed

    Peña, Juliet C; Ho, Wen-Zhe

    2016-08-01

    Among the animal models of tuberculosis (TB), the non-human primates, particularly rhesus macaques (Macaca fascicularis) and cynomolgus macaques (Macaca mulatta), share the greatest anatomical and physiological similarities with humans. Macaques are highly susceptible to Mycobacterium tuberculosis infection and manifest the complete spectrum of clinical and pathological manifestations of TB as seen in humans. Therefore, the macaque models have been used extensively for investigating the pathogenesis of M. tuberculosis infection and for preclinical testing of drugs and vaccines against TB. This review focuses on published major studies that exemplify how the rhesus and cynomolgus macaques have enhanced and may continue to advance global efforts in TB research.

  4. Microgravity Flight - Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1994-01-01

    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

  5. Microgravity Flight - Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1994-01-01

    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

  6. Promoting Autoimmune Diabetes in Non-Human Primates

    DTIC Science & Technology

    2014-04-01

    0417 TITLE: Promoting Autoimmune Diabetes in Non -Human Primates PRINCIPAL INVESTIGATOR: Massimo Trucco, M.D...11 January 2014 4. TITLE AND SUBTITLE Promoting Autoimmune Diabetes in Non -Human Primates 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11...the genetically diabetes -prone non -obese diabetic mouse strain, whose etio-pathogenesis is widely-held to parallel the one that occurs in humans

  7. Microgravity Flight: Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1995-01-01

    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

  8. Microgravity Flight - Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1994-01-01

    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

  9. Microgravity Flight: Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1995-01-01

    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

  10. Microgravity Flight - Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1994-01-01

    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

  11. Characterization of interleukin-8 receptors in non-human primates

    SciTech Connect

    Alvarez, V.; Coto, E.; Gonzalez-Roces, S.; Lopez-Larrea, C.

    1996-09-01

    Interleukin-8 is a chemokine with a potent neutrophil chemoatractant activity. In humans, two different cDNAs encoding human IL8 receptors designated IL8RA and IL8RB have been cloned. IL8RA binds IL8, while IL8RB binds IL8 as well as other {alpha}-chemokines. Both human IL8Rs are encoded by two genes physically linked on chromosome 2. The IL8RA and IL8RB genes have open reading frames (ORF) lacking introns. By direct sequencing of the polymerase chain reaction products, we sequenced the IL8R genes of cell lines from four non-human primates: chimpanzee, gorilla, orangutan, and macaca. The IL8RB encodes an ORF in the four non-human primates, showing 95%-99% similarity to the human IL8RB sequence. The IL8RA homologue in gorilla and chimpanzee consisted of two ORF 98%-99% identical to the human sequence. The macaca and orangutan IL8RA homologues are pseudogenes: a 2 base pair insertion generated a sequence with several stop codons. In addition, we describe the physical linkage of these genes in the four non-human primates and discuss the evolutionary implications of these findings. 25 refs., 5 figs., 3 tabs.

  12. Voice processing in human and non-human primates.

    PubMed

    Belin, Pascal

    2006-12-29

    Humans share with non-human primates a number of voice perception abilities of crucial importance in social interactions, such as the ability to identify a conspecific individual from its vocalizations. Speech perception is likely to have evolved in our ancestors on the basis of pre-existing neural mechanisms involved in extracting behaviourally relevant information from conspecific vocalizations (CVs). Studying the neural bases of voice perception in primates thus not only has the potential to shed light on cerebral mechanisms that may be--unlike those involved in speech perception--directly homologous between species, but also has direct implications for our understanding of how speech appeared in humans. In this comparative review, we focus on behavioural and neurobiological evidence relative to two issues central to voice perception in human and non-human primates: (i) are CVs 'special', i.e. are they analysed using dedicated cerebral mechanisms not used for other sound categories, and (ii) to what extent and using what neural mechanisms do primates identify conspecific individuals from their vocalizations?

  13. Whisper-like behavior in a non-human primate.

    PubMed

    Morrison, Rachel; Reiss, Diana

    2013-01-01

    In humans, whispering has evolved as a counteractive strategy against eavesdropping. Some evidence for whisper-like behavior exists in a few other species, but has not been reported in non-human primates. We discovered the first evidence of whisper-like behavior in a non-human primate, the cotton-top tamarin (Saguinus oedipus), in the course of investigating their use of human-directed mobbing calls. We exposed a family of captive cotton-top tamarins to a supervisor who previously elicited a strong mobbing response. Simultaneous audio-video recordings documented the animals' behavioral and vocal responses in the supervisor's presence and absence. Rather than exhibiting a mobbing response and producing loud human-directed mobbing calls, the tamarins exhibited other anti-predator behaviors and produced low amplitude vocalizations that initially eluded our detection. A post-hoc analysis of the data was conducted to test a new hypothesis-the tamarins were reducing the amplitude of their vocalizations in the context of exposure to a potential threat. Consistent with whisper-like behavior, the amplitude of the tamarins' vocalizations was significantly reduced only in the presence of the supervisor. Due to its subtle properties, this phenomenon may have eluded detection in this species. Increasing evidence of whisper-like behavior in non-human species suggests that such low amplitude signaling may represent a convergence in a communication strategy amongst highly social and cooperative species.

  14. [Diversity and development of positional behavior in non-human primates].

    PubMed

    Zhang, Jing; Qi, Xiao-Guang; Zhang, Kan; Zhang, Pei; Guo, Song-Tao; Wei, Wei; Li, Bao-Guo

    2012-10-01

    In long-term evolution, wildlife in general and primates in particular have formed specific patterns of behavior to adapt to a diverse variety of habitat environments. Current research on positional behavior in non-human primates has been found to explain a great deal about primate adaptability diversification, ecology, anatomy and evolution. Here, we summarize the noted classifications and differences in seasonal, site-specific and sex-age positional behaviors while also reviewing the development and status of non-human primate positional behavior research. This review is intended to provide reference for the future research of non-human primates and aid in further research on behavioral ecology of primates.

  15. Suffixation influences receivers' behaviour in non-human primates

    PubMed Central

    Coye, Camille; Ouattara, Karim; Zuberbühler, Klaus; Lemasson, Alban

    2015-01-01

    Compared to humans, non-human primates have very little control over their vocal production. Nonetheless, some primates produce various call combinations, which may partially offset their lack of acoustic flexibility. A relevant example is male Campbell's monkeys (Cercopithecus campbelli), which give one call type (‘Krak’) to leopards, while the suffixed version of the same call stem (‘Krak-oo’) is given to unspecific danger. To test whether recipients attend to this suffixation pattern, we carried out a playback experiment in which we broadcast naturally and artificially modified suffixed and unsuffixed ‘Krak’ calls of male Campbell's monkeys to 42 wild groups of Diana monkeys (Cercopithecus diana diana). The two species form mixed-species groups and respond to each other's vocalizations. We analysed the vocal response of male and female Diana monkeys and overall found significantly stronger vocal responses to unsuffixed (leopard) than suffixed (unspecific danger) calls. Although the acoustic structure of the ‘Krak’ stem of the calls has some additional effects, subject responses were mainly determined by the presence or the absence of the suffix. This study indicates that suffixation is an evolved function in primate communication in contexts where adaptive responses are particularly important. PMID:25925101

  16. Individualized recording chambers for non-human primate neurophysiology

    PubMed Central

    McAndrew, R.M.; VanGilder, J.L. Lingo; Naufel, S.N.; Tillery, S.I. Helms

    2012-01-01

    While neural recording chambers for non-human primates can be purchased commercially, these generic chambers do not contour to the animal’s skull. In order to seal gaps, a cap of dental acrylic (methyl methacrylate) is often applied around the chamber. There are multiple disadvantages associated with this method. Applying acrylic delays and further complicates surgical procedure, and overheating during the curing process can cause damage to the bone. Post-surgery, acrylic margins can give rise to bacterial growth and infection. Here we describe a method to develop custom implants which conform to the individual’s skull, thereby eliminating the need for acrylic. This method shortens surgery time and significantly improves the hygiene of chamber margins. PMID:22498201

  17. Mediodorsal thalamus and cognition in non-human primates.

    PubMed

    Baxter, Mark G

    2013-01-01

    Several recent studies in non-human primates have provided new insights into the role of the medial thalamus in different aspects of cognitive function. The mediodorsal nucleus of the thalamus (MD), by virtue of its connectivity with the frontal cortex, has been implicated in an array of cognitive functions. Rather than serving as an engine or relay for the prefrontal cortex, this area seems to be more specifically involved in regulating plasticity and flexibility of prefrontal-dependent cognitive functions. Focal damage to MD may also exacerbate the effects of damage to other subcortical relays. Thus, a wide range of distributed circuits and cognitive functions may be disrupted from focal damage within the medial thalamus (for example as a consequence of stroke or brain injury). Conversely, this region may make an interesting target for neuromodulation of cognitive function via deep brain stimulation or related methods, in conditions associated with dysfunction of these neural circuits.

  18. Mediodorsal thalamus and cognition in non-human primates

    PubMed Central

    Baxter, Mark G.

    2013-01-01

    Several recent studies in non-human primates have provided new insights into the role of the medial thalamus in different aspects of cognitive function. The mediodorsal nucleus of the thalamus (MD), by virtue of its connectivity with the frontal cortex, has been implicated in an array of cognitive functions. Rather than serving as an engine or relay for the prefrontal cortex, this area seems to be more specifically involved in regulating plasticity and flexibility of prefrontal-dependent cognitive functions. Focal damage to MD may also exacerbate the effects of damage to other subcortical relays. Thus, a wide range of distributed circuits and cognitive functions may be disrupted from focal damage within the medial thalamus (for example as a consequence of stroke or brain injury). Conversely, this region may make an interesting target for neuromodulation of cognitive function via deep brain stimulation or related methods, in conditions associated with dysfunction of these neural circuits. PMID:23964206

  19. Immunology studies in non-human primate models of tuberculosis.

    PubMed

    Flynn, JoAnne L; Gideon, Hannah P; Mattila, Joshua T; Lin, Philana Ling

    2015-03-01

    Non-human primates, primarily macaques, have been used to study tuberculosis for decades. However, in the last 15 years, this model has been refined substantially to allow careful investigations of the immune response and host-pathogen interactions in Mycobacterium tuberculosis infection. Low-dose challenge with fully virulent strains in cynomolgus macaques result in the full clinical spectrum seen in humans, including latent and active infection. Reagents from humans are usually cross-reactive with macaques, further facilitating the use of this model system to study tuberculosis. Finally, macaques develop the spectrum of granuloma types seen in humans, providing a unique opportunity to investigate bacterial and host factors at the local (lung and lymph node) level. Here, we review the past decade of immunology and pathology studies in macaque models of tuberculosis.

  20. A Non-Human Primate Model of Severe Pneumococcal Pneumonia

    PubMed Central

    Reyes, Luis F.; Restrepo, Marcos I.; Hinojosa, Cecilia A.; Soni, Nilam J.; Shenoy, Anukul T.; Gilley, Ryan P.; Gonzalez-Juarbe, Norberto; Noda, Julio R.; Winter, Vicki T.; de la Garza, Melissa A.; Shade, Robert E.; Coalson, Jacqueline J.; Giavedoni, Luis D.; Anzueto, Antonio; Orihuela, Carlos J.

    2016-01-01

    Rationale Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and infectious death in adults worldwide. A non-human primate model is needed to study the molecular mechanisms that underlie the development of severe pneumonia, identify diagnostic tools, explore potential therapeutic targets, and test clinical interventions during pneumococcal pneumonia. Objective To develop a non-human primate model of pneumococcal pneumonia. Methods Seven adult baboons (Papio cynocephalus) were surgically tethered to a continuous monitoring system that recorded heart rate, temperature, and electrocardiography. Animals were inoculated with 109 colony-forming units of S. pneumoniae using bronchoscopy. Three baboons were rescued with intravenous ampicillin therapy. Pneumonia was diagnosed using lung ultrasonography and ex vivo confirmation by histopathology and immunodetection of pneumococcal capsule. Organ failure, using serum biomarkers and quantification of bacteremia, was assessed daily. Results Challenged animals developed signs and symptoms of pneumonia 4 days after infection. Infection was characterized by the presence of cough, tachypnea, dyspnea, tachycardia and fever. All animals developed leukocytosis and bacteremia 24 hours after infection. A severe inflammatory reaction was detected by elevation of serum cytokines, including Interleukin (IL)1Ra, IL-6, and IL-8, after infection. Lung ultrasonography precisely detected the lobes with pneumonia that were later confirmed by pathological analysis. Lung pathology positively correlated with disease severity. Antimicrobial therapy rapidly reversed symptomology and reduced serum cytokines. Conclusions We have developed a novel animal model for severe pneumococcal pneumonia that mimics the clinical presentation, inflammatory response, and infection kinetics seen in humans. This is a novel model to test vaccines and treatments, measure biomarkers to diagnose pneumonia, and predict outcomes. PMID:27855182

  1. Low profile halo head fixation in non-human primates.

    PubMed

    Azimi, Kousha; Prescott, Ian A; Marino, Robert A; Winterborn, Andrew; Levy, Ron

    2016-08-01

    We present a new halo technique for head fixation of non-human primates during electrophysiological recording experiments. Our aim was to build on previous halo designs in order to create a simple low profile system that provided long-term stability. Our design incorporates sharp skull pins that are directly threaded through a low set halo frame and are seated into implanted titanium foot plates on the skull. The inwardly directed skull pins provide an easily calibrated force against the skull. This device allowed for head fixation within 1 week after implantation surgery. The low-profile design maximized the area of the skull available and potential implant orientations for electrophysiological experiments. It was easily maintained and was stable in 2 animals for the 6-8 months of testing. The quality of single unit neural recordings collected while using this device to head fix was indistinguishable from traditional head-post fixation. The foot plates used in this system did not result in significant MRI distortion in the location of deep brain targets (∼0.5mm) of a 3D printed phantom skull. The low profile design of this halo design allows greater access to the majority of the frontal, parietal, and occipital skull. It has fewer parts and can hold larger animals than previous halo designs. Given the stability, simplicity, immediate usability, and low profile of our head fixation device, we propose that it is a practical and useful means for performing electrophysiological recording experiments on non-human primates. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. High reinforcing efficacy of nicotine in non-human primates.

    PubMed

    Le Foll, Bernard; Wertheim, Carrie; Goldberg, Steven R

    2007-02-21

    Although tobacco appears highly addictive in humans, there has been persistent controversy about the ability of its psychoactive ingredient nicotine to induce self-administration behavior in laboratory animals, bringing into question nicotine's role in reinforcing tobacco smoking. Because of ethical difficulties in inducing nicotine dependence in naïve human subjects, we explored reinforcing effects of nicotine in experimentally-naive non-human primates given access to nicotine for periods of time up to two years. Five squirrel monkeys with no experimental history were allowed to intravenously self-administer nicotine by pressing one of two levers. The number of presses on the active lever needed to obtain each injection was fixed (fixed-ratio schedule) or increased progressively with successive injections during the session (progressive-ratio schedule), allowing evaluation of both reinforcing and motivational effects of nicotine under conditions of increasing response cost. Over time, a progressive shift toward high rates of responding on the active lever, but not the inactive lever, developed. The monkeys' behavior was clearly directed toward nicotine self-administration, rather than presentation of environmental stimuli associated with nicotine injection. Both schedules of reinforcement revealed a high motivation to self-administer nicotine, with monkeys continuing to press the lever when up to 600 lever-presses were needed for each injection of nicotine. Thus, nicotine, by itself, in the absence of behavioral or drug-exposure history, is a robust and highly effective reinforcer of drug-taking behavior in a non-human primate model predictive of human behavior. This supports the use of nicotinic ligands for the treatment of smokers, and this novel preclinical model offers opportunities to test future medications for the treatment of nicotine dependence.

  3. High Reinforcing Efficacy of Nicotine in Non-Human Primates

    PubMed Central

    Le Foll, Bernard; Wertheim, Carrie; Goldberg, Steven R.

    2007-01-01

    Although tobacco appears highly addictive in humans, there has been persistent controversy about the ability of its psychoactive ingredient nicotine to induce self-administration behavior in laboratory animals, bringing into question nicotine's role in reinforcing tobacco smoking. Because of ethical difficulties in inducing nicotine dependence in naïve human subjects, we explored reinforcing effects of nicotine in experimentally-naive non-human primates given access to nicotine for periods of time up to two years. Five squirrel monkeys with no experimental history were allowed to intravenously self-administer nicotine by pressing one of two levers. The number of presses on the active lever needed to obtain each injection was fixed (fixed-ratio schedule) or increased progressively with successive injections during the session (progressive-ratio schedule), allowing evaluation of both reinforcing and motivational effects of nicotine under conditions of increasing response cost. Over time, a progressive shift toward high rates of responding on the active lever, but not the inactive lever, developed. The monkeys' behavior was clearly directed toward nicotine self-administration, rather than presentation of environmental stimuli associated with nicotine injection. Both schedules of reinforcement revealed a high motivation to self-administer nicotine, with monkeys continuing to press the lever when up to 600 lever-presses were needed for each injection of nicotine. Thus, nicotine, by itself, in the absence of behavioral or drug-exposure history, is a robust and highly effective reinforcer of drug-taking behavior in a non-human primate model predictive of human behavior. This supports the use of nicotinic ligands for the treatment of smokers, and this novel preclinical model offers opportunities to test future medications for the treatment of nicotine dependence. PMID:17311094

  4. Striatal Volume Differences Between Non-human and Human Primates

    PubMed Central

    Yin, Dali; Valles, Francisco E.; Fiandaca, Massimo S.; Forsayeth, John; Larson, Paul; Starr, Phillip; Bankiewicz, Krystof S.

    2009-01-01

    Convection-enhanced delivery (CED) has recently entered the clinic and represents a promising new delivery option for targeted gene therapy in Parkinson’s disease (PD). The prime stereotactic target for the majority of recent gene therapy clinical trials has been the human putamen. The stereotactic delivery of therapeutic agents into putamen (or other subcortical structures) via CED remains problematic due to the difficulty in knowing what volume of therapeutic agent to deliver. Preclinical studies in non-human primates (NHP) offer a way to model treatment strategies prior to clinical trials. Understanding more accurately the volumetric differences in striatum, especially putamen, between NHP and humans is essential in predicting convective volume parameters in human clinical trials. In this study, magnetic resonance images (MRI) were obtained for volumetric measurements of striatum (putamen and caudate nucleus) and whole brain from 11 PD patients, 13 aged healthy human subjects, as well as 8 parkinsonian and 30 normal NHP. The human brain is 13–18 times larger than the monkey brain. However, this ratio is significantly smaller for striatum (5.7–6.5), caudate nucleus (4.6–6.6) and putamen (4.4–6.6). Size and species of the monkeys used for this comparative study are responsible for differences in ratios for each structure between monkeys and humans. This volumetric ratio may have important implications in the design of clinical therapies for PD and Huntington’s disease and should be considered when local therapies such as gene transfer, local protein administration or cellular replacement are translated based on non-human primate research. PMID:18809434

  5. Oscillatory Correlates of Memory in Non-human Primates

    PubMed Central

    Jutras, Michael J.; Buffalo, Elizabeth A.

    2013-01-01

    The ability to navigate through our environment, explore with our senses, track the passage of time, and integrate these various components to form the experiences which make up our lives is shared among humans and animals. The use of animal models to study memory, coupled with electrophysiological techniques that permit the direct measurement of neural activity as memories are formed and retrieved, has provided a wealth of knowledge about these mechanisms. Here, we discuss current knowledge regarding the specific role of neural oscillations in memory, with particular emphasis on findings derived from non-human primates. Some of these findings provide evidence for the existence in the primate brain of mechanisms previously identified only in rodents and other lower mammals, while other findings suggest parallels between memory-related activity and processes observed in other cognitive modalities, including attention and sensory perception. Taken together, these results provide insight into how network activity may be organized to promote memory formation, and suggest that key aspects of this activity are similar across species, providing important information about the organization of human memory. PMID:23867554

  6. Oscillatory correlates of memory in non-human primates.

    PubMed

    Jutras, Michael J; Buffalo, Elizabeth A

    2014-01-15

    The ability to navigate through our environment, explore with our senses, track the passage of time, and integrate these various components to form the experiences which make up our lives is shared among humans and animals. The use of animal models to study memory, coupled with electrophysiological techniques that permit the direct measurement of neural activity as memories are formed and retrieved, has provided a wealth of knowledge about these mechanisms. Here, we discuss current knowledge regarding the specific role of neural oscillations in memory, with particular emphasis on findings derived from non-human primates. Some of these findings provide evidence for the existence in the primate brain of mechanisms previously identified only in rodents and other lower mammals, while other findings suggest parallels between memory-related activity and processes observed in other cognitive modalities, including attention and sensory perception. Taken together, these results provide insight into how network activity may be organized to promote memory formation, and suggest that key aspects of this activity are similar across species, providing important information about the organization of human memory. © 2013 Elsevier Inc. All rights reserved.

  7. Enumeration of Objects and Substances in Non-Human Primates: Experiments with Brown Lemurs ("Eulemur Fulvus")

    ERIC Educational Resources Information Center

    Mahajan, Neha; Barnes, Jennifer L.; Blanco, Marissa; Santos, Laurie R.

    2009-01-01

    Both human infants and adult non-human primates share the capacity to track small numbers of objects across time and occlusion. The question now facing developmental and comparative psychologists is whether similar mechanisms give rise to this capacity across the two populations. Here, we explore whether non-human primates' object tracking…

  8. Enumeration of Objects and Substances in Non-Human Primates: Experiments with Brown Lemurs ("Eulemur Fulvus")

    ERIC Educational Resources Information Center

    Mahajan, Neha; Barnes, Jennifer L.; Blanco, Marissa; Santos, Laurie R.

    2009-01-01

    Both human infants and adult non-human primates share the capacity to track small numbers of objects across time and occlusion. The question now facing developmental and comparative psychologists is whether similar mechanisms give rise to this capacity across the two populations. Here, we explore whether non-human primates' object tracking…

  9. The Non-Human Primate Experimental Glaucoma Model

    PubMed Central

    Burgoyne, Claude F.

    2015-01-01

    The purpose of this report is to summarize the current strengths and weaknesses of the non-human primate (NHP) experimental glaucoma (EG) model through sections devoted to its history, methods, important findings, alternative optic neuropathy models and future directions. NHP EG has become well established for studying human glaucoma in part because the NHP optic nerve head (ONH) shares a close anatomic association with the human ONH and because it provides the only means of systematically studying the very earliest visual system responses to chronic IOP elevation, i.e. the conversion from ocular hypertension to glaucomatous damage. However, NHPs are impractical for studies that require large animal numbers, demonstrate spontaneous glaucoma only rarely, do not currently provide a model of the neuropathy at normal levels of IOP, and cannot easily be genetically manipulated, except through tissue-specific, viral vectors. The goal of this summary is to direct NHP EG and non-NHP EG investigators to the previous, current and future accomplishment of clinically relevant knowledge in this model. PMID:26070984

  10. African Non-Human Primates Host Diverse Enteroviruses.

    PubMed

    Mombo, Illich Manfred; Lukashev, Alexander N; Bleicker, Tobias; Brünink, Sebastian; Berthet, Nicolas; Maganga, Gael D; Durand, Patrick; Arnathau, Céline; Boundenga, Larson; Ngoubangoye, Barthélémy; Boué, Vanina; Liégeois, Florian; Ollomo, Benjamin; Prugnolle, Franck; Drexler, Jan Felix; Drosten, Christian; Renaud, François; Rougeron, Virginie; Leroy, Eric

    2017-01-01

    Enteroviruses (EVs) belong to the family Picornaviridae and are responsible for mild to severe diseases in mammals including humans and non-human primates (NHP). Simian EVs were first discovered in the 1950s in the Old World Monkeys and recently in wild chimpanzee, gorilla and mandrill in Cameroon. In the present study, we screened by PCR EVs in 600 fecal samples of wild apes and monkeys that were collected at four sites in Gabon. A total of 32 samples were positive for EVs (25 from mandrills, 7 from chimpanzees, none from gorillas). The phylogenetic analysis of VP1 and VP2 genes showed that EVs identified in chimpanzees were members of two human EV species, EV-A and EV-B, and those identified in mandrills were members of the human species EV-B and the simian species EV-J. The identification of two novel enterovirus types, EV-B112 in a chimpanzee and EV-B113 in a mandrill, suggests these NHPs could be potential sources of new EV types. The identification of EV-B107 and EV90 that were previously found in humans indicates cross-species transfers. Also the identification of chimpanzee-derived EV110 in a mandrill demonstrated a wide host range of this EV. Further research of EVs in NHPs would help understanding emergence of new types or variants, and evaluating the real risk of cross-species transmission for humans as well for NHPs populations.

  11. African Non-Human Primates Host Diverse Enteroviruses

    PubMed Central

    Mombo, Illich Manfred; Lukashev, Alexander N.; Bleicker, Tobias; Brünink, Sebastian; Berthet, Nicolas; Maganga, Gael D.; Durand, Patrick; Arnathau, Céline; Boundenga, Larson; Ngoubangoye, Barthélémy; Boué, Vanina; Liégeois, Florian; Ollomo, Benjamin; Prugnolle, Franck; Drexler, Jan Felix; Drosten, Christian; Renaud, François; Rougeron, Virginie; Leroy, Eric

    2017-01-01

    Enteroviruses (EVs) belong to the family Picornaviridae and are responsible for mild to severe diseases in mammals including humans and non-human primates (NHP). Simian EVs were first discovered in the 1950s in the Old World Monkeys and recently in wild chimpanzee, gorilla and mandrill in Cameroon. In the present study, we screened by PCR EVs in 600 fecal samples of wild apes and monkeys that were collected at four sites in Gabon. A total of 32 samples were positive for EVs (25 from mandrills, 7 from chimpanzees, none from gorillas). The phylogenetic analysis of VP1 and VP2 genes showed that EVs identified in chimpanzees were members of two human EV species, EV-A and EV-B, and those identified in mandrills were members of the human species EV-B and the simian species EV-J. The identification of two novel enterovirus types, EV-B112 in a chimpanzee and EV-B113 in a mandrill, suggests these NHPs could be potential sources of new EV types. The identification of EV-B107 and EV90 that were previously found in humans indicates cross-species transfers. Also the identification of chimpanzee-derived EV110 in a mandrill demonstrated a wide host range of this EV. Further research of EVs in NHPs would help understanding emergence of new types or variants, and evaluating the real risk of cross-species transmission for humans as well for NHPs populations. PMID:28081564

  12. Non-Human Primate Models for AIDS Vaccine Research

    PubMed Central

    Hu, Shiu-Lok

    2006-01-01

    Since the discovery of simian immunodeficiency viruses (SIV) causing AIDS-like diseases in Asian macaques, non-human primates (NHP) have played an important role in AIDS vaccine research. A multitude of vaccines and immunization approaches have been evaluated, including live attenuated viruses, DNA vaccines, viral and bacterial vectors, subunit proteins, and combinations thereof. Depending on the particular vaccine and model used, varying degrees of protection have been achieved, including prevention of infection, reduction of viral load, and amelioration of disease. In a few instances, potential safety concerns and vaccine-enhanced pathogenicity have also been noted. In the past decade, sophisticated methodologies have been developed to define the mechanisms of protective immunity. However, a clear road map for HIV vaccine development has yet to emerge. This is in part because of the intrinsic nature of the surrogate model and in part because of the improbability of any single model to fully capture the complex interactions of natural HIV infection in humans. The lack of standardization, the limited models available, and the incomplete understanding of the immunobiology of NHP contribute to the difficulty to extrapolate findings from such models to HIV vaccine development. Until efficacy data become available from studies of parallel vaccine concepts in humans and macaques, the predictive value of any NHP model remains unknown. Towards this end, greater appreciation of the utility and limitations of the NHP model and further developments to better mimic HIV infection in humans will likely help inform future AIDS vaccine efforts. PMID:15975024

  13. Role of non-human primates in malaria vaccine development: Memorandum from a WHO Meeting*

    PubMed Central

    1988-01-01

    This Memorandum discusses the coordination and standardization of malaria vaccine research in non-human primates to encourage optimum use of the available animals in experiments that are fully justified both scientifically and ethically. The requirements for experimentation in non-human primates, the availability of suitable animals for malaria vaccine studies, and the criteria for testing candidate vaccines are considered. The policy and legislation relevant to the use of non-human primates in biomedical research are also briefly discussed. The Memorandum concludes with eight recommendations. PMID:3266112

  14. Non-human Primate Models for Brain Disorders - Towards Genetic Manipulations via Innovative Technology.

    PubMed

    Qiu, Zilong; Li, Xiao

    2017-04-01

    Modeling brain disorders has always been one of the key tasks in neurobiological studies. A wide range of organisms including worms, fruit flies, zebrafish, and rodents have been used for modeling brain disorders. However, whether complicated neurological and psychiatric symptoms can be faithfully mimicked in animals is still debatable. In this review, we discuss key findings using non-human primates to address the neural mechanisms underlying stress and anxiety behaviors, as well as technical advances for establishing genetically-engineered non-human primate models of autism spectrum disorders and other disorders. Considering the close evolutionary connections and similarity of brain structures between non-human primates and humans, together with the rapid progress in genome-editing technology, non-human primates will be indispensable for pathophysiological studies and exploring potential therapeutic methods for treating brain disorders.

  15. Using non-human primates to benefit humans: research and organ transplantation.

    PubMed

    Shaw, David; Dondorp, Wybo; de Wert, Guido

    2014-11-01

    Emerging biotechnology may soon allow the creation of genetically human organs inside animals, with non-human primates (henceforth simply "primates") and pigs being the best candidate species. This prospect raises the question of whether creating organs in primates in order to then transplant them into humans would be more (or less) acceptable than using them for research. In this paper, we examine the validity of the purported moral distinction between primates and other animals, and analyze the ethical acceptability of using primates to create organs for human use.

  16. Utility of non-human primates in drug development: Comparison of non-human primate and human drug-metabolizing cytochrome P450 enzymes.

    PubMed

    Uno, Yasuhiro; Uehara, Shotaro; Yamazaki, Hiroshi

    2016-12-01

    Cynomolgus monkeys (Macaca fascicularis, an Old World Monkey) have been widely used as a non-human primate model in preclinical studies because of their genetic and physiological similarity to humans. This trend has been followed by common marmoset (Callithrix jacchus, a New World Monkey). However, drug-metabolism properties in these non-human primates have not been fully understood due to limited information on cytochrome P450 (P450) enzymes, major drug-metabolizing enzymes in humans. Multiple forms of cynomolgus monkey P450 enzymes have been identified and characterized in comparison to those of humans, including a cynomolgus monkey specific form, P450 2C76. Similarly, marmoset P450 1A/B, 2A, 2C, 2D, and 4F enzymes were recently identified and characterized to understand drug metabolism properties. In this research update, updates for marmoset, cynomolgus monkey, and human P450 cDNAs are provided. Marmoset and cynomolgus monkey P450 enzymes showed high sequence homology to their human counterparts and generally had similar substrate recognition functionality to human P450 enzymes; however, they also possibly contribute to limited specific differences in drug oxidative metabolism partly due to small differences in amino acid residues. These findings provide a foundation for successful use of non-human primates as preclinical models and will help to further understand molecular mechanisms of human P450 function. In addition to the P450 enzymes, flavin-containing monooxygenases, another monooxygenase family, in these non-human primates have been found to be involved in the oxidation of a variety of compounds associated with pharmacological and/or toxicological effects in humans and are also described. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Neurophysiology and Neuroanatomy of Reflexive and Voluntary Saccades in Non-Human Primates

    ERIC Educational Resources Information Center

    Johnston, Kevin; Everling, Stefan

    2008-01-01

    A multitude of cognitive functions can easily be tested by a number of relatively simple saccadic eye movement tasks. This approach has been employed extensively with patient populations to investigate the functional deficits associated with psychiatric disorders. Neurophysiological studies in non-human primates performing the same tasks have…

  18. Biokinetics of plutonium-238 injected in non-human primates

    NASA Astrophysics Data System (ADS)

    Chelidze, Nino

    Seventeen intravenously injected monkey data were analyzed using PowerBasic and SAAM II softwares. The study was divided into three parts. In the first part SAAM II predictions were compared with those calculated by Birchall algorithm based on the ICRP 67 systemic model for plutonium. In the second part SAAM II simulations were performed and compared for two representations of systemic model for plutonium: the ICRP 67 model and the Leggett model. In the third part, optimization of transfer rates suggested by ICRP 67 and Leggett models were attempted by solving each monkey case independently. The Birchall algorithm and SAAM II predicted values coincide with each other for all data presented: blood, urine and feces. Unfortunately, these predictions do not coincide with the measurement values. Plutonium activity in liver is about 50% of the injected activity. The uptake of plutonium in liver in primates seems to be close to the assumption of equal distribution of 45% plutonium in liver and skeleton in humans. For longer sacrificed monkeys we have prolonged liver retention compared to plutonium liver retention in humans. Pu retention in urine and blood has been simulated based on the ICRP 67 and Leggett models respectively and plotted against the measured data points to acquire the understanding of the models with respect to reality. Pu activity was also evaluated in liver and skeleton at the time of the sacrifice for both models and compared with the autopsy measurements for individual cases. Optimization of transfer rates suggested in the ICRP 67 and Leggett models was attempted. Default transfer rates were varied to improve the fits to the data and predict activities in the liver and skeleton at the time of death has been carried out in SAAM II. Good fits for the individual cases were obtained successfully, however, consistency among parameters from case to case was not observed.

  19. Are non-human primates capable of rhythmic entrainment? Evidence for the gradual audiomotor evolution hypothesis.

    PubMed

    Merchant, Hugo; Honing, Henkjan

    2013-01-01

    We propose a decomposition of the neurocognitive mechanisms that might underlie interval-based timing and rhythmic entrainment. Next to reviewing the concepts central to the definition of rhythmic entrainment, we discuss recent studies that suggest rhythmic entrainment to be specific to humans and a selected group of bird species, but, surprisingly, is not obvious in non-human primates. On the basis of these studies we propose the gradual audiomotor evolution hypothesis that suggests that humans fully share interval-based timing with other primates, but only partially share the ability of rhythmic entrainment (or beat-based timing). This hypothesis accommodates the fact that non-human primates (i.e., macaques) performance is comparable to humans in single interval tasks (such as interval reproduction, categorization, and interception), but show differences in multiple interval tasks (such as rhythmic entrainment, synchronization, and continuation). Furthermore, it is in line with the observation that macaques can, apparently, synchronize in the visual domain, but show less sensitivity in the auditory domain. And finally, while macaques are sensitive to interval-based timing and rhythmic grouping, the absence of a strong coupling between the auditory and motor system of non-human primates might be the reason why macaques cannot rhythmically entrain in the way humans do.

  20. Is somnambulism a distinct disorder of humans and not seen in non-human primates?

    PubMed

    Kantha, S S

    2003-01-01

    Though somnambulism (sleepwalking) is a well-recognized sleep disorder in humans, a biomedical literature search in Medline and Primate Literature bibliographic databases showed no publications on sleepwalking in non-human primates. From this finding, two inferences can be made. First is that somnambulism may be present in non-human primates; but due to limitations in expertise and methodological resources as well as narrow focus of research interest, until now researchers have not detected it in wild and/or captive conditions. Second, somnambulism does not exist in non-human primates including apes (chimpanzee, gorilla, orang-utan and gibbon); and thus, it is a unique behavioral disorder present only in humans. It is premature to conclude which of these two inferences is correct. In Jane Goodall's view, sleepwalking behavior is absent in chimpanzees. If further field observations can confirm Goodall's assertion that somnambulism is indeed absent in chimpanzees, it will be of evolutionary and medical interest to know why this parasomnic behavior became established in humans during the past 5.5 million years or so.

  1. Continuities in Emotion Lateralization in Human and Non-Human Primates

    PubMed Central

    Lindell, Annukka K.

    2013-01-01

    Where hemispheric lateralization was once considered an exclusively human trait, it is increasingly recognized that hemispheric asymmetries are evident throughout the animal kingdom. Emotion is a prime example of a lateralized function: given its vital role in promoting adaptive behavior and hence survival, a growing body of research in affective neuroscience is working to illuminate the cortical bases of emotion processing. Presuming that human and non-human primates evolved from a shared ancestor, one would anticipate evidence of organizational continuity in the neural substrate supporting emotion processing. This paper thus reviews research examining the patterns of lateralization for the expression and perception of facial emotion in non-human primates, aiming to determine whether the patterns of hemispheric asymmetry that characterize the human brain are similarly evident in other primate species. As such, this review seeks to enhance understanding of the evolution of hemispheric specialization for emotion, using emotion lateralization in non-human primates as a window through which to view emotion lateralization in humans. PMID:23964230

  2. Breast cancer in intraductal carcinogen-treated non-human primates.

    PubMed

    Lillie, Madeline A; Ambrus, Clara M; Pickren, John W; Akhter, Selina; Islam, Abul; Ambrus, Julian L

    2004-01-01

    Eight female Macaca arctoides monkeys were given dimethylbenzanthracene (DMBA) directly into the milk ducts. During a 4-year observation period, ending with euthanasia and autopsy, no mammary cancers were noticed. However, one animal developed a superficial localized squamous cell carcinoma. DMBA is highly carcinogenic in rodents, e.g. producing a high incidence of breast cancer in C3H mice. It was concluded that carcinogenicity testing should be extended beyond testing in rodents to non-human primates in order to distinguish "primary rodent carcinogens" from those highly active in primates as well. Studies are in progress to study carcinogens in human cell lines transplanted into nu/nu mice.

  3. Characterization of a 2016 Clinical Isolate of Zika Virus in Non-human Primates.

    PubMed

    Li, Xiao-Feng; Dong, Hao-Long; Huang, Xing-Yao; Qiu, Ye-Feng; Wang, Hong-Jiang; Deng, Yong-Qiang; Zhang, Na-Na; Ye, Qing; Zhao, Hui; Liu, Zhong-Yu; Fan, Hang; An, Xiao-Ping; Sun, Shi-Hui; Gao, Bo; Fa, Yun-Zhi; Tong, Yi-Gang; Zhang, Fu-Chun; Gao, George F; Cao, Wu-Chun; Shi, Pei-Yong; Qin, Cheng-Feng

    2016-10-01

    Animal models are critical to understand disease and to develop countermeasures for the ongoing epidemics of Zika virus (ZIKV). Here we report a non-human primate model using a 2016 contemporary clinical isolate of ZIKV. Upon subcutaneous inoculation, rhesus macaques developed fever and viremia, with robust excretion of ZIKV RNA in urine, saliva, and lacrimal fluid. Necropsy of two infected animals revealed that systematic infections involving central nervous system and visceral organs were established at the acute phrase. ZIKV initially targeted the intestinal tracts, spleen, and parotid glands, and retained in spleen and lymph nodes till 10days post infection. ZIKV-specific immune responses were readily induced in all inoculated animals. The non-human primate model described here provides a valuable platform to study ZIKV pathogenesis and to evaluate vaccine and therapeutics. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

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

    NASA Technical Reports Server (NTRS)

    Koenig, S. C.; Reister, C.; Schaub, J.; Muniz, G.; Ferguson, T.; Fanton, J. W.

    1995-01-01

    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.

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

    NASA Technical Reports Server (NTRS)

    Koenig, S. C.; Reister, C.; Schaub, J.; Muniz, G.; Ferguson, T.; Fanton, J. W.

    1995-01-01

    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.

  6. Technique for enhanced accuracy and reliability in non-human primate stereotaxy

    PubMed Central

    Walbridge, Stuart; Murad, Gregory J.A.; Heiss, John D.; Oldfield, Edward H.; Lonser, Russell R.

    2014-01-01

    Despite the importance of enhancing the accuracy and reliability of non-human primate stereotaxy, a number of limitations exist using currently described techniques. To overcome these problems, we present a simple universally available approach that combines pre-operative magnetic resonance imaging and the non-surgical creation of reference points (teeth marking). We have found that this approach improves stereotaxic targeting reliability and permits accurate reproducible stereotaxic localization at time points distant from the pre-operative imaging. PMID:16516975

  7. Isolation and Characterization of Adenoviruses Persistently Shed from the Gastrointestinal Tract of Non-Human Primates

    PubMed Central

    Kryazhimskiy, Sergey; Grant, Rebecca; Calcedo, Roberto; Yuan, Xin; Keough, Martin; Sandhu, Arbans; Wang, Qiang; Medina-Jaszek, C. Angelica; Plotkin, Joshua B.; Wilson, James M.

    2009-01-01

    Adenoviruses are important human pathogens that have been developed as vectors for gene therapies and genetic vaccines. Previous studies indicated that human infections with adenoviruses are self-limiting in immunocompetent hosts with evidence of some persistence in adenoid tissue. We sought to better understand the natural history of adenovirus infections in various non-human primates and discovered that healthy populations of great apes (chimpanzees, bonobos, gorillas, and orangutans) and macaques shed substantial quantities of infectious adenoviruses in stool. Shedding in stools from asymptomatic humans was found to be much less frequent, comparable to frequencies reported before. We purified and fully sequenced 30 novel adenoviruses from apes and 3 novel adenoviruses from macaques. Analyses of the new ape adenovirus sequences (as well as the 4 chimpanzee adenovirus sequences we have previously reported) together with 22 complete adenovirus genomes available from GenBank revealed that (a) the ape adenoviruses could clearly be classified into species corresponding to human adenovirus species B, C, and E, (b) there was evidence for intraspecies recombination between adenoviruses, and (c) the high degree of phylogenetic relatedness of adenoviruses across their various primate hosts provided evidence for cross species transmission events to have occurred in the natural history of B and E viruses. The high degree of asymptomatic shedding of live adenovirus in non-human primates and evidence for zoonotic transmissions warrants caution for primate handling and housing. Furthermore, the presence of persistent and/or latent adenovirus infections in the gut should be considered in the design and interpretation of human and non-human primate studies with adenovirus vectors. PMID:19578438

  8. Distinctiveness enhances long-term event memory in non-human primates, irrespective of reinforcement.

    PubMed

    Lewis, Amy; Call, Josep; Berntsen, Dorthe

    2017-04-13

    Non-human primates are capable of recalling events that occurred as long as 3 years ago, and are able to distinguish between similar events; akin to human memory. In humans, distinctiveness enhances memory for events, however, it is unknown whether the same occurs in non-human primates. As such, we tested three great ape species on their ability to remember an event that varied in distinctiveness. Across three experiments, apes witnessed a baiting event in which one of three identical containers was baited with food. After a delay of 2 weeks, we tested their memory for the location of the baited container. Apes failed to recall the baited container when the event was undistinctive (Experiment 1), but were successful when it was distinctive (Experiment 2), although performance was equally good in a less-distinctive condition. A third experiment (Experiment 3) confirmed that distinctiveness, independent of reinforcement, was a consistent predictor of performance. These findings suggest that distinctiveness may enhance memory for events in non-human primates in the same way as in humans, and provides further evidence of basic similarities between the ways apes and humans remember past events.

  9. AAV9-mediated engineering of autotransplanted kidney of non-human primates.

    PubMed

    Tomasoni, S; Trionfini, P; Azzollini, N; Zentilin, L; Giacca, M; Aiello, S; Longaretti, L; Cozzi, E; Baldan, N; Remuzzi, G; Benigni, A

    2017-05-01

    Ex vivo gene transfer to the graft before transplantation is an attractive option for circumventing systemic side effects of chronic antirejection therapy. Gene delivery of the immunomodulatory protein cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) prevented chronic kidney rejection in a rat model of allotransplantation without the need for systemic immunosuppression. Here we generated adeno-associated virus type 2 (AAV2) and AAV9 vectors encoding for LEA29Y, an optimized version of CTLA4-Ig. Both LEA29Y vectors were equally efficient for reducing T-cell proliferation in vitro. Serotype 9 was chosen for in vivo experiments owing to a lower frequency of preformed antibodies against the AAV9 capsid in 16 non-human primate tested sera. AAV9-LEA29Y was able to transduce the kidney of non-human primates in an autotransplantation model. Expression of LEA29Y mRNA by renal cells translated into the production of the corresponding protein, which was confined to the graft but not detected in serum. Results in non-human primates represent a step forward in maintaining the portability of this strategy into clinics.

  10. Investigation of sleep–wake rhythm in non-human primates without restraint during data collection

    PubMed Central

    Ishikawa, Akiyoshi; Sakai, Keita; Maki, Takehiro; Mizuno, Yuri; Niimi, Kimie; Oda, Yasuhiro; Takahashi, Eiki

    2016-01-01

    To understand sleep mechanisms and develop treatments for sleep disorders, investigations using animal models are essential. The sleep architecture of rodents differs from that of diurnal mammals including humans and non-human primates. Sleep studies have been conducted in non-human primates; however, these sleep assessments were performed on animals placed in a restraint chair connected via the umbilical area to the recording apparatus. To avoid restraints, cables, and other stressful apparatuses and manipulations, telemetry systems have been developed. In the present study, sleep recordings in unrestrained cynomolgus monkeys (Macaca fascicularis) and common marmoset monkeys (Callithrix jacchus) were conducted to characterize normal sleep. For the analysis of sleep–wake rhythms in cynomolgus monkeys, telemetry electroencephalography (EEG), electromyography (EMG), and electrooculography (EOG) signals were used. For the analysis of sleep–wake rhythms in marmosets, telemetry EEG and EOG signals were used. Both monkey species showed monophasic sleep patterns during the dark phase. Although non-rapid eye movement (NREM) deep sleep showed higher levels at the beginning of the dark phase in cynomolgus monkeys, NREM deep sleep rarely occurred during the dark phase in marmosets. Our results indicate that the use of telemetry in non-human primate models is useful for sleep studies, and that the different NREM deep sleep activities between cynomolgus monkeys and common marmoset monkeys are useful to examine sleep functions. PMID:27760892

  11. Investigation of sleep-wake rhythm in non-human primates without restraint during data collection.

    PubMed

    Ishikawa, Akiyoshi; Sakai, Keita; Maki, Takehiro; Mizuno, Yuri; Niimi, Kimie; Oda, Yasuhiro; Takahashi, Eiki

    2017-01-27

    To understand sleep mechanisms and develop treatments for sleep disorders, investigations using animal models are essential. The sleep architecture of rodents differs from that of diurnal mammals including humans and non-human primates. Sleep studies have been conducted in non-human primates; however, these sleep assessments were performed on animals placed in a restraint chair connected via the umbilical area to the recording apparatus. To avoid restraints, cables, and other stressful apparatuses and manipulations, telemetry systems have been developed. In the present study, sleep recordings in unrestrained cynomolgus monkeys (Macaca fascicularis) and common marmoset monkeys (Callithrix jacchus) were conducted to characterize normal sleep. For the analysis of sleep-wake rhythms in cynomolgus monkeys, telemetry electroencephalography (EEG), electromyography (EMG), and electrooculography (EOG) signals were used. For the analysis of sleep-wake rhythms in marmosets, telemetry EEG and EOG signals were used. Both monkey species showed monophasic sleep patterns during the dark phase. Although non-rapid eye movement (NREM) deep sleep showed higher levels at the beginning of the dark phase in cynomolgus monkeys, NREM deep sleep rarely occurred during the dark phase in marmosets. Our results indicate that the use of telemetry in non-human primate models is useful for sleep studies, and that the different NREM deep sleep activities between cynomolgus monkeys and common marmoset monkeys are useful to examine sleep functions.

  12. Initial gene vector dosing for studying symptomatology of amyotrophic lateral sclerosis in non-human primates

    PubMed Central

    Jackson, Kasey L.; Dayton, Robert D.; Fisher-Perkins, Jeanne M.; Didier, Peter J.; Baker, Kate C.; Weimer, Maria; Gutierrez, Amparo; Cain, Cooper D.; Mathis, J. Michael; Gitcho, Michael A.; Bunnell, Bruce A.; Klein, Ronald L.

    2015-01-01

    Background Most amyotrophic lateral sclerosis (ALS) research has focused on mice, but there are distinct differences in the functional neuroanatomy of the corticospinal pathway in primates vs. rodents. A non-human primate model may be more sensitive and more predictive for therapeutic efficacy. Methods Rhesus macaques received recombinant adeno-associated virus (AAV9) encoding either the ALS-related pathological protein TDP-43 or a green fluorescent protein (GFP) control by intravenous administration. Motor function and electromyography were assessed over a nine-month expression interval followed by post-mortem analyses. Results Recombinant TDP-43 or GFP was stably expressed long term. Although the TDP-43 subjects did not manifest severe paralysis and atrophy, there were trends of a partial disease state in the TDP-43 subjects relative to the control. Conclusions These data indicate that a higher gene vector dose will likely be necessary for more robust effects, yet augur that a relevant primate model is feasible. PMID:25639184

  13. Primate Drum Kit: A System for Studying Acoustic Pattern Production by Non-Human Primates Using Acceleration and Strain Sensors

    PubMed Central

    Ravignani, Andrea; Olivera, Vicente Matellán; Gingras, Bruno; Hofer, Riccardo; Hernández, Carlos Rodríguez; Sonnweber, Ruth-Sophie; Fitch, W. Tecumseh

    2013-01-01

    The possibility of achieving experimentally controlled, non-vocal acoustic production in non-human primates is a key step to enable the testing of a number of hypotheses on primate behavior and cognition. However, no device or solution is currently available, with the use of sensors in non-human animals being almost exclusively devoted to applications in food industry and animal surveillance. Specifically, no device exists which simultaneously allows: (i) spontaneous production of sound or music by non-human animals via object manipulation, (ii) systematical recording of data sensed from these movements, (iii) the possibility to alter the acoustic feedback properties of the object using remote control. We present two prototypes we developed for application with chimpanzees (Pan troglodytes) which, while fulfilling the aforementioned requirements, allow to arbitrarily associate sounds to physical object movements. The prototypes differ in sensing technology, costs, intended use and construction requirements. One prototype uses four piezoelectric elements embedded between layers of Plexiglas and foam. Strain data is sent to a computer running Python through an Arduino board. A second prototype consists in a modified Wii Remote contained in a gum toy. Acceleration data is sent via Bluetooth to a computer running Max/MSP. We successfully pilot tested the first device with a group of chimpanzees. We foresee using these devices for a range of cognitive experiments. PMID:23912427

  14. Primate drum kit: a system for studying acoustic pattern production by non-human primates using acceleration and strain sensors.

    PubMed

    Ravignani, Andrea; Matellán Olivera, Vicente; Gingras, Bruno; Hofer, Riccardo; Rodríguez Hernández, Carlos; Sonnweber, Ruth-Sophie; Fitch, W Tecumseh

    2013-07-31

    The possibility of achieving experimentally controlled, non-vocal acoustic production in non-human primates is a key step to enable the testing of a number of hypotheses on primate behavior and cognition. However, no device or solution is currently available, with the use of sensors in non-human animals being almost exclusively devoted to applications in food industry and animal surveillance. Specifically, no device exists which simultaneously allows: (i) spontaneous production of sound or music by non-human animals via object manipulation, (ii) systematical recording of data sensed from these movements, (iii) the possibility to alter the acoustic feedback properties of the object using remote control. We present two prototypes we developed for application with chimpanzees (Pan troglodytes) which, while fulfilling the aforementioned requirements, allow to arbitrarily associate sounds to physical object movements. The prototypes differ in sensing technology, costs, intended use and construction requirements. One prototype uses four piezoelectric elements embedded between layers of Plexiglas and foam. Strain data is sent to a computer running Python through an Arduino board. A second prototype consists in a modified Wii Remote contained in a gum toy. Acceleration data is sent via Bluetooth to a computer running Max/MSP. We successfully pilot tested the first device with a group of chimpanzees. We foresee using these devices for a range of cognitive experiments.

  15. Impact of Visual Context on Public Perceptions of Non-Human Primate Performers

    PubMed Central

    Leighty, Katherine A.; Valuska, Annie J.; Grand, Alison P.; Bettinger, Tamara L.; Mellen, Jill D.; Ross, Stephen R.; Boyle, Paul; Ogden, Jacqueline J.

    2015-01-01

    Prior research has shown that the use of apes, specifically chimpanzees, as performers in the media negatively impacts public attitudes of their conservation status and desirability as a pet, yet it is unclear whether these findings generalize to other non-human primates (specifically non-ape species). We evaluated the impact of viewing an image of a monkey or prosimian in an anthropomorphic or naturalistic setting, either in contact with or in the absence of a human. Viewing the primate in an anthropomorphic setting while in contact with a person significantly increased their desirability as a pet, which also correlated with increased likelihood of believing the animal was not endangered. The majority of viewers felt that the primates in all tested images were “nervous.” When shown in contact with a human, viewers felt they were “sad” and “scared”, while also being less “funny.” Our findings highlight the potential broader implications of the use of non-human primate performers by the entertainment industry. PMID:25714101

  16. Impact of visual context on public perceptions of non-human primate performers.

    PubMed

    Leighty, Katherine A; Valuska, Annie J; Grand, Alison P; Bettinger, Tamara L; Mellen, Jill D; Ross, Stephen R; Boyle, Paul; Ogden, Jacqueline J

    2015-01-01

    Prior research has shown that the use of apes, specifically chimpanzees, as performers in the media negatively impacts public attitudes of their conservation status and desirability as a pet, yet it is unclear whether these findings generalize to other non-human primates (specifically non-ape species). We evaluated the impact of viewing an image of a monkey or prosimian in an anthropomorphic or naturalistic setting, either in contact with or in the absence of a human. Viewing the primate in an anthropomorphic setting while in contact with a person significantly increased their desirability as a pet, which also correlated with increased likelihood of believing the animal was not endangered. The majority of viewers felt that the primates in all tested images were "nervous." When shown in contact with a human, viewers felt they were "sad" and "scared", while also being less "funny." Our findings highlight the potential broader implications of the use of non-human primate performers by the entertainment industry.

  17. Human and Non-Human Primate Genomes Share Hotspots of Positive Selection

    PubMed Central

    Enard, David; Depaulis, Frantz; Roest Crollius, Hugues

    2010-01-01

    Among primates, genome-wide analysis of recent positive selection is currently limited to the human species because it requires extensive sampling of genotypic data from many individuals. The extent to which genes positively selected in human also present adaptive changes in other primates therefore remains unknown. This question is important because a gene that has been positively selected independently in the human and in other primate lineages may be less likely to be involved in human specific phenotypic changes such as dietary habits or cognitive abilities. To answer this question, we analysed heterozygous Single Nucleotide Polymorphisms (SNPs) in the genomes of single human, chimpanzee, orangutan, and macaque individuals using a new method aiming to identify selective sweeps genome-wide. We found an unexpectedly high number of orthologous genes exhibiting signatures of a selective sweep simultaneously in several primate species, suggesting the presence of hotspots of positive selection. A similar significant excess is evident when comparing genes positively selected during recent human evolution with genes subjected to positive selection in their coding sequence in other primate lineages and identified using a different test. These findings are further supported by comparing several published human genome scans for positive selection with our findings in non-human primate genomes. We thus provide extensive evidence that the co-occurrence of positive selection in humans and in other primates at the same genetic loci can be measured with only four species, an indication that it may be a widespread phenomenon. The identification of positive selection in humans alongside other primates is a powerful tool to outline those genes that were selected uniquely during recent human evolution. PMID:20140238

  18. [Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (II)].

    PubMed

    Toledano, A; Álvarez, M I; López-Rodríguez, A B; Toledano-Díaz, A; Fernández-Verdecia, C I

    2014-01-01

    In the ageing process there are some species of non-human primates which can show some of the defining characteristics of the Alzheimer's disease (AD) of man, both in neuropathological changes and cognitive-behavioural symptoms. The study of these species is of prime importance to understand AD and develop therapies to combat this neurodegenerative disease. In this second part of the study, these AD features are discussed in the most important non-experimental AD models (Mouse Lemur -Microcebus murinus, Caribbean vervet -Chlorocebus aethiops, and the Rhesus and stump-tailed macaque -Macaca mulatta and M. arctoides) and experimental models (lesional, neurotoxic, pharmacological, immunological, etc.) non-human primates. In all these models cerebral amyloid neuropathology can occur in senility, although with different levels of incidence (100% in vervets;<30% in macaques). The differences between normal and pathological (Alzheimer's) senility in these species are difficult to establish due to the lack of cognitive-behavioural studies in the many groups analysed, as well as the controversy in the results of these studies when they were carried out. However, in some macaques, a correlation between a high degree of functional brain impairment and a large number of neuropathological changes ("possible AD") has been found. In some non-human primates, such as the macaque, the existence of a possible continuum between "normal" ageing process, "normal" ageing with no deep neuropathological and cognitive-behavioural changes, and "pathological ageing" (or "Alzheimer type ageing"), may be considered. In other cases, such as the Caribbean vervet, neuropathological changes are constant and quite marked, but its impact on cognition and behaviour does not seem to be very important. This does assume the possible existence in the human senile physiological regression of a stable phase without dementia even if neuropathological changes appeared. Copyright © 2011 Sociedad Española de

  19. Phylogenetic Evidence That Two Distinct Trichuris Genotypes Infect both Humans and Non-Human Primates

    PubMed Central

    Ravasi, Damiana F.; O’Riain, Mannus J.; Davids, Faezah; Illing, Nicola

    2012-01-01

    Although there has been extensive debate about whether Trichuris suis and Trichuris trichiura are separate species, only one species of the whipworm T. trichiura has been considered to infect humans and non-human primates. In order to investigate potential cross infection of Trichuris sp. between baboons and humans in the Cape Peninsula, South Africa, we sequenced the ITS1-5.8S-ITS2 region of adult Trichuris sp. worms isolated from five baboons from three different troops, namely the Cape Peninsula troop, Groot Olifantsbos troop and Da Gama Park troop. This region was also sequenced from T. trichiura isolated from a human patient from central Africa (Cameroon) for comparison. By combining this dataset with Genbank records for Trichuris isolated from other humans, non-human primates and pigs from several different countries in Europe, Asia, and Africa, we confirmed the identification of two distinct Trichuris genotypes that infect primates. Trichuris sp. isolated from the Peninsula baboons fell into two distinct clades that were found to also infect human patients from Cameroon, Uganda and Jamaica (named the CP-GOB clade) and China, Thailand, the Czech Republic, and Uganda (named the DG clade), respectively. The divergence of these Trichuris clades is ancient and precedes the diversification of T. suis which clustered closely to the CP-GOB clade. The identification of two distinct Trichuris genotypes infecting both humans and non-human primates is important for the ongoing treatment of Trichuris which is estimated to infect 600 million people worldwide. Currently baboons in the Cape Peninsula, which visit urban areas, provide a constant risk of infection to local communities. A reduction in spatial overlap between humans and baboons is thus an important measure to reduce both cross-transmission and zoonoses of helminthes in Southern Africa. PMID:22952922

  20. Phylogenetic evidence that two distinct Trichuris genotypes infect both humans and non-human primates.

    PubMed

    Ravasi, Damiana F; O'Riain, Mannus J; Davids, Faezah; Illing, Nicola

    2012-01-01

    Although there has been extensive debate about whether Trichuris suis and Trichuris trichiura are separate species, only one species of the whipworm T. trichiura has been considered to infect humans and non-human primates. In order to investigate potential cross infection of Trichuris sp. between baboons and humans in the Cape Peninsula, South Africa, we sequenced the ITS1-5.8S-ITS2 region of adult Trichuris sp. worms isolated from five baboons from three different troops, namely the Cape Peninsula troop, Groot Olifantsbos troop and Da Gama Park troop. This region was also sequenced from T. trichiura isolated from a human patient from central Africa (Cameroon) for comparison. By combining this dataset with Genbank records for Trichuris isolated from other humans, non-human primates and pigs from several different countries in Europe, Asia, and Africa, we confirmed the identification of two distinct Trichuris genotypes that infect primates. Trichuris sp. isolated from the Peninsula baboons fell into two distinct clades that were found to also infect human patients from Cameroon, Uganda and Jamaica (named the CP-GOB clade) and China, Thailand, the Czech Republic, and Uganda (named the DG clade), respectively. The divergence of these Trichuris clades is ancient and precedes the diversification of T. suis which clustered closely to the CP-GOB clade. The identification of two distinct Trichuris genotypes infecting both humans and non-human primates is important for the ongoing treatment of Trichuris which is estimated to infect 600 million people worldwide. Currently baboons in the Cape Peninsula, which visit urban areas, provide a constant risk of infection to local communities. A reduction in spatial overlap between humans and baboons is thus an important measure to reduce both cross-transmission and zoonoses of helminthes in Southern Africa.

  1. Molecular phylogeny of anoplocephalid tapeworms (Cestoda: Anoplocephalidae) infecting humans and non-human primates.

    PubMed

    Doležalová, Jana; Vallo, Peter; Petrželková, Klára J; Foitová, Ivona; Nurcahyo, Wisnu; Mudakikwa, Antoine; Hashimoto, Chie; Jirků, Milan; Lukeš, Julius; Scholz, Tomáš; Modrý, David

    2015-09-01

    Anoplocephalid tapeworms of the genus Bertiella Stiles and Hassall, 1902 and Anoplocephala Blanchard, 1848, found in the Asian, African and American non-human primates are presumed to sporadic ape-to-man transmissions. Variable nuclear (5.8S-ITS2; 28S rRNA) and mitochondrial genes (cox1; nad1) of isolates of anoplocephalids originating from different primates (Callicebus oenanthe, Gorilla beringei, Gorilla gorilla, Pan troglodytes and Pongo abelii) and humans from various regions (South America, Africa, South-East Asia) were sequenced. In most analyses, Bertiella formed a monophyletic group within the subfamily Anoplocephalinae, however, the 28S rRNA sequence-based analysis indicated paraphyletic relationship between Bertiella from primates and Australian marsupials and rodents, which should thus be regarded as different taxa. Moreover, isolate determined as Anoplocephala cf. gorillae from mountain gorilla clustered within the Bertiella clade from primates. This either indicates that A. gorillae deserves to be included into the genus Bertiella, or, that an unknown Bertiella species infects also mountain gorillas. The analyses allowed the genetic differentiation of the isolates, albeit with no obvious geographical or host-related patterns. The unexpected genetic diversity of the isolates studied suggests the existence of several Bertiella species in primates and human and calls for revision of the whole group, based both on molecular and morphological data.

  2. From Sweeping to the Caress: Similarities and Discrepancies between Human and Non-Human Primates' Pleasant Touch.

    PubMed

    Grandi, Laura C

    2016-01-01

    Affective touch plays a key role in affiliative behavior, offering a mechanism for the formation and maintenance of social bonds among conspecifics, both in humans and non-human primates. Furthermore, it has been speculated that the CT fiber system is a specific coding channel for affiliative touch that occurs during skin-to-skin interactions with conspecifics. In humans, this touch is commonly referred to as the caress, and its correlation with the CT fiber system has been widely demonstrated. It has been hypothesized that the sweeping touch that occurs during grooming in non-human primates may modulate the CT fibers, with recent preliminary studies on rhesus monkeys supporting this hypothesis. The present mini-review proposes a comparison between the pleasant touch, caress and sweeping of humans and non-human primates, respectively. The currently available data was therefore reviewed regarding (i) the correlation between pleasant touch and CT fibers both in humans and non-human primates, (ii) the autonomic effects, (iii) the encoding at the central nervous system, (iv) the development from early life to adulthood, and (v) the potential applications of pleasant touch in the daily lives of both humans and non-human primates. Moreover, by considering both the similarities and discrepancies between the human caress and non-human primate sweeping, a possible evolutionary mechanism can be proposed that has developed from sweeping as a utilitarian action with affiliative meaning among monkeys, to the caress as a purely affective gesture associated with humans.

  3. Rodent, large animal and non-human primate models of spinal cord injury.

    PubMed

    Nardone, Raffaele; Florea, Cristina; Höller, Yvonne; Brigo, Francesco; Versace, Viviana; Lochner, Piergiorgio; Golaszewski, Stefan; Trinka, Eugen

    2017-08-01

    In this narrative review we aimed to assess the usefulness of the different animal models in identifying injury mechanisms and developing therapies for humans suffering from spinal cord injury (SCI). Results obtained from rodent studies are useful but, due to the anatomical, molecular and functional differences, confirmation of these findings in large animals or non-human primates may lead to basic discoveries that cannot be made in rodent models and that are more useful for developing treatment strategies in humans. SCI in dogs can be considered as intermediate between rodent models and human clinical trials, but the primate models could help to develop appropriate methods that might be more relevant to humans. Ideally, an animal model should meet the requirements of availability and repeatability as well as reproduce the anatomical features and the clinical pathological changing process of SCI. An animal model that completely simulates SCI in humans does not exist. The different experimental models of SCI have advantages and disadvantages for investigating the different aspects of lesion development, recovery mechanisms and potential therapeutic interventions. The potential advantages of non-human primate models include genetic similarities, similar caliber/length of the spinal cord as well as biological and physiological responses to injury which are more similar to humans. Among the potential disadvantages, high operating costs, infrastructural requirements and ethical concerns should be considered. The translation from experimental repair strategies to clinical applications needs to be investigated in future carefully designed studies. Copyright © 2017 Elsevier GmbH. All rights reserved.

  4. Incorporating the gut microbiota into models of human and non-human primate ecology and evolution.

    PubMed

    Amato, Katherine R

    2016-01-01

    The mammalian gut is home to a diverse community of microbes. Advances in technology over the past two decades have allowed us to examine this community, the gut microbiota, in more detail, revealing a wide range of influences on host nutrition, health, and behavior. These host-gut microbe interactions appear to shape host plasticity and fitness in a variety of contexts, and therefore represent a key factor missing from existing models of human and non-human primate ecology and evolution. However, current studies of the gut microbiota tend to include limited contextual data or are clinical, making it difficult to directly test broad anthropological hypotheses. Here, I review what is known about the animal gut microbiota and provide examples of how gut microbiota research can be integrated into the study of human and non-human primate ecology and evolution with targeted data collection. Specifically, I examine how the gut microbiota may impact primate diet, energetics, disease resistance, and cognition. While gut microbiota research is proliferating rapidly, especially in the context of humans, there remain important gaps in our understanding of host-gut microbe interactions that will require an anthropological perspective to fill. Likewise, gut microbiota research will be an important tool for filling remaining gaps in anthropological research.

  5. Cloning of non-human primates: the road "less traveled by".

    PubMed

    Sparman, Michelle L; Tachibana, Masahito; Mitalipov, Shoukhrat M

    2010-01-01

    Early studies on cloning of non-human primates by nuclear transfer utilized embryonic blastomeres from preimplantation embryos which resulted in the reproducible birth of live offspring. Soon after, the focus shifted to employing somatic cells as a source of donor nuclei (somatic cell nuclear transfer, SCNT). However, initial efforts were plagued with inefficient nuclear reprogramming and poor embryonic development when standard SCNT methods were utilized. Implementation of several key SCNT modifications was critical to overcome these problems. In particular, a non-invasive method of visualizing the metaphase chromosomes during enucleation was developed to preserve the reprogramming capacity of monkey oocytes. These modifications dramatically improved the efficiency of SCNT, yielding high blastocyst development in vitro. To date, SCNT has been successfully used to derive pluripotent embryonic stem cells (ESCs) from adult monkey skin fibroblasts. These remarkable advances have the potential for development of human autologous ESCs and cures for many human diseases. Reproductive cloning of nonhuman primates by SCNT has not been achieved yet. We have been able to establish several pregnancies with SCNT embryos which, so far, did not progress to term. In this review, we summarize the approaches, obstacles and accomplishments of SCNT in a non-human primate model.

  6. Cloning of non-human primates: the road “less traveled by”

    PubMed Central

    SPARMAN, MICHELLE L.; TACHIBANA, MASAHITO; MITALIPOV, SHOUKHRAT M.

    2011-01-01

    Early studies on cloning of non-human primates by nuclear transfer utilized embryonic blastomeres from preimplantation embryos which resulted in the reproducible birth of live offspring. Soon after, the focus shifted to employing somatic cells as a source of donor nuclei (somatic cell nuclear transfer, SCNT). However, initial efforts were plagued with inefficient nuclear reprogramming and poor embryonic development when standard SCNT methods were utilized. Implementation of several key SCNT modifications was critical to overcome these problems. In particular, a non-invasive method of visualizing the metaphase chromosomes during enucleation was developed to preserve the reprogramming capacity of monkey oocytes. These modifications dramatically improved the efficiency of SCNT, yielding high blastocyst development in vitro. To date, SCNT has been successfully used to derive pluripotent embryonic stem cells (ESCs) from adult monkey skin fibroblasts. These remarkable advances have the potential for development of human autologous ESCs and cures for many human diseases. Reproductive cloning of nonhuman primates by SCNT has not been achieved yet. We have been able to establish several pregnancies with SCNT embryos which, so far, did not progress to term. In this review, we summarize the approaches, obstacles and accomplishments of SCNT in a non-human primate model. PMID:21404187

  7. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

    PubMed

    Zhang, Xiao-Liang; Pang, Wei; Hu, Xin-Tian; Li, Jia-Li; Yao, Yong-Gang; Zheng, Yong-Tang

    2014-11-18

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China.

  8. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress

    PubMed Central

    ZHANG, Xiao-Liang; PANG, Wei; HU, Xin-Tian; LI, Jia-Li; YAO, Yong-Gang; ZHENG, Yong-Tang

    2014-01-01

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China’s growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China’s life sciences and pharmaceutical industry, and enhance China’s position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China. PMID:25465081

  9. Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates.

    PubMed

    Mueller, Jerel K; Grigsby, Erinn M; Prevosto, Vincent; Petraglia, Frank W; Rao, Hrishikesh; Deng, Zhi-De; Peterchev, Angel V; Sommer, Marc A; Egner, Tobias; Platt, Michael L; Grill, Warren M

    2014-08-01

    Transcranial magnetic stimulation (TMS) is a widely used, noninvasive method for stimulating nervous tissue, yet its mechanisms of effect are poorly understood. Here we report new methods for studying the influence of TMS on single neurons in the brain of alert non-human primates. We designed a TMS coil that focuses its effect near the tip of a recording electrode and recording electronics that enable direct acquisition of neuronal signals at the site of peak stimulus strength minimally perturbed by stimulation artifact in awake monkeys (Macaca mulatta). We recorded action potentials within ∼1 ms after 0.4-ms TMS pulses and observed changes in activity that differed significantly for active stimulation as compared with sham stimulation. This methodology is compatible with standard equipment in primate laboratories, allowing easy implementation. Application of these tools will facilitate the refinement of next generation TMS devices, experiments and treatment protocols.

  10. Simultaneous transcranial magnetic stimulation and single neuron recording in alert non-human primates

    PubMed Central

    Mueller, Jerel K.; Grigsby, Erinn M.; Prevosto, Vincent; Petraglia, Frank W.; Rao, Hrishikesh; Deng, Zhi-De; Peterchev, Angel V.; Sommer, Marc A.; Egner, Tobias; Platt, Michael L.; Grill, Warren M.

    2014-01-01

    Transcranial magnetic stimulation (TMS) is a widely used, noninvasive method for stimulating nervous tissue, yet its mechanisms of effect are poorly understood. Here we report novel methods for studying the influence of TMS on single neurons in the brain of alert non-human primates. We designed a TMS coil that focuses its effect near the tip of a recording electrode and recording electronics that enable direct acquisition of neuronal signals at the site of peak stimulus strength minimally perturbed by stimulation artifact in intact, awake monkeys (Macaca mulatta). We recorded action potentials within ~1 ms after 0.4 ms TMS pulses and observed changes in activity that differed significantly for active stimulation as compared to sham stimulation. The methodology is compatible with standard equipment in primate laboratories, allowing for easy implementation. Application of these new tools will facilitate the refinement of next generation TMS devices, experiments, and treatment protocols. PMID:24974797

  11. Daily feeding rhythm in proboscis monkeys: a preliminary comparison with other non-human primates.

    PubMed

    Matsuda, Ikki; Akiyama, Yoshihiro; Tuuga, Augustine; Bernard, Henry; Clauss, Marcus

    2014-04-01

    In non-human primates, the daily feeding rhythm, i.e., temporal fluctuation in feeding activity across the day, has been described but has rarely received much analytical interpretation, though it may play a crucial part in understanding the adaptive significance of primate foraging strategies. This study is the first to describe the detailed daily feeding rhythm in proboscis monkeys (Nasalis larvatus) based on data collected from both riverbank and inland habitats. From May 2005 to May 2006, data on feeding behavior in a group of proboscis monkeys consisting of an alpha-male, six adult females and immatures was collected via continuous focal animal sampling technique in a forest along the Menanggul River, Sabah, Malaysia. In both the male and females, the highest peak of feeding activity was in the late afternoon at 15:00-17:00, i.e., shortly before sleeping. The differences in the feeding rhythm among the seasons appeared to reflect the time spent eating fruit and/or the availability of fruit; clearer feeding peaks were detected when the monkeys spent a relevant amount of time eating fruit, but no clear peak was detected when fruit eating was less frequent. The daily feeding rhythm was not strongly influenced by daily temperature fluctuations. When comparing the daily feeding rhythm of proboscis monkeys to that of other primates, one of the most common temporal patterns detected across primates was a feeding peak in the late afternoon, although it was impossible to demonstrate this statistically because of methodological differences among studies.

  12. Perinatal tobacco smoke exposure increases vascular oxidative stress and mitochondrial damage in non-human primates.

    PubMed

    Westbrook, David G; Anderson, Peter G; Pinkerton, Kent E; Ballinger, Scott W

    2010-09-01

    Epidemiological studies suggest that events occurring during fetal and early childhood development influence disease susceptibility. Similarly, molecular studies in mice have shown that in utero exposure to cardiovascular disease (CVD) risk factors such as environmental tobacco smoke (ETS) increased adult atherogenic susceptibility and mitochondrial damage; however, the molecular effects of similar exposures in primates are not yet known. To determine whether perinatal ETS exposure increased mitochondrial damage, dysfunction and oxidant stress in primates, archived tissues from the non-human primate model Macaca mulatta (M. mulatta) were utilized. M. mulatta were exposed to low levels of ETS (1 mg/m(3) total suspended particulates) from gestation (day 40) to early childhood (1 year), and aortic tissues were assessed for oxidized proteins (protein carbonyls), antioxidant activity (SOD), mitochondrial function (cytochrome oxidase), and mitochondrial damage (mitochondrial DNA damage). Results revealed that perinatal ETS exposure resulted in significantly increased oxidative stress, mitochondrial dysfunction and damage which were accompanied by significantly decreased mitochondrial antioxidant capacity and mitochondrial copy number in vascular tissue. Increased mitochondrial damage was also detected in buffy coat tissues in exposed M. mulatta. These studies suggest that perinatal tobacco smoke exposure increases vascular oxidative stress and mitochondrial damage in primates, potentially increasing adult disease susceptibility.

  13. [Symbol-based communication in non-human primates: a C. S. Peirce's semiotic analysis].

    PubMed

    Queiroz, João

    2003-12-01

    Are (or were) there any other symbolic species? This question has been addressed by researchers from many different fields and is responsible for a historical controversy on the existence of a threshold between "symbolic creatures" vs "simple forms of language creatures". According to the mainstream ethology and comparative psychology only the Homo sapiens is cognitively equiped to produce and interpret symbols. Here, I introduce an empirically testable model of symbolic semiosis ("symbolic action of sign") supported by C.S.Peirce logical-phenomenological theory of categories. I suggest that a specific sign-user pattern of behavior, observed in non-human primate communication, indicate a transition from indexical to symbolic semiosis.

  14. Protection of Non-Human Primates against Rabies with an Adenovirus Recombinant Vaccine

    PubMed Central

    Xiang, Z.Q.; Greenberg, L.; Ertl, H. C.; Rupprecht, C.E.

    2014-01-01

    Rabies remains a major neglected global zoonosis. New vaccine strategies are needed for human rabies prophylaxis. A single intramuscular immunization with a moderate dose of an experimental chimpanzee adenovirus (Ad) vector serotype SAd-V24, also termed AdC68, expressing the rabies virus glycoprotein, resulted in sustained titers of rabies virus neutralizing antibodies and protection against a lethal rabies virus challenge infection in a non-human primate model. Taken together, these data demonstrate the safety, immunogenicity, and efficacy of the recombinant Ad-rabies vector for further consideration in human clinical trials. PMID:24503087

  15. Prospects for genetically modified non-human primate models, including the common marmoset.

    PubMed

    Sasaki, Erika

    2015-04-01

    Genetically modified mice have contributed much to studies in the life sciences. In some research fields, however, mouse models are insufficient for analyzing the molecular mechanisms of pathology or as disease models. Often, genetically modified non-human primate (NHP) models are desired, as they are more similar to human physiology, morphology, and anatomy. Recent progress in studies of the reproductive biology in NHPs has enabled the introduction of exogenous genes into NHP genomes or the alteration of endogenous NHP genes. This review summarizes recent progress in the production of genetically modified NHPs, including the common marmoset, and future perspectives for realizing genetically modified NHP models for use in life sciences research.

  16. A Chronically Implantable Bidirectional Neural Interface for Non-human Primates.

    PubMed

    Komatsu, Misako; Sugano, Eriko; Tomita, Hiroshi; Fujii, Naotaka

    2017-01-01

    Optogenetics has potential applications in the study of epilepsy and neuroprostheses, and for studies on neural circuit dynamics. However, to achieve translation to clinical usage, optogenetic interfaces that are capable of chronic stimulation and monitoring with minimal brain trauma are required. We aimed to develop a chronically implantable device for photostimulation of the brain of non-human primates. We used a micro-light-emitting diode (LED) array with a flexible polyimide film. The array was combined with a whole-cortex electrocorticographic (ECoG) electrode array for simultaneous photostimulation and recording. Channelrhodopsin-2 (ChR2) was virally transduced into the cerebral cortex of common marmosets, and then the device was epidurally implanted into their brains. We recorded the neural activity during photostimulation of the awake monkeys for 4 months. The neural responses gradually increased after the virus injection for ~8 weeks and remained constant for another 8 weeks. The micro-LED and ECoG arrays allowed semi-invasive simultaneous stimulation and recording during long-term implantation in the brains of non-human primates. The development of this device represents substantial progress in the field of optogenetic applications.

  17. Preference for Averageness in Faces Does Not Generalize to Non-Human Primates

    PubMed Central

    Tomeo, Olivia B.; Ungerleider, Leslie G.; Liu, Ning

    2017-01-01

    Facial attractiveness is a long-standing topic of active study in both neuroscience and social science, motivated by its positive social consequences. Over the past few decades, it has been established that averageness is a major factor influencing judgments of facial attractiveness in humans. Non-human primates share similar social behaviors as well as neural mechanisms related to face processing with humans. However, it is unknown whether monkeys, like humans, also find particular faces attractive and, if so, which kind of facial traits they prefer. To address these questions, we investigated the effect of averageness on preferences for faces in monkeys. We tested three adult male rhesus macaques using a visual paired comparison (VPC) task, in which they viewed pairs of faces (both individual faces, or one individual face and one average face); viewing time was used as a measure of preference. We did find that monkeys looked longer at certain individual faces than others. However, unlike humans, monkeys did not prefer the average face over individual faces. In fact, the more the individual face differed from the average face, the longer the monkeys looked at it, indicating that the average face likely plays a role in face recognition rather than in judgments of facial attractiveness: in models of face recognition, the average face operates as the norm against which individual faces are compared and recognized. Taken together, our study suggests that the preference for averageness in faces does not generalize to non-human primates. PMID:28744207

  18. Promoting Cas9 degradation reduces mosaic mutations in non-human primate embryos

    PubMed Central

    Tu, Zhuchi; Yang, Weili; Yan, Sen; Yin, An; Gao, Jinquan; Liu, Xudong; Zheng, Yinghui; Zheng, Jiezhao; Li, Zhujun; Yang, Su; Li, Shihua; Guo, Xiangyu; Li, Xiao-Jiang

    2017-01-01

    CRISPR-Cas9 is a powerful new tool for genome editing, but this technique creates mosaic mutations that affect the efficiency and precision of its ability to edit the genome. Reducing mosaic mutations is particularly important for gene therapy and precision genome editing. Although the mechanisms underlying the CRSIPR/Cas9-mediated mosaic mutations remain elusive, the prolonged expression and activity of Cas9 in embryos could contribute to mosaicism in DNA mutations. Here we report that tagging Cas9 with ubiquitin-proteasomal degradation signals can facilitate the degradation of Cas9 in non-human primate embryos. Using embryo-splitting approach, we found that shortening the half-life of Cas9 in fertilized zygotes reduces mosaic mutations and increases its ability to modify genomes in non-human primate embryos. Also, injection of modified Cas9 in one-cell embryos leads to live monkeys with the targeted gene modifications. Our findings suggest that modifying Cas9 activity can be an effective strategy to enhance precision genome editing. PMID:28155910

  19. Olive baboons: a non-human primate model for testing dengue virus type 2 replication.

    PubMed

    Valdés, Iris; Gil, Lázaro; Castro, Jorge; Odoyo, Damián; Hitler, Rikoi; Munene, Elephas; Romero, Yaremis; Ochola, Lucy; Cosme, Karelia; Kariuki, Thomas; Guillén, Gerardo; Hermida, Lisset

    2013-12-01

    This study evaluated the use of a non-human primate, the olive baboon (Papio anubis), as a model of dengue infection. Olive baboons closely resemble humans genetically and physiologically and have been used extensively for assessing novel vaccine formulations. Two doses of dengue virus type 2 (DENV-2) were tested in baboons: 10(3) and 10(4) pfu. Similarly, African green monkeys received the same quantity of virus and acted as positive controls. Following exposure, high levels of viremia were detected in both animal species. There was a trend to detect more days of viremia and more homogeneous viral titers in animals receiving the low viral dose. In addition, baboons infected with the virus generally exhibited positive virus isolation 1 day later than African green monkeys. Humoral responses consisting of antiviral and neutralizing antibodies were detected in all animals after infection. We conclude that baboons provide an alternative non-human primate species for experimental DENV-2 infection and we recommend their use for further tests of vaccines, administering the lowest dose assayed: 10(3) pfu. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  20. No monkey business: why studying NK cells in non-human primates pays off.

    PubMed

    Hong, Henoch S; Rajakumar, Premeela A; Billingsley, James M; Reeves, R Keith; Johnson, R Paul

    2013-01-01

    Human NK (hNK) cells play a key role in mediating host immune responses against various infectious diseases. For practical reasons, the majority of the data on hNK cells has been generated using peripheral blood lymphocytes. In contrast, our knowledge of NK cells in human tissues is limited, and not much is known about developmental pathways of hNK cell subpopulations in vivo. Although research in mice has elucidated a number of fundamental features of NK cell biology, mouse, and hNK cells significantly differ in their subpopulations, functions, and receptor repertoires. Thus, there is a need for a model that is more closely related to humans and yet allows experimental manipulations. Non-human primate models offer numerous opportunities for the study of NK cells, including the study of the role of NK cells after solid organ and stem cell transplantation, as well as in acute viral infection. Macaque NK cells can be depleted in vivo or adoptively transferred in an autologous system. All of these studies are either difficult or unethical to carry out in humans. Here we highlight recent advances in rhesus NK cell research and their parallels in humans. Using high-throughput transcriptional profiling, we demonstrate that the human CD56(bright) and CD56(dim) NK cell subsets have phenotypically and functionally analogous counterparts in rhesus macaques. Thus, the use of non-human primate models offers the potential to substantially advance hNK cell research.

  1. Nicotinic receptors in non-human primates: analysis of genetic and functional conservation with humans

    PubMed Central

    Shorey-Kendrick, Lyndsey E.; Ford, Matthew M.; Allen, Daicia C.; Kuryatov, Alexander; Lindstrom, Jon; Wilhelm, Larry; Grant, Kathleen A.; Spindel, Eliot R.

    2015-01-01

    Nicotinic acetylcholine receptors (nAChRs) are highly conserved between humans and non-human primates. Conservation exists at the level of genomic structure, protein structure and epigenetics. Overall homology of nAChRs at the protein level is 98% in macaques versus 89% in mice, which is highly relevant for evaluating subtype-specific ligands that have different affinities in humans versus rodents. In addition to conservation at the protein level, there is high conservation of genomic structure in terms of intron and exon size and placement of CpG sites that play a key role in epigenetic regulation. Analysis of single nucleotide polymorphisms (SNPs) shows that while the majority of SNPs are not conserved between humans and macaques, some functional polymorphisms are. Most significantly, cynomolgus monkeys express a similar α5 nAChR Asp398Asn polymorphism to the human α5 Asp398Asn polymorphism that has been linked to greater nicotine addiction and smoking related disease. Monkeys can be trained to readily self-administer nicotine, and in an initial study we have demonstrated that cynomolgus monkeys bearing the α5 D398N polymorphism show a reduced behavioral sensitivity to oral nicotine and tend to consume it in a different pattern when compared to wild-type monkeys. Thus the combination of highly homologous nAChR, higher cortical functions and capacity for complex training makes non-human primates a unique model to study in vivo functions of nicotinic receptors. In particular, primate studies on nicotine addiction and evaluation of therapies to prevent or overcome nicotine addiction are likely to be highly predictive of treatment outcomes in humans. PMID:25661700

  2. Neurochemistry Study of Spinal Cord in Non-Human Primate (Sapajus Spp.)

    PubMed Central

    Torres-da-Silva, K.R.; da Silva, A.V.; Barioni, N.O.; Tessarin, G.W.L.; de Oliveira, J.A.; Ervolino, E.; Horta-Júnior, J.A.C.; Casatti, C.A.

    2016-01-01

    The spinal cord is involved in local, ascending and descending neural pathways. Few studies analyzed the distribution of neuromediators in the laminae of non-human primates along all segments. The present study described the classic neuromediators in the spinal cord of the non-human primate Sapajus spp. through histochemical and immunohistochemical methods. Nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) method showed neuronal somata in the intermediolateral column (IML), central cervical nucleus (CCN), laminae I, II, III, IV, V, VI, VII, VIII and X, besides dense presence of nerve fibers in laminae II and IX. Acetylcholinesterase (AChE) activity was evident in the neuronal somata in laminae V, VI, VII, VIII, IX, CCN, IML and in the Clarke’s column (CC). Immunohistochemistry data revealed neuronal nitric oxide synthase (nNOS) immunoreactivity in neuronal somata and in fibers of laminae I, II, III, VII, VIII, X and IML; choline acetyltransferase (ChAT) in neuronal somata and in fibers of laminae VII, VIII and IX; calcitonin gene-related peptide (CGRP) was noticed in neuronal somata of lamina IX and in nerve fibers of laminae I, II, III, IV, V, VI and VII; substance P (SP) in nerve fibers of laminae I, II, III, IV, V, VI, VII, VIII, IX, X, CCN, CC and IML; serotonin (5-HT) and vesicular glutamate transporter-1 (VGLUT1) was noticed in nerve fibers of all laminae; somatostatin (SOM) in neuronal somata of laminae III, IV, V, VI, VII, VIII and IX and nerve fibers in laminae I, II, V, VI, VII, X and IML; calbindin (Cb) in neuronal somata of laminae I, II, VI, VII, IX and X; parvalbumin (PV) was found in neuronal somata and in nerve fibers of laminae III, IV, V, VI, VII, VIII, IX and CC; finally, gamma-amino butyric acid (GABA) was present in neuronal somata of laminae V, VI, VII, VIII, IX and X. This study revealed interesting results concerning the chemoarchitecture of the Sapajus spp. spinal cord with a distribution pattern mostly similar to

  3. An ethnoprimatological approach to assessing levels of tolerance between human and commensal non-human primates in Sri Lanka.

    PubMed

    Nekaris, Anne-Isola; Boulton, Alex; Nijman, Vincent

    2013-01-01

    Human and non-human primates increasingly are forced to live commensally, and understanding the human-nonhuman interconnections are paramount in understanding tolerance and conflict. In our study area, the heavily deforested parts of southern Sri Lanka humans and primates live side by side and prevalent religious tenets encourage a peaceful co-existence. We quantify the attitudes of rural communities towards three resident primate species (red slender loris, purple-faced langur, toque macaque) and wildlife conservation through semi-structured interviews with 301 people. Presence of the three primates on people' s land or farms was not related to the distance to the nearest forest but for langurs the incidence of crop-raiding was negatively related to distance to the forest. Despite Buddhist' s beliefs about 10% of interviewees indicated having killed primates (in the past) but levels of killing was not related to awareness of protective status of the primates. Overall however positive attitudes towards primates prevailed, without noticeable influence of sex, education or employment type. There was overwhelming support for forest protection measures - not because of the primates but mainly for water preservation and for ensuring a steady timber supply. We found that despite high levels of deforestation, and an increase of encroachment of humans into primate habitats, attitudes has led only to a limited increased level of tension between humans and primates.

  4. Brains, innovations, tools and cultural transmission in birds, non-human primates, and fossil hominins

    PubMed Central

    Lefebvre, Louis

    2013-01-01

    Recent work on birds and non-human primates has shown that taxonomic differences in field measures of innovation, tool use and social learning are associated with size of the mammalian cortex and avian mesopallium and nidopallium, as well as ecological traits like colonization success. Here, I review this literature and suggest that many of its findings are relevant to hominin intelligence. In particular, our large brains and increased intelligence may be partly independent of our ape phylogeny and the result of convergent processes similar to those that have molded avian and platyrrhine intelligence. Tool use, innovativeness and cultural transmission might be linked over our past and in our brains as operations of domain-general intelligence. Finally, colonization of new areas may have accompanied increases in both brain size and innovativeness in hominins as they have in other mammals and in birds, potentially accelerating hominin evolution via behavioral drive. PMID:23761751

  5. Brains, innovations, tools and cultural transmission in birds, non-human primates, and fossil hominins.

    PubMed

    Lefebvre, Louis

    2013-01-01

    Recent work on birds and non-human primates has shown that taxonomic differences in field measures of innovation, tool use and social learning are associated with size of the mammalian cortex and avian mesopallium and nidopallium, as well as ecological traits like colonization success. Here, I review this literature and suggest that many of its findings are relevant to hominin intelligence. In particular, our large brains and increased intelligence may be partly independent of our ape phylogeny and the result of convergent processes similar to those that have molded avian and platyrrhine intelligence. Tool use, innovativeness and cultural transmission might be linked over our past and in our brains as operations of domain-general intelligence. Finally, colonization of new areas may have accompanied increases in both brain size and innovativeness in hominins as they have in other mammals and in birds, potentially accelerating hominin evolution via behavioral drive.

  6. Protection of non-human primates against rabies with an adenovirus recombinant vaccine

    SciTech Connect

    Xiang, Z.Q.; Greenberg, L.; Ertl, H.C.; Rupprecht, C.E.

    2014-02-15

    Rabies remains a major neglected global zoonosis. New vaccine strategies are needed for human rabies prophylaxis. A single intramuscular immunization with a moderate dose of an experimental chimpanzee adenovirus (Ad) vector serotype SAd-V24, also termed AdC68, expressing the rabies virus glycoprotein, resulted in sustained titers of rabies virus neutralizing antibodies and protection against a lethal rabies virus challenge infection in a non-human primate model. Taken together, these data demonstrate the safety, immunogenicity, and efficacy of the recombinant Ad-rabies vector for further consideration in human clinical trials. - Highlights: • Pre-exposure vaccination with vaccine based on a chimpanzee derived adenovirus protects against rabies. • Protection is sustained. • Protection is achieved with single low-dose of vaccine given intramuscularly. • Protection is not affected by pre-existing antibodies to common human serotypes of adenovirus.

  7. Studying brain functions with mesoscopic measurements: advances in electrocorticography for non-human primates

    PubMed Central

    Fukushima, Makoto; Chao, Zenas C.

    2015-01-01

    Our brain is organized in a modular structure. Information in different modalities is processed within distinct cortical areas. However, individual cortical areas cannot enable complex cognitive functions without interacting with other cortical areas. Electrocorticography (ECoG) has recently become an important tool for studying global network activity across cortical areas in animal models. With stable recordings of electrical field potentials from multiple cortical areas, ECoG provides an opportunity to systematically study large-scale cortical activity at a mesoscopic spatiotemporal resolution under various experimental conditions. Recent developments in thin, flexible ECoG electrodes permit recording field potentials from not only gyral but intrasulcal cortical surfaces. Our review here focuses on the recent advances of ECoG applications to non-human primates. PMID:25889531

  8. The translational value of non-human primates in preclinical research on infection and immunopathology.

    PubMed

    't Hart, Bert A; Bogers, Willy M; Haanstra, Krista G; Verreck, Frank A; Kocken, Clemens H

    2015-07-15

    The immune system plays a central role in the defense against environmental threats - such as infection with viruses, parasites or bacteria - but can also be a cause of disease, such as in the case of allergic or autoimmune disorders. In the past decades the impressive development of biotechnology has provided scientists with biological tools for the development of highly selective treatments for the different types of disorders. However, despite some clear successes the translation of scientific discoveries into effective treatments has remained challenging. The often-disappointing predictive validity of the preclinical animal models that are used in the selection of the most promising vaccine or drug candidates is the Achilles heel in the therapy development process. This publication summarizes the relevance and usage of non-human primates as pre-clinical model in infectious and autoimmune diseases, in particular for biologicals, which due to their high species-specificity are inactive in lower species.

  9. The protective effect of Canova homeopathic medicine in cyclophosphamide-treated non-human primates.

    PubMed

    Leal, Mariana Ferreira; Antunes, Lusânia Maria Greggi; Lamarão, Maria Fernanda Vita; da Silva, Carla Elvira Araújo; da Silva, Ismael Dale Cotrim Guerreiro; Assumpção, Paulo Pimentel; Andrade, Edilson Ferreira; Rezende, Alexandre Pingarilho; Imbeloni, Aline Amaral; Muniz, José Augusto Pereira Carneiro; Pinto, Giovanny Rebouças; Smith, Marília de Arruda Cardoso; Burbano, Rommel Rodríguez

    2012-12-01

    Canova activates macrophages and indirectly induces lymphocyte proliferation. Here we evaluated the effects of Canova in cyclophosphamide-treated non-human primates. Twelve Cebus apella were evaluated. Four animals were treated with Canova only. Eight animals were treated with two doses of cyclophosphamide (50 mg/kg) and four of these animals received Canova. Body weight, biochemistry and hematologic analyses were performed for 40 days. Micronucleus and comet assays were performed for the evaluation of DNA damage. We observed that cyclophosphamide induced abnormal WBC count in all animals. However, the group treated with cyclophosphamide plus Canova presented a higher leukocyte count than that which received only cyclophosphamide. Cyclophosphamide induced micronucleus and DNA damage in all animals. The frequency of these alterations was significantly lower in the Canova group than in the group without this medicine. Our results demonstrated that Canova treatment minimizes cyclophosphamide myelotoxicity in C. apella. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Non-human primate models of experimental autoimmune encephalomyelitis: Variations on a theme.

    PubMed

    't Hart, Bert A; Bauer, Jan; Brok, Herbert P M; Amor, Sandra

    2005-11-01

    Despite years of intensive research into multiple sclerosis (MS) scientists have not yet succeeded in developing an absolute therapy for the treatment of this disabling disease of the human central nervous system. The wide immunological gap between inbred rodent strains and the heterogeneous human population is probably the single most important factor that hampers the translation of scientific principles developed in rodents into effective therapies for MS. Because of the closer immunological proximity to humans, non-human primates provide useful experimental models that may help to bridge this gap. Here we review the models of experimental autoimmune encephalomyelitis in rhesus macaques and common marmosets. We will discuss the salient points of the models and suggest how these may represent the spectrum of inflammatory demyelinating diseases of the central nervous system in humans.

  11. Attenuation correction for the large non-human primate brain imaging using microPET

    NASA Astrophysics Data System (ADS)

    Naidoo-Variawa, S.; Lehnert, W.; Kassiou, M.; Banati, R.; Meikle, S. R.

    2010-04-01

    Assessment of the biodistribution and pharmacokinetics of radiopharmaceuticals in vivo is often performed on animal models of human disease prior to their use in humans. The baboon brain is physiologically and neuro-anatomically similar to the human brain and is therefore a suitable model for evaluating novel CNS radioligands. We previously demonstrated the feasibility of performing baboon brain imaging on a dedicated small animal PET scanner provided that the data are accurately corrected for degrading physical effects such as photon attenuation in the body. In this study, we investigated factors affecting the accuracy and reliability of alternative attenuation correction strategies when imaging the brain of a large non-human primate (papio hamadryas) using the microPET Focus 220 animal scanner. For measured attenuation correction, the best bias versus noise performance was achieved using a 57Co transmission point source with a 4% energy window. The optimal energy window for a 68Ge transmission source operating in singles acquisition mode was 20%, independent of the source strength, providing bias-noise performance almost as good as for 57Co. For both transmission sources, doubling the acquisition time had minimal impact on the bias-noise trade-off for corrected emission images, despite observable improvements in reconstructed attenuation values. In a [18F]FDG brain scan of a female baboon, both measured attenuation correction strategies achieved good results and similar SNR, while segmented attenuation correction (based on uncorrected emission images) resulted in appreciable regional bias in deep grey matter structures and the skull. We conclude that measured attenuation correction using a single pass 57Co (4% energy window) or 68Ge (20% window) transmission scan achieves an excellent trade-off between bias and propagation of noise when imaging the large non-human primate brain with a microPET scanner.

  12. Clinical veterinarian's perspective of non-human primate (NHP) use in drug safety studies.

    PubMed

    Taylor, Katrina

    2010-01-01

    Owing to their size, cost, and availability, the cynomolgus macaque (Macaca fascicularis) has surpassed the rhesus macaque in its use as a non-human primate preclinical model for drug safety studies. There are three major regions where cynomolgus macaques are bred: China, Southeast Asia, and the island of Mauritius. Country of origin of the macaque is important, as disease status and background disease incidence in non-human primates from each of these sites can differ. Once a source of macaque has been decided, careful monitoring of the animal during breeding and by the importing vendor while the animals are in quarantine is important. During vendor quarantine, the animals should be monitored and evaluated for disease, response to tuberculosis testing, retroviral status, and both ecto- and endoparasites. After animals arrive at the test facility, additional quarantine and acclimation are important to ascertain health status further and to reduce stress on the animals, thereby providing a better research model. The type of caging, food, water, and enrichment should be carefully selected to best suit the needs of the study while working within Federal Regulations (i.e., Animal Welfare Act and Good Laboratory Practices). Careful prescreening by performing tests (such as physical, neurologic, and ophthalmologic examinations), complete blood count, biochemical profile, urinanalysis, electrocardiograms, and pulse oximetry is important when selecting the most appropriate animals for the study. After the in-life portion of the study begins, animals that present with clinical signs should be examined and an appropriate treatment course begun while maintaining study objectives. As many commonly used medications have immunomodulatory effects, having an understanding of the mechanism of action of test articles will aid in the appropriate choice of treatment of study animals. A tiered approach to the treatment of these animals is a conservative and usually acceptable approach.

  13. Motor Stereotypies and Cognitive Perseveration in Non-human Primates Exposed to Early Gestational Irradiation

    PubMed Central

    Selemon, Lynn D.; Friedman, Harriet R.

    2013-01-01

    A number of psychiatric illnesses have been associated with prenatal disturbance of brain development, including autism, attention deficit hyperactivity disorder, and schizophrenia. Individuals afflicted with these disorders exhibit both repetitive motor and cognitive behavior. The potential role that environmental insult to the developing brain may play in generating these aberrant behaviors is unclear. Here we examine the behavioral consequences of an early gestational insult in the non-human primate. Rhesus macaques were exposed to x-irradiation during the first trimester of development to disrupt neurogenesis. The behavior of five fetally irradiated monkeys (FIMs) and five control monkeys (CONs) was observed as they matured from juvenile (1.5 years) to adult ages (4–5 years). Home-cage behavior was indistinguishable in the two groups. In the testing cage, circling was prevalent in both groups at juvenile ages,persisting to adulthood in three of the five FIMs. One FIM executed a ritualized motor sequence marked by semi-circling and undulating head movements. Seven macaques (4 FIMs, 3 CONs)were tested on a spatial Delayed Alternation (DA) task as adults. Perseverative errors and non-perseverative errors were recorded in early stages of the testing, at the 0 delay interval. while performing DA, FIMs made more errors of perseveration than CONs yet the number of total errors committed did not differ between groups. The presence of motor stereotypies and cognitive perseveration in fetally irradiated non-human primates suggests that environmental insult to the embryonic brain may contribute to repetitive motor and cognitive behaviors in neuropsychiatric diseases. PMID:23769911

  14. Motor stereotypies and cognitive perseveration in non-human primates exposed to early gestational irradiation.

    PubMed

    Selemon, L D; Friedman, H R

    2013-09-17

    A number of psychiatric illnesses have been associated with prenatal disturbance of brain development, including autism, attention deficit hyperactivity disorder, and schizophrenia. Individuals afflicted with these disorders exhibit both repetitive motor and cognitive behavior. The potential role that environmental insult to the developing brain may play in generating these aberrant behaviors is unclear. Here we examine the behavioral consequences of an early gestational insult in the non-human primate. Rhesus macaques were exposed to x-irradiation during the first trimester of development to disrupt neurogenesis. The behavior of five fetally irradiated monkeys (FIMs) and five control monkeys (CONs) was observed as they matured from juvenile (1.5 years) to adult ages (4-5 years). Home-cage behavior was indistinguishable in the two groups. In the testing cage, circling was prevalent in both groups at juvenile ages, persisting to adulthood in three of the five FIMs. One FIM executed a ritualized motor sequence marked by semi-circling and undulating head movements. Seven macaques (4 FIMs, 3 CONs) were tested on a spatial Delayed Alternation (DA) task as adults. Perseverative errors and non-perseverative errors were recorded in early stages of the testing, at the 0 delay interval. While performing DA, FIMs made more errors of perseveration than CONs yet the number of total errors committed did not differ between groups. The presence of motor stereotypies and cognitive perseveration in fetally irradiated non-human primates suggests that environmental insult to the embryonic brain may contribute to repetitive motor and cognitive behaviors in neuropsychiatric diseases. Published by Elsevier Ltd.

  15. Detection of Toxoplasma gondii antibodies in captive non-human primates in the Amazon region, Brazil.

    PubMed

    Minervino, Antonio Humberto Hamad; Cassinelli, Ana Beatriz Melles; de Souza, Alex Junior Souza; Alves, Max Moreira; Soares, Manoel do Carmo Pereira; Ferreira, Dayana Alersa Conceição; Pereira, Washington Luiz Assunção; Gennari, Solange Maria

    2017-10-03

    Toxoplasma gondii infections in captive non-human primates are of interest because often they die due to severe toxoplasmosis. Thus, we aimed to evaluate samples from a serum bank to T. gondii antibodies. Serum samples of 179 monkeys from the National Center of Primates, Brazil, were retrospective analyzed for T. gondii IgG antibodies by modified agglutination test using formalin-fixed whole parasites as antigen (cutoff 1:25). Among the 179 samples tested, 88 (49.2%) were positive. Twelve of the 18 evaluated species presented at least one positive animal. A higher occurrence of positive animals was found in New World (52.2%) than Old World (22.2%) monkeys (P = .023) and in the animals from domestic donation origin, which had lived in human homes as pets (P = .004). We confirm the widespread presence of T. gondii in captive monkeys and contribute to the range of species that can be infected by this parasite. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Titi Monkeys as a Novel Non-Human Primate Model for the Neurobiology of Pair Bonding


    PubMed Central

    Bales, Karen L.; Arias del Razo, Rocío; Conklin, Quinn A.; Hartman, Sarah; Mayer, Heather S.; Rogers, Forrest D.; Simmons, Trenton C.; Smith, Leigh K.; Williams, Alexia; Williams, Donald R.; Witczak, Lynea R.; Wright, Emily C.

    2017-01-01

    It is now widely recognized that social bonds are critical to human health and well-being. One of the most important social bonds is the attachment relationship between two adults, known as the pair bond. The pair bond involves many characteristics that are inextricably linked to quality of health, including providing a secure psychological base and acting as a social buffer against stress. The majority of our knowledge about the neurobiology of pair bonding comes from studies of a socially monogamous rodent, the prairie vole (Microtus ochrogaster), and from human imaging studies, which inherently lack control. Here, we first review what is known of the neurobiology of pair bonding from humans and prairie voles. We then present a summary of the studies we have conducted in titi monkeys (Callicebus cupreus)—a species of socially monogamous New World primates. Finally, we construct a neural model based on the location of neuropeptide receptors in the titi monkey brain, as well as the location of neural changes in our imaging studies, with some basic assumptions based on the prairie vole model. In this model, we emphasize the role of visual mating stimuli as well as contributions of the dopaminergic reward system and a strong role for the lateral septum. This model represents an important step in understanding the neurobiology of social bonds in non-human primates, which will in turn facilitate a better understanding of these mechanisms in humans. PMID:28955178

  17. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.

    PubMed

    Chong, James J H; Yang, Xiulan; Don, Creighton W; Minami, Elina; Liu, Yen-Wen; Weyers, Jill J; Mahoney, William M; Van Biber, Benjamin; Cook, Savannah M; Palpant, Nathan J; Gantz, Jay A; Fugate, James A; Muskheli, Veronica; Gough, G Michael; Vogel, Keith W; Astley, Cliff A; Hotchkiss, Charlotte E; Baldessari, Audrey; Pabon, Lil; Reinecke, Hans; Gill, Edward A; Nelson, Veronica; Kiem, Hans-Peter; Laflamme, Michael A; Murry, Charles E

    2014-06-12

    Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

  18. A Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates (Macaca mulatta).

    PubMed

    Salegio, Ernesto A; Bresnahan, Jacqueline C; Sparrey, Carolyn J; Camisa, William; Fischer, Jason; Leasure, Jeremi; Buckley, Jennifer; Nout-Lomas, Yvette S; Rosenzweig, Ephron S; Moseanko, Rod; Strand, Sarah; Hawbecker, Stephanie; Lemoy, Marie-Josee; Haefeli, Jenny; Ma, Xiaokui; Nielson, Jessica L; Edgerton, V R; Ferguson, Adam R; Tuszynski, Mark H; Beattie, Michael S

    2016-03-01

    The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animal's spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies.

  19. Alternative methods for the use of non-human primates in biomedical research.

    PubMed

    Burm, Saskia M; Prins, Jan-Bas; Langermans, Jan; Bajramovic, Jeffrey J

    2014-01-01

    The experimental use of non-human primates (NHP) in Europe is tightly regulated and is only permitted when there are no alternatives available. As a result, NHP are most often used in late, pre-clinical phases of biomedical research. Although the impetus for scientists, politicians and the general public to replace, reduce and refine NHP in biomedical research is strong, the development of 3Rs technology for NHP poses specific challenges. In February 2014 a workshop on "Alternative methods for the use of NHP in biomedical research" was organized within the international exchange program of EUPRIM-Net II, a European infrastructure initiative that links biomedical primate research centers. The workshop included lectures by key scientists in the field of alternatives as well as by experts from governmental and non-governmental organizations. Furthermore, parallel sessions were organized to stimulate discussion on the challenges of advancing the use of alternative methods for NHP. Subgroups voted on four statements and together composed a list with opportunities and priorities. This report summarizes the presentations that were held, the content of the discussion sessions and concludes with recommendations on 3Rs development for NHP specifically. These include technical, conceptual as well as political topics.

  20. A Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates (Macaca mulatta)

    PubMed Central

    Salegio, Ernesto A.; Sparrey, Carolyn J.; Camisa, William; Fischer, Jason; Leasure, Jeremi; Buckley, Jennifer; Nout-Lomas, Yvette S.; Rosenzweig, Ephron S.; Moseanko, Rod; Strand, Sarah; Hawbecker, Stephanie; Lemoy, Marie-Josee; Haefeli, Jenny; Ma, Xiaokui; Nielson, Jessica L.; Edgerton, V.R.; Ferguson, Adam R.; Tuszynski, Mark H.

    2016-01-01

    Abstract The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animal's spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies. PMID:26788611

  1. A new, quantitative rating scale for dyskinesia in non-human primates

    PubMed Central

    Potts, Lisa F.; Uthayathas, Subramaniam; Greven, Alexander C. M.; Dyavarshetty, Bhagyalaxmi; Mouradian, M. Maral; Papa, Stella M.

    2014-01-01

    The aim of this study was to develop a quantitative scale to assess levodopa-induced dyskinesias (LID) in non-human primates using a video-based scoring system (Quantitative Dyskinesia Scale, QDS). Six macaques with stable parkinsonism and LID were used for tests of the new QDS, in comparison with our current standardized scale (Drug Related Side-effects, DRS), which provides a classic subjective measurement of dyskinesia. QDS scoring is based on systematic movement counts in time frames, using videotape recordings. For both scales, body segments scored included each extremity, trunk, neck and face, and raters were blinded to L-dopa treatments. Comparisons of the two scales revealed that their scores are highly correlated and parallel to the L-dopa pharmacokinetic profile, although the QDS provided significantly more quantifiable measurements. This remained the case after separating animals into groups of mild and severe dyskinesias. Inter-rater reliability for application of the QDS was confirmed with scores obtained by three examiners. We conclude that the QDS is a quantitative tool for reliably scoring LID in parkinsonian monkeys at all levels of severity of dyskinesia. The application of this new standard for scoring LID in primates will allow for more precise measurements of the effects of experimental treatments and improve the quality of results obtained in translational studies. PMID:25171151

  2. Mosquitoes as Potential Bridge Vectors of Malaria Parasites from Non-Human Primates to Humans

    PubMed Central

    Verhulst, Niels O.; Smallegange, Renate C.; Takken, Willem

    2012-01-01

    Malaria is caused by Plasmodium parasites which are transmitted by mosquitoes. Until recently, human malaria was considered to be caused by human-specific Plasmodium species. Studies on Plasmodium parasites in non-human primates (NHPs), however, have identified parasite species in gorillas and chimpanzees that are closely related to human Plasmodium species. Moreover, P. knowlesi, long known as a parasite of monkeys, frequently infects humans. The requirements for such a cross-species exchange and especially the role of mosquitoes in this process are discussed, as the latter may act as bridge vectors of Plasmodium species between different primates. Little is known about the mosquito species that would bite both humans and NHPs and if so, whether humans and NHPs share the same Plasmodium vectors. To understand the vector-host interactions that can lead to an increased Plasmodium transmission between species, studies are required that reveal the nature of these interactions. Studying the potential role of NHPs as a Plasmodium reservoir for humans will contribute to the ongoing efforts of human malaria elimination, and will help to focus on critical areas that should be considered in achieving this goal. PMID:22701434

  3. Absence of mutations associated with sulfa resistance in Pneumocystis carinii dihydropteroate synthase gene from non-human primates.

    PubMed

    Demanche, C; Guillot, J; Berthelemy, M; Petitt, T; Roux, P; Wakefield, A E

    2002-06-01

    The dihydropteroate synthase (DHPS) gene from Pneumocystis carinii isolated from non-human primates was amplified using a polymerase chain reaction (PCR) and sequenced to analyse point mutations associated with sulfa resistance. P. carinii DHPS gene amplification was obtained from eight lung samples from five New World primate species and one Old World primate species. None of the animals had been exposed to sulfa drugs and only the wild-type P. carinii DHPS sequence at codons 55 and 57 was observed. These data support the hypothesis that high rates of DHPS mutants in P. carinii f. sp. hominis have arisen with increased use of sulfa drugs for P. carinii pneumonia prophylaxis.

  4. Longitudinal Characterization of Escherichia coli in Healthy Captive Non-Human Primates

    PubMed Central

    Clayton, Jonathan B.; Danzeisen, Jessica L.; Trent, Ava M.; Murphy, Tami; Johnson, Timothy J.

    2014-01-01

    The gastrointestinal (GI) tracts of non-human primates (NHPs) are well known to harbor Escherichia coli, a known commensal of human beings and animals. While E. coli is a normal inhabitant of the mammalian gut, it also exists in a number of pathogenic forms or pathotypes, including those with predisposition for the GI tract as well as the urogenital tract. Diarrhea in captive NHPs has long been a problem in both zoo settings and research colonies, including the Como Zoo. It is an animal welfare concern, as well as a public health concern. E. coli has not been extensively studied; therefore, a study was performed during the summer of 2009 in collaboration with a zoo in Saint Paul, MN, which was previously experiencing an increased incidence and severity of diarrhea among their NHP collection. Fresh fecal samples were collected weekly from each member of the primate collection, between June and August of 2009, and E. coli were isolated. A total of 33 individuals were included in the study, representing eight species. E. coli isolates were examined for their genetic relatedness, phylogenetic relationships, plasmid replicon types, virulence gene profiles, and antimicrobial susceptibility profiles. A number of isolates were identified containing virulence genes commonly found in several different E. coli pathotypes, and there was evidence of clonal transmission of isolates between animals and over time. Overall, the manifestation of chronic diarrhea in the Como Zoo primate collection is a complex problem whose solution will require regular screening for microbial agents and consideration of environmental causes. This study provides some insight toward the sharing of enteric bacteria between such animals. PMID:26664923

  5. The neural bases of crossmodal object recognition in non-human primates and rodents: a review.

    PubMed

    Cloke, Jacob M; Jacklin, Derek L; Winters, Boyer D

    2015-05-15

    The ability to integrate information from different sensory modalities to form unique multisensory object representations is a highly adaptive cognitive function. Surprisingly, non-human animal studies of the neural substrates of this form of multisensory integration have been somewhat sparse until very recently, and this may be due in part to a relative paucity of viable testing methods. Here we review the historical development and use of various "crossmodal" cognition tasks for non-human primates and rodents, focusing on tests of "crossmodal object recognition", the ability to recognize an object across sensory modalities. Such procedures have great potential to elucidate the cognitive and neural bases of object representation as it pertains to perception and memory. Indeed, these studies have revealed roles in crossmodal cognition for various brain regions (e.g., prefrontal and temporal cortices) and neurochemical systems (e.g., acetylcholine). A recent increase in behavioral and physiological studies of crossmodal cognition in rodents augurs well for the future of this research area, which should provide essential information about the basic mechanisms of object representation in the brain, in addition to fostering a better understanding of the causes of, and potential treatments for, cognitive deficits in human diseases characterized by atypical multisensory integration.

  6. Modeling Zika plasma viral dynamics in non-human primates: insights into viral pathogenesis and antiviral strategies

    SciTech Connect

    Best, Katharine; Guedj, Jeremie; Madelain, Vincent; de Lamballerie, Xavier; L, So-Yonim; Osuna, Christa E; Whitney, James; Perelson, Alan S.

    2016-10-24

    The recent outbreak of Zika virus (ZIKV) has been associated with fetal abnormalities and neurological complications, prompting global concern. Here we present the first mathematical analysis of the within-host dynamics of plasma ZiKV burden in a non-human primate model, allowing for characterization of the growth and clearance of ZIKV within an individual macaque.

  7. Broca's region: linking human brain functional connectivity data and non-human primate tracing anatomy studies.

    PubMed

    Kelly, Clare; Uddin, Lucina Q; Shehzad, Zarrar; Margulies, Daniel S; Castellanos, F Xavier; Milham, Michael P; Petrides, Michael

    2010-08-01

    Brodmann areas 6, 44 and 45 in the ventrolateral frontal cortex of the left hemisphere of the human brain constitute the anterior language production zone. The anatomical connectivity of these areas with parietal and temporal cortical regions was recently examined in an autoradiographic tract-tracing study in the macaque monkey. Studies suggest strong correspondence between human resting state functional connectivity (RSFC) based on functional magnetic resonance imaging data and experimentally demonstrated anatomical connections in non-human primates. Accordingly, we hypothesized that areas 6, 44 and 45 of the human brain would exhibit patterns of RSFC consistent with patterns of anatomical connectivity observed in the macaque. In a primary analysis, we examined the RSFC associated with regions-of-interest placed in ventrolateral frontal areas 6, 44 and 45, on the basis of local sulcal and gyral anatomy. We validated the results of the primary hypothesis-driven analysis with a data-driven partitioning of ventrolateral frontal cortex into regions exhibiting distinct RSFC patterns, using a spectral clustering algorithm. The RSFC of ventrolateral frontal areas 6, 44 and 45 was consistent with patterns of anatomical connectivity shown in the macaque. We observed a striking dissociation between RSFC for the ventral part of area 6 that is involved in orofacial motor control and RSFC associated with Broca's region (areas 44 and 45). These findings indicate rich and differential RSFC patterns for the ventrolateral frontal areas controlling language production, consistent with known anatomical connectivity in the macaque brain, and suggest conservation of connectivity during the evolution of the primate brain.

  8. Can non-human primates serve as models for investigating dengue disease pathogenesis?

    PubMed Central

    Clark, Kristina B.; Onlamoon, Nattawat; Hsiao, Hui-Mien; Perng, Guey C.; Villinger, Francois

    2013-01-01

    Dengue Virus (DV) infects between 50 and 100 million people globally, with public health costs totaling in the billions. It is the causative agent of dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), vector-borne diseases that initially predominated in the tropics. Due to the expansion of its mosquito vector, Aedes spp., DV is increasingly becoming a global problem. Infected individuals may present with a wide spectrum of symptoms, spanning from a mild febrile to a life-threatening illness, which may include thrombocytopenia, leucopenia, hepatomegaly, hemorrhaging, plasma leakage and shock. Deciphering the underlining mechanisms responsible for these symptoms has been hindered by the limited availability of animal models that can induce classic human pathology. Currently, several permissive non-human primate (NHP) species and mouse breeds susceptible to adapted DV strains are available. Though virus replication occurs in these animals, none of them recapitulate the cardinal features of human symptomatology, with disease only occasionally observed in NHPs. Recently our group established a DV serotype 2 intravenous infection model with the Indian rhesus macaque, which reliably produced cutaneous hemorrhages after primary virus exposure. Further manipulation of experimental parameters (virus strain, immune cell expansion, depletion, etc.) can refine this model and expand its relevance to human DF. Future goals include applying this model to elucidate the role of pre-existing immunity upon secondary infection and immunopathogenesis. Of note, virus titers in primates in vivo and in vitro, even with our model, have been consistently 1000-fold lower than those found in humans. We submit that an improved model, capable of demonstrating severe pathogenesis may only be achieved with higher virus loads. Nonetheless, our DV coagulopathy disease model is valuable for the study of select pathomechanisms and testing DV drug and vaccine candidates

  9. The serial organisation of behaviour by non-human primates; an evaluation of experimental paradigms.

    PubMed

    De Lillio, C

    1996-11-01

    On close examination of research programs which focus, either implicitly or explicitly, on the problem of the organisation of serial order in non-human primates, it is possible to detect some limitations in the paradigms conventionally used. Serial learning studies, which focus on the acquisition of arbitrary lists of unconnected elements point towards a distinction between the representation of ordered series formed by monkeys and pigeons. However, the use of unconnected items prevents an assay of the degree to which primates might be able to impose a structure over the list to be reported. The study of transitive reasoning has been implemented by means of a paradigm where the order of a series is conveyed be presenting a common item in pairs of binary discriminations. Animals tested with this paradigm develop control strategies using more information than that provided by reward contingencies alone. A restriction of this paradigm is that, in its binary form, it does not allow a differentiation between the performance of monkeys and pigeons and even simple models account for a transitive bias in the task. On the basis of these observations it is proposed that novel paradigms which go beyond the binary context, feature multiple connected items, and accord a high degree of spontaneity to the subjects might allow better than traditional ones to uncover qualitative different ways in which different organisms serially organise their behaviour. Some recent research programs based on such rationale, and implemented as search tasks, are then outlined and compared with other approaches to the study of search behaviour. Preliminary results obtained from these studies indicate that the spontaneous serial organisation of multiple connected items might uncover new dimensions of promising comparative relevance.

  10. Protective Potential of Antioxidant Enzymes as Vaccines for Schistosomiasis in a Non-Human Primate Model

    PubMed Central

    Carvalho-Queiroz, Claudia; Nyakundi, Ruth; Ogongo, Paul; Rikoi, Hitler; Egilmez, Nejat K.; Farah, Idle O.; Kariuki, Thomas M.; LoVerde, Philip T.

    2015-01-01

    Schistosomiasis remains a major cause of morbidity in the world. The challenge today is not so much in the clinical management of individual patients, but rather in population-based control of transmission in endemic areas. Despite recent large-scale efforts, such as integrated control programs aimed at limiting schistosomiasis by improving education and sanitation, molluscicide treatment programs and chemotherapy with praziquantel, there has only been limited success. There is an urgent need for complementary approaches, such as vaccines. We demonstrated previously that anti-oxidant enzymes, such as Cu–Zn superoxide dismutase (SOD) and glutathione S peroxidase (GPX), when administered as DNA-based vaccines induced significant levels of protection in inbred mice, greater than the target 40% reduction in worm burden compared to controls set as a minimum by the WHO. These results led us to investigate if immunization of non-human primates with antioxidants would stimulate an immune response that could confer protection as a prelude study for human trials. Issues of vaccine toxicity and safety that were difficult to address in mice were also investigated. All baboons in the study were examined clinically throughout the study and no adverse reactions occurred to the immunization. When our outbred baboons were vaccinated with two different formulations of SOD (SmCT-SOD and SmEC-SOD) or one of GPX (SmGPX), they showed a reduction in worm number to varying degrees, when compared with the control group. More pronounced, vaccinated animals showed decreased bloody diarrhea, days of diarrhea, and egg excretion (transmission), as well as reduction of eggs in the liver tissue and in the large intestine (pathology) compared to controls. Specific IgG antibodies were present in sera after immunizations and 10 weeks after challenge infection compared to controls. Peripheral blood mononuclear cells, mesenteric, and inguinal node cells from vaccinated animals proliferated and

  11. Ethical issues when modelling brain disorders in non-human primates.

    PubMed

    Neuhaus, Carolyn P

    2017-08-11

    Non-human animal models of human diseases advance our knowledge of the genetic underpinnings of disease and lead to the development of novel therapies for humans. While mice are the most common model organisms, their usefulness is limited. Larger animals may provide more accurate and valuable disease models, but it has, until recently, been challenging to create large animal disease models. Genome editors, such as Clustered Randomised Interspersed Palindromic Repeat (CRISPR), meet some of these challenges and bring routine genome engineering of larger animals and non-human primates (NHPs) well within reach. There is growing interest in creating NHP models of brain disorders such as autism, depression and Alzheimer's, which are very difficult to model or study in other organisms, including humans. New treatments are desperately needed for this set of disorders. This paper is novel in asking: Insofar as NHPs are being considered for use as model organisms for brain disorders, can this be done ethically? The paper concludes that it cannot. Notwithstanding ongoing debate about NHPs' moral status, (1) animal welfare concerns, (2) the availability of alternative methods of studying brain disorders and (3) unmet expectations of benefit justify a stop on the creation of NHP model organisms to study brain disorders. The lure of using new genetic technologies combined with the promise of novel therapeutics presents a formidable challenge to those who call for slow, careful, and only necessary research involving NHPs. But researchers should not create macaques with social deficits or capuchin monkeys with memory deficits just because they can. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  12. [Ethical and legal aspects of animal experiments on non-human primates].

    PubMed

    Luy, J

    2007-03-01

    Animal experiments on non-human primates give cause for ethical concerns for three reasons (1) the inclusion of "ethical animal protection" in the German Constitution (Article 20a of the "Grundgesetz" GG, 2002) has led to real consequences for the application process with respect to the use of primates for fundamental research; (2) the legal requirements in Europe to ensure animal welfare are currently being tightened and (3) the global problem of the protection of species, especially with respect to the capturing and subsequent sale of primates is still unsolved. As a result of the way humans interpret the term justice (the principle of equality) it was to be expected that great apes, being the animals that most closely resemble humans, would play a key role in the establishment of animal protection laws. In 1997,Great Britain and Ireland made it illegal to conduct experiments on great apes. In 1999, New Zealand went even further and created a kind of basic rights for great apes. In 2003,The Netherlands forbade animal experiments using great apes as did Sweden, which also included gibbons in this ban (which is in line with current taxonomy, which considers gibbons to belong to the family Hominidae). In 2006 Austria forbade experiments carried out on chimpanzees, bonobos, gorillas, orang-utans, and gibbons. Only recently, a state commission on ethics in Switzerland demanded that the Swiss government do the same. And the summer of 2006 saw a debate in Spain on the inclusion of the protection of great apes in the primary goals of the state. Due to the principle of equality, a further extension (both geographically and systemically) of the exclusion of great apes from animal experiments is to be expected. Since Article 20a GG on "ethical animal protection" came into effect on August 1,2002, the regulatory authorities in Germany have the right to independently check and control animal experiments as to their ethical tenability (Administrative Court Giessen, confirmed

  13. Simian foamy virus in non-human primates and cross-species transmission to humans in Gabon: an emerging zoonotic disease in central Africa?

    PubMed

    Mouinga-Ondémé, Augustin; Kazanji, Mirdad

    2013-06-19

    It is now known that all human retroviruses have a non-human primate counterpart. It has been reported that the presence of these retroviruses in humans is the result of interspecies transmission. Several authors have described the passage of a simian retrovirus, simian foamy virus (SFV), from primates to humans. To better understand this retroviral "zoonosis" in natural settings, we evaluated the presence of SFV in both captive and wild non-human primates and in humans at high risk, such as hunters and people bitten by a non-human primate, in Gabon, central Africa. A high prevalence of SFV was found in blood samples from non-human primates and in bush meat collected across the country. Mandrills were found to be highly infected with two distinct strains of SFV, depending on their geographical location. Furthermore, samples collected from hunters and non-human primate laboratory workers showed clear, extensive cross-species transmission of SFV. People who had been bitten by mandrills, gorillas and chimpanzees had persistent SFV infection with low genetic drift. Thus, SFV is presumed to be transmitted from non-human primates mainly through severe bites, involving contact between infected saliva and blood. In this review, we summarize and discuss our five-year observations on the prevalence and dissemination of SFV in humans and non-human primates in Gabon.

  14. Do non-human primates cooperate? Evidences of motor coordination during a joint action task in macaque monkeys.

    PubMed

    Visco-Comandini, Federica; Ferrari-Toniolo, Simone; Satta, Eleonora; Papazachariadis, Odysseas; Gupta, Rajnish; Nalbant, Laura Elena; Battaglia-Mayer, Alexandra

    2015-09-01

    Humans are intensively social primates, therefore many of their actions are dedicated to communication and interaction with other individuals. Despite the progress in understanding the cognitive and neural processes that allow humans to perform cooperative actions, in non-human primates only few studies have investigated the ability to interact with a partner in order to reach a common goal. These studies have shown that in naturalistic conditions animals engage in various types of social behavior that involve forms of mutual coordination and cooperation. However, little is known on the capacity of non-human primates to actively cooperate in a controlled experimental setting, which allows full characterization of the motor parameters underlying individual action and their change during motor cooperation. To this aim, we analyzed the behavior of three pairs of macaque monkeys trained to perform solo and joint-actions by exerting a force on an isometric joystick, as to move an individual or a common cursor toward visual targets on a screen. We found that during cooperation monkeys reciprocally adapt their behavior by changing the parameters that define the spatial and temporal aspects of their action, as to fine tune their joint effort, and maximize their common performance. Furthermore the results suggest that when acting together the movement parameters that specify each actor's behavior are not only modulated during execution, but also during planning. These findings provide the first quantitative description of action coordination in non-human primates during the performance of a joint action task.

  15. Genetic heterogeneity and phylogeny of Trichuris spp. from captive non-human primates based on ribosomal DNA sequence data.

    PubMed

    Cavallero, Serena; De Liberato, Claudio; Friedrich, Klaus G; Di Cave, David; Masella, Valentina; D'Amelio, Stefano; Berrilli, Federica

    2015-08-01

    Nematodes of the genus Trichuris, known as whipworms, are recognized to infect numerous mammalian species including humans and non-human primates. Several Trichuris spp. have been described and species designation/identification is traditionally based on host-affiliation, although cross-infection and hybridization events may complicate species boundaries. The main aims of the present study were to genetically characterize adult Trichuris specimens from captive Japanese macaques (Macaca fuscata) and grivets (Chlorocebus aethiops), using the ribosomal DNA (ITS) as molecular marker and to investigate the phylogeny and the extent of genetic variation also by comparison with data on isolates from other humans, non-human primates and other hosts. The phylogenetic analysis of Trichuris sequences from M. fuscata and C. aethiops provided evidences of distinct clades and subclades thus advocating the existence of additional separated taxa. Neighbor Joining and Bayesian trees suggest that specimens from M. fuscata may be distinct from, but related to Trichuris trichiura, while a close relationship is suggested between the subclade formed by the specimens from C. aethiops and the subclade formed by T. suis. The tendency to associate Trichuris sp. to host species can lead to misleading taxonomic interpretations (i.e. whipworms found in primates are identified as T. trichiura). The results here obtained confirm previous evidences suggesting the existence of Trichuris spp. other than T. trichiura infecting non-human living primates. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. A word in the hand: action, gesture and mental representation in humans and non-human primates

    PubMed Central

    Cartmill, Erica A.; Beilock, Sian; Goldin-Meadow, Susan

    2012-01-01

    The movements we make with our hands both reflect our mental processes and help to shape them. Our actions and gestures can affect our mental representations of actions and objects. In this paper, we explore the relationship between action, gesture and thought in both humans and non-human primates and discuss its role in the evolution of language. Human gesture (specifically representational gesture) may provide a unique link between action and mental representation. It is kinaesthetically close to action and is, at the same time, symbolic. Non-human primates use gesture frequently to communicate, and do so flexibly. However, their gestures mainly resemble incomplete actions and lack the representational elements that characterize much of human gesture. Differences in the mirror neuron system provide a potential explanation for non-human primates' lack of representational gestures; the monkey mirror system does not respond to representational gestures, while the human system does. In humans, gesture grounds mental representation in action, but there is no evidence for this link in other primates. We argue that gesture played an important role in the transition to symbolic thought and language in human evolution, following a cognitive leap that allowed gesture to incorporate representational elements. PMID:22106432

  17. A word in the hand: action, gesture and mental representation in humans and non-human primates.

    PubMed

    Cartmill, Erica A; Beilock, Sian; Goldin-Meadow, Susan

    2012-01-12

    The movements we make with our hands both reflect our mental processes and help to shape them. Our actions and gestures can affect our mental representations of actions and objects. In this paper, we explore the relationship between action, gesture and thought in both humans and non-human primates and discuss its role in the evolution of language. Human gesture (specifically representational gesture) may provide a unique link between action and mental representation. It is kinaesthetically close to action and is, at the same time, symbolic. Non-human primates use gesture frequently to communicate, and do so flexibly. However, their gestures mainly resemble incomplete actions and lack the representational elements that characterize much of human gesture. Differences in the mirror neuron system provide a potential explanation for non-human primates' lack of representational gestures; the monkey mirror system does not respond to representational gestures, while the human system does. In humans, gesture grounds mental representation in action, but there is no evidence for this link in other primates. We argue that gesture played an important role in the transition to symbolic thought and language in human evolution, following a cognitive leap that allowed gesture to incorporate representational elements.

  18. Why bother using non-human primate models of cognitive disorders in translational research?

    PubMed

    Camus, Sandrine; Ko, Wai Kin D; Pioli, Elsa; Bezard, Erwan

    2015-10-01

    Although everyone would agree that successful translation of therapeutic candidates for central nervous disorders should involve non-human primate (nhp) models of cognitive disorders, we are left with the paucity of publications reporting either the target validation or the actual preclinical testing in heuristic nhp models. In this review, we discuss the importance of nhps in translational research, highlighting the advances in technological/methodological approaches for 'bridging the gap' between preclinical and clinical experiments. In this process, we acknowledge that nhps remain a vital tool for the investigation of complex cognitive functions, given their resemblance to humans in aspects of behaviour, anatomy and physiology. The recent improvements made for a suitable nhp model in cognitive research, including new surrogates of disease and application of innovative methodological approaches, are continuous strides for reaching efficient translation for human benefit. This will ultimately aid the development of innovative treatments against the current and future threat of neurological and psychiatric disorders to the global population. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Consequences of early adverse rearing experience (EARE) on development: insights from non-human primate studies

    PubMed Central

    Zhang, Bo

    2017-01-01

    Early rearing experiences are important in one's whole life, whereas early adverse rearing experience (EARE) is usually related to various physical and mental disorders in later life. Although there were many studies on human and animals, regarding the effect of EARE on brain development, neuroendocrine systems, as well as the consequential mental disorders and behavioral abnormalities, the underlying mechanisms remain unclear. Due to the close genetic relationship and similarity in social organizations with humans, non-human primate (NHP) studies were performed for over 60 years. Various EARE models were developed to disrupt the early normal interactions between infants and mothers or peers. Those studies provided important insights of EARE induced effects on the physiological and behavioral systems of NHPs across life span, such as social behaviors (including disturbance behavior, social deficiency, sexual behavior, etc), learning and memory ability, brain structural and functional developments (including influences on neurons and glia cells, neuroendocrine systems, e.g., hypothalamic-pituitary-adrenal (HPA) axis, etc). In this review, the effects of EARE and the underlying epigenetic mechanisms were comprehensively summarized and the possibility of rehabilitation was discussed. PMID:28271667

  20. SEASONAL MORTALITY PATTERNS IN NON-HUMAN PRIMATES: IMPLICATIONS FOR VARIATION IN SELECTION PRESSURES ACROSS ENVIRONMENTS

    PubMed Central

    Gogarten, Jan F.; Brown, Leone M.; Chapman, Colin A.; Cords, Marina; Doran-Sheehy, Diane; Fedigan, Linda M.; Grine, Frederick E.; Perry, Susan; Pusey, Anne E.; Sterck, Elisabeth H. M.; Wich, Serge A.; Wright, Patricia C.

    2014-01-01

    Examining seasonal mortality patterns can yield insights into the drivers of mortality and thus potential selection pressures acting on individuals in different environments. We compiled adult and juvenile mortality data from nine wild non-human primate taxa to investigate the role of seasonality in patterns of mortality and address the following questions: Is mortality highly seasonal across species? Does greater environmental seasonality lead to more seasonal mortality patterns? If mortality is seasonal, is it higher during wet seasons or during periods of food scarcity? and Do folivores show less seasonal mortality than frugivores? We found seasonal mortality patterns in five of nine taxa, and mortality was more often tied to wet seasons than food-scarce periods, a relationship that may be driven by disease. Controlling for phylogeny, we found a positive relationship between the degree of environmental seasonality and mortality, with folivores exhibiting more seasonal mortality than frugivores. These results suggest that mortality patterns are influenced both by diet and degree of environmental seasonality. Applied to a wider array of taxa, analyses of seasonal mortality patterns may aid understanding of life-history evolution and selection pressures acting across a broad spectrum of environments and spatial and temporal scales. PMID:23025613

  1. Correlation between cerebral hemodynamic and perfusion pressure changes in non-human primates

    NASA Astrophysics Data System (ADS)

    Ruesch, A.; Smith, M. A.; Wollstein, G.; Sigal, I. A.; Nelson, S.; Kainerstorfer, J. M.

    2017-02-01

    The mechanism that maintains a stable blood flow in the brain despite changes in cerebral perfusion pressure (CPP), and therefore guaranties a constant supply of oxygen and nutrients to the neurons, is known as cerebral auto-regulation (CA). In a certain range of CPP, blood flow is mediated by a vasomotor adjustment in vascular resistance through dilation of blood vessels. CA is known to be impaired in diseases like traumatic brain injury, Parkinson's disease, stroke, hydrocephalus and others. If CA is impaired, blood flow and pressure changes are coupled and thee oxygen supply might be unstable. Lassen's blood flow auto-regulation curve describes this mechanism, where a plateau of stable blood flow in a specific range of CPP corresponds to intact auto-regulation. Knowing the limits of this plateau and maintaining CPP within these limits can improve patient outcome. Since CPP is influenced by both intracranial pressure and arterial blood pressure, long term changes in either can lead to auto-regulation impairment. Non-invasive methods for monitoring blood flow auto-regulation are therefore needed. We propose too use Near infrared spectroscopy (NIRS) too fill this need. NIRS is an optical technique, which measures microvascular changes in cerebral hemoglobin concentration. We performed experiments on non-human primates during exsanguination to demonstrate that thee limits of blood flow auto-regulation can be accessed with NIRS.

  2. Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Non-Human Primates

    PubMed Central

    Freitas, AM; Samy, KP; Farris, AB; Leopardi, FV; Song, M; Stempora, L; Strobert, EA; Jenkins, JA; Kirk, AD; Cendales, LC

    2016-01-01

    Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the non-lifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin-based regimens. In this study, we used a non-human-primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7-specific costimulation blockade with and without adhesion blockade with LFA3-Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3-Ig reduced CD2hi memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model. PMID:26139552

  3. Endocrine-Immune Interactions in Pregnant Non-Human Primates With Intrauterine Infection

    PubMed Central

    Novy, Miles J.

    1997-01-01

    Preterm birth remains the most common cause of perinatal mortality. Although the causes of preterm labor are multifactorial and vary according to gestational age, preterm labor and term labor share common cellular and molecular mechanisms, including stimulation of the fetal hypothalamic-pituitary-adrenal (HPA) axis and endocrine/immune system interactions. We have developed a non-human primate experimental model for intrauterine infection and preterm labor using chronically instrumented rhesus monkeys (Macaca mulatta) with timed gestations. We have documented the temporal and quantitative relationships among intrauterine infection, the synthesis and release of proinflammatory cytokines, prostaglandins, and fetal-placental steroid biosynthesis in this model. Infection-induced preterm parturition is characterized by significant elevations in amniotic fluid proinflammatory cytokines and by increases in fetal adrenal steroid biosynthesis, but not by corresponding increases in placental estrogen biosynthesis characteristic of spontaneous parturition. This suggests that activation of the fetal HPA axis by the stress of infection is accompanied by placental dysfunction and also that infection-induced preterm parturition is not dependent upon the increased estrogen biosynthesis observed in spontaneous parturition. These different endocrine and immune responses have important diagnostic and therapeutic implications in the management of preterm labor. PMID:18476167

  4. Vocal turn-taking in a non-human primate is learned during ontogeny.

    PubMed

    Chow, Cecilia P; Mitchell, Jude F; Miller, Cory T

    2015-05-22

    Conversational turn-taking is an integral part of language development, as it reflects a confluence of social factors that mitigate communication. Humans coordinate the timing of speech based on the behaviour of another speaker, a behaviour that is learned during infancy. While adults in several primate species engage in vocal turn-taking, the degree to which similar learning processes underlie its development in these non-human species or are unique to language is not clear. We recorded the natural vocal interactions of common marmosets (Callithrix jacchus) occurring with both their sibling twins and parents over the first year of life and observed at least two parallels with language development. First, marmoset turn-taking is a learned vocal behaviour. Second, marmoset parents potentially played a direct role in guiding the development of turn-taking by providing feedback to their offspring when errors occurred during vocal interactions similarly to what has been observed in humans. Though species-differences are also evident, these findings suggest that similar learning mechanisms may be implemented in the ontogeny of vocal turn-taking across our Order, a finding that has important implications for our understanding of language evolution. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  5. A non-human primate system for large-scale genetic studies of complex traits

    PubMed Central

    Jasinska, Anna J.; Lin, Michelle K.; Service, Susan; Choi, Oi-Wa; DeYoung, Joseph; Grujic, Olivera; Kong, Sit-Yee; Jung, Yoon; Jorgensen, Mathew J.; Fairbanks, Lynn A.; Turner, Trudy; Cantor, Rita M.; Wasserscheid, Jessica; Dewar, Ken; Warren, Wesley; Wilson, Richard K.; Weinstock, George; Jentsch, J. David; Freimer, Nelson B.

    2012-01-01

    Non-human primates provide genetic model systems biologically intermediate between humans and other mammalian model organisms. Populations of Caribbean vervet monkeys (Chlorocebus aethiops sabaeus) are genetically homogeneous and large enough to permit well-powered genetic mapping studies of quantitative traits relevant to human health, including expression quantitative trait loci (eQTL). Previous transcriptome-wide investigation in an extended vervet pedigree identified 29 heritable transcripts for which levels of expression in peripheral blood correlate strongly with expression levels in the brain. Quantitative trait linkage analysis using 261 microsatellite markers identified significant (n = 8) and suggestive (n = 4) linkages for 12 of these transcripts, including both cis- and trans-eQTL. Seven transcripts, located on different chromosomes, showed maximum linkage to markers in a single region of vervet chromosome 9; this observation suggests the possibility of a master trans-regulator locus in this region. For one cis-eQTL (at B3GALTL, beta-1,3-glucosyltransferase), we conducted follow-up single nucleotide polymorphism genotyping and fine-scale association analysis in a sample of unrelated Caribbean vervets, localizing this eQTL to a region of <200 kb. These results suggest the value of pedigree and population samples of the Caribbean vervet for linkage and association mapping studies of quantitative traits. The imminent whole genome sequencing of many of these vervet samples will enhance the power of such investigations by providing a comprehensive catalog of genetic variation. PMID:22556363

  6. Frontal Non-Invasive Neurostimulation Modulates Antisaccade Preparation in Non-Human Primates

    PubMed Central

    Valero-Cabre, Antoni; Wattiez, Nicolas; Monfort, Morgane; François, Chantal; Rivaud-Péchoux, Sophie; Gaymard, Bertrand; Pouget, Pierre

    2012-01-01

    A combination of oculometric measurements, invasive electrophysiological recordings and microstimulation have proven instrumental to study the role of the Frontal Eye Field (FEF) in saccadic activity. We hereby gauged the ability of a non-invasive neurostimulation technology, Transcranial Magnetic Stimulation (TMS), to causally interfere with frontal activity in two macaque rhesus monkeys trained to perform a saccadic antisaccade task. We show that online single pulse TMS significantly modulated antisaccade latencies. Such effects proved dependent on TMS site (effects on FEF but not on an actively stimulated control site), TMS modality (present under active but not sham TMS on the FEF area), TMS intensity (intensities of at least 40% of the TMS machine maximal output required), TMS timing (more robust for pulses delivered at 150 ms than at 100 post target onset) and visual hemifield (relative latency decreases mainly for ipsilateral AS). Our results demonstrate the feasibility of using TMS to causally modulate antisaccade-associated computations in the non-human primate brain and support the use of this approach in monkeys to study brain function and its non-invasive neuromodulation for exploratory and therapeutic purposes. PMID:22701691

  7. Decision making in avoidance-reward conflict: a paradigm for non-human primates and humans.

    PubMed

    Sierra-Mercado, Demetrio; Deckersbach, Thilo; Arulpragasam, Amanda R; Chou, Tina; Rodman, Alexandra M; Duffy, Amanda; McDonald, Eric J; Eckhardt, Christine A; Corse, Andrew K; Kaur, Navneet; Eskandar, Emad N; Dougherty, Darin D

    2015-09-01

    Decision making in both animals and humans is influenced by the anticipation of reward and/or punishment. Little is known about how reward and punishment interact in the context of decision making. The Avoidance-Reward Conflict (ARC) Task is a new paradigm that varies the degree of reward and the probability of punishment in a single paradigm that can be used in both non-human primates (NHPs) and humans. This study examined the behavioral pattern in the ARC task in both NHPs and humans. Two adult male NHPs (macaca mulatta) and 20 healthy human volunteers (12 females) participated in the ARC task. NHPs and humans perform similarly on the ARC task. With a high probability of punishment (an aversive air puff to the eye), both NHPs and humans are more likely to forgo reward if it is small or medium magnitude than when it is large. Both NHPs and humans perform similarly on the same behavioral task suggesting the reliability of animal models in predicting human behavior.

  8. Protection of non-human primates against glanders with a gold nanoparticle glycoconjugate vaccine.

    PubMed

    Torres, Alfredo G; Gregory, Anthony E; Hatcher, Christopher L; Vinet-Oliphant, Heather; Morici, Lisa A; Titball, Richard W; Roy, Chad J

    2015-01-29

    The Gram-negative Burkholderia mallei is a zoonotic pathogen and the causative agent of glanders disease. Because the bacteria maintain the potential to be used as a biothreat agent, vaccine strategies are required for human glanders prophylaxis. A rhesus macaque (Macaca mulatta) model of pneumonic (inhalational) glanders was established and the protective properties of a nanoparticle glycoconjugate vaccine composed of Burkholderia thailandensis LPS conjugated to FliC was evaluated. An aerosol challenge dose of ∼1×10(4) CFU B. mallei produced mortality in 50% of naïve animals (n=2/4), 2-3 days post-exposure. Although survival benefit was not observed by vaccination with a glycoconjugate glanders vaccine (p=0.42), serum LPS-specific IgG titers were significantly higher on day 80 in 3 vaccinated animals who survived compared with 3 vaccinated animals who died. Furthermore, B. mallei was isolated from multiple organs of both non-vaccinated survivors, but not from any organs of 3 vaccinated survivors at 30 days post-challenge. Taken together, this is the first time a candidate vaccine has been evaluated in a non-human primate aerosol model of glanders and represents the initial step for consideration in pre-clinical studies.

  9. Wearable wireless sensor platform for studying autonomic activity and social behavior in non-human primates.

    PubMed

    Fletcher, Richard Ribón; Amemori, Ken-ichi; Goodwin, Matthew; Graybiel, Ann M

    2012-01-01

    A portable system has been designed to enable remote monitoring of autonomic nervous system output in non-human primates for the purpose of studying neural function related to social behavior over extended periods of time in an ambulatory setting. In contrast to prior systems which only measure heart activity, are restricted to a constrained laboratory setting, or require surgical attachment, our system is comprised of a multi-sensor self-contained wearable vest that can easily be transferred from one subject to another. The vest contains a small detachable low-power electronic sensor module for measuring electrodermal activity (EDA), electrocardiography (ECG), 3-axis acceleration, and temperature. The wireless transmission is implemented using a standard Bluetooth protocol and a mobile phone, which enables freedom of movement for the researcher as well as for the test subject. A custom Android software application was created on the mobile phone for viewing and recording live data as well as creating annotations. Data from up to seven monkeys can be recorded simultaneously using the mobile phone, with the option of real-time upload to a remote web server. Sample data are presented from two rhesus macaque monkeys showing stimulus-induced response in the laboratory as well as long-term ambulatory data collected in a large monkey cage. This system enables new possibilities for studying underlying mechanisms between autonomic brain function and social behavior with connection to human research in areas such as autism, substance abuse, and mood disorders.

  10. Isolation of Anti-Ricin Protective Antibodies Exhibiting High Affinity from Immunized Non-Human Primates

    PubMed Central

    Noy-Porat, Tal; Rosenfeld, Ronit; Ariel, Naomi; Epstein, Eyal; Alcalay, Ron; Zvi, Anat; Kronman, Chanoch; Ordentlich, Arie; Mazor, Ohad

    2016-01-01

    Ricin, derived from the castor bean plant Ricinus communis, is one of the most potent and lethal toxins known, against which there is no available antidote. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this study was to isolate high affinity anti-ricin antibodies that possess potent toxin-neutralization capabilities. Two non-human primates were immunized with either a ricin-holotoxin- or subunit-based vaccine, to ensure the elicitation of diverse high affinity antibodies. By using a comprehensive set of primers, immune scFv phage-displayed libraries were constructed and panned. A panel of 10 antibodies (five directed against the A subunit of ricin and five against the B subunit) was isolated and reformatted into a full-length chimeric IgG. All of these antibodies were found to neutralize ricin in vitro, and several conferred full protection to ricin-intoxicated mice when given six hours after exposure. Six antibodies were found to possess exceptionally high affinity toward the toxin, with KD values below pM (koff < 1 × 10−7 s−1) that were well correlated with their ability to neutralize ricin. These antibodies, alone or in combination, could be used for the development of a highly-effective therapeutic preparation for post-exposure treatment of ricin intoxication. PMID:26950154

  11. Perceptual learning in a non-human primate model of artificial vision

    PubMed Central

    Killian, Nathaniel J.; Vurro, Milena; Keith, Sarah B.; Kyada, Margee J.; Pezaris, John S.

    2016-01-01

    Visual perceptual grouping, the process of forming global percepts from discrete elements, is experience-dependent. Here we show that the learning time course in an animal model of artificial vision is predicted primarily from the density of visual elements. Three naïve adult non-human primates were tasked with recognizing the letters of the Roman alphabet presented at variable size and visualized through patterns of discrete visual elements, specifically, simulated phosphenes mimicking a thalamic visual prosthesis. The animals viewed a spatially static letter using a gaze-contingent pattern and then chose, by gaze fixation, between a matching letter and a non-matching distractor. Months of learning were required for the animals to recognize letters using simulated phosphene vision. Learning rates increased in proportion to the mean density of the phosphenes in each pattern. Furthermore, skill acquisition transferred from trained to untrained patterns, not depending on the precise retinal layout of the simulated phosphenes. Taken together, the findings suggest that learning of perceptual grouping in a gaze-contingent visual prosthesis can be described simply by the density of visual activation. PMID:27874058

  12. Perceptual learning in a non-human primate model of artificial vision.

    PubMed

    Killian, Nathaniel J; Vurro, Milena; Keith, Sarah B; Kyada, Margee J; Pezaris, John S

    2016-11-22

    Visual perceptual grouping, the process of forming global percepts from discrete elements, is experience-dependent. Here we show that the learning time course in an animal model of artificial vision is predicted primarily from the density of visual elements. Three naïve adult non-human primates were tasked with recognizing the letters of the Roman alphabet presented at variable size and visualized through patterns of discrete visual elements, specifically, simulated phosphenes mimicking a thalamic visual prosthesis. The animals viewed a spatially static letter using a gaze-contingent pattern and then chose, by gaze fixation, between a matching letter and a non-matching distractor. Months of learning were required for the animals to recognize letters using simulated phosphene vision. Learning rates increased in proportion to the mean density of the phosphenes in each pattern. Furthermore, skill acquisition transferred from trained to untrained patterns, not depending on the precise retinal layout of the simulated phosphenes. Taken together, the findings suggest that learning of perceptual grouping in a gaze-contingent visual prosthesis can be described simply by the density of visual activation.

  13. A microneedle patch containing measles vaccine is immunogenic in non-human primates.

    PubMed

    Edens, Chris; Collins, Marcus L; Goodson, James L; Rota, Paul A; Prausnitz, Mark R

    2015-09-08

    Very high vaccination coverage is required to eliminate measles, but achieving high coverage can be constrained by the logistical challenges associated with subcutaneous injection. To simplify the logistics of vaccine delivery, a patch containing micron-scale polymeric needles was formulated to encapsulate the standard dose of measles vaccine (1000 TCID₅₀) and the immunogenicity of the microneedle patch was compared with subcutaneous injection in rhesus macaques. The microneedle patch was administered without reconstitution with diluent, dissolved in skin within 10 min, and caused only mild, transient skin erythema. Both groups of rhesus macaques generated neutralizing antibody responses to measles that were consistent with protection and the neutralizing antibody titers were equivalent. In addition, the microneedle patches maintained an acceptable level of potency after storage at elevated temperature suggesting improved thermostability compared to standard lyophilized vaccine. In conclusion, a measles microneedle patch vaccine was immunogenic in non-human primates, and this approach offers a promising delivery method that could help increase vaccination coverage.

  14. Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.

    PubMed

    Verina, Tatyana; Schneider, Jay S; Guilarte, Tomás R

    2013-03-13

    Aggregation of α-synuclein (α-syn) in the brain is a defining pathological feature of neurodegenerative disorders classified as synucleinopathies. They include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism. In this study, we examined α-syn immunoreactivity in the frontal cortex of Cynomolgus macaques as part of a multidisciplinary assessment of the neurological effects produced by exposure to moderate levels of Mn. We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers. Some of these neurons displayed loss of Nissl staining with α-syn-positive spherical aggregates. In the white matter we also observed α-syn-positive glial cells and in some cases α-syn-positive neurites. These findings suggest that Mn exposure promotes α-syn aggregation in neuronal and glial cells that may ultimately lead to degeneration in the frontal cortex gray and white matter. To our knowledge, this is the first report of Mn-induced neuronal and glial cell α-syn accumulation and aggregation in the frontal cortex of non-human primates.

  15. Non-human primate FOG develops with advanced parkinsonism induced by MPTP Treatment.

    PubMed

    Revuelta, Gonzalo J; Uthayathas, Subramaniam; Wahlquist, Amy E; Factor, Stewart A; Papa, Stella M

    2012-10-01

    Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD) and other forms of parkinsonism. The anatomical or pathophysiological correlates are poorly understood largely due to the lack of a well-established animal model. Here we studied whether FOG is reproduced in the non-human primate (NHP) model of PD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (Genus Macaca, n=29) were examined for the development of FOG, and the leg movements were recorded with accelerometry. The relationships between developing FOG and the animals' characteristics, the MPTP treatments, and the modeled outcomes were determined. In parkinsonian monkeys FOG developed frequently (48%) manifesting similar characteristics to those seen in PD patients. In addition, FOG episodes in the monkey were accompanied by leg trembling with the typical duration (2-10s) and frequency (~7 Hz). The development of NHP FOG was significantly associated with the severity of parkinsonism, as shown by high motor disability scores (≥ 20) and levodopa-induced dyskinesia scores (p=0.01 and p=0.04, respectively). Differences in demographics and MPTP treatments (doses, treatment duration, etc.) had no influence on NHP FOG occurrence, with the exception of gender that showed FOG predominance in males (p=0.03). The unique features of FOG in PD can be replicated in severely parkinsonian macaques, and this represents the first description of a FOG animal model.

  16. Neurovirulence Properties of Recombinant Vesicular Stomatitis Virus Vectors in Non-Human Primates

    PubMed Central

    Johnson, J. Erik; Nasar, Farooq; Coleman, John W.; Price, Roger E.; Javadian, Ali; Draper, Kenneth; Lee, Margaret; Reilly, Patricia A.; Clarke, David K.; Hendry, R. Michael; Udem, Stephen A.

    2007-01-01

    Although vesicular stomatitis virus (VSV) neurovirulence and pathogenicity in rodents have been well studied, little is known about VSV pathogenicity in non-human primates. To address this question, we measured VSV viremia, shedding, and neurovirulence in macaques. Following intranasal inoculation, macaques shed minimal recombinant VSV (rVSV) in nasal washes for one day post-inoculation; viremia was not detected. Following intranasal inoculation of macaques, wild type (wt) VSV, rVSV, and two rVSV-HIV vectors showed no evidence of spread to CNS tissues. However, macaques inoculated intrathalamically with wt VSV developed severe neurological disease. One of four macaques receiving rVSV developed clinical and histological signs similar to the wt group, while the remaining three macaques in this group and all of the macaques in the rVSV-HIV vector groups showed no clinical signs of disease and reduced severity of histopathology compared to the wt group. The implications of these findings for rVSV vaccine development are discussed. PMID:17098273

  17. Seasonal mortality patterns in non-human primates: implications for variation in selection pressures across environments.

    PubMed

    Gogarten, Jan F; Brown, Leone M; Chapman, Colin A; Cords, Marina; Doran-Sheehy, Diane; Fedigan, Linda M; Grine, Frederick E; Perry, Susan; Pusey, Anne E; Sterck, Elisabeth H M; Wich, Serge A; Wright, Patricia C

    2012-10-01

    Examining seasonal mortality patterns can yield insights into the drivers of mortality and thus potential selection pressures acting on individuals in different environments. We compiled adult and juvenile mortality data from nine wild non-human primate taxa to investigate the role of seasonality in patterns of mortality and address the following questions: Is mortality highly seasonal across species? Does greater environmental seasonality lead to more seasonal mortality patterns? If mortality is seasonal, is it higher during wet seasons or during periods of food scarcity? and Do folivores show less seasonal mortality than frugivores? We found seasonal mortality patterns in five of nine taxa, and mortality was more often tied to wet seasons than food-scarce periods, a relationship that may be driven by disease. Controlling for phylogeny, we found a positive relationship between the degree of environmental seasonality and mortality, with folivores exhibiting more seasonal mortality than frugivores. These results suggest that mortality patterns are influenced both by diet and degree of environmental seasonality. Applied to a wider array of taxa, analyses of seasonal mortality patterns may aid understanding of life-history evolution and selection pressures acting across a broad spectrum of environments and spatial and temporal scales.

  18. Evaluation of four hematology and a chemistry portable benchtop analyzers using non-human primate blood.

    PubMed

    Snider, C L; Dick, E J; McGlasson, D L; Robbins, M C; Sholund, R L; Bommineni, Y R; Hubbard, G B

    2009-12-01

    Near patient testing (NPT) and point-of-care testing (POCT) using portable benchtop analyzers has become necessary in many areas of the medical community, including biocontainment. We evaluated the Beckman AcT diff, Abaxis Vetscan HMII (two instruments), Abbott Cell-Dyn 1800, and Abaxis Vetscan VS2 for within-run precision and correlation to central laboratory instruments using non-human primates blood. Compared with the central laboratory instruments, the Beckman AcT diff correlated on 80%; the HMII instruments on 31% and 44%, the CD1800 on 31%, and the VS2 on 71% of assays. For assays with published manufacturers precision guidelines, the AcT diff met all nine, the HMII instruments met one and six of six, and the CD 1800 met one of six. Laboratories using NPT/POCT must test their individual instruments for precision and correlation, identify assays that are reliable, and exclude or develop supplemental procedures for assays that are not.

  19. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration

    PubMed Central

    Freeman, Willard M.; VanGuilder, Heather D.; Guidone, Elizabeth; Krystal, John H.; Grant, Kathleen A.; Vrana, Kent E.

    2011-01-01

    Objective diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. 2-dimensional in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within subject samples collected before exposure to ethanol and after three months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of SAA4, RBP, ITIH4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption. PMID:21303580

  20. Non-human primates in neuroscience research: The case against its scientific necessity.

    PubMed

    Bailey, Jarrod; Taylor, Kathy

    2016-03-01

    Public opposition to non-human primate (NHP) experiments is significant, yet those who defend them cite minimal harm to NHPs and substantial human benefit. Here we review these claims of benefit, specifically in neuroscience, and show that: a) there is a default assumption of their human relevance and benefit, rather than robust evidence; b) their human relevance and essential contribution and necessity are wholly overstated; c) the contribution and capacity of non-animal investigative methods are greatly understated; and d) confounding issues, such as species differences and the effects of stress and anaesthesia, are usually overlooked. This is the case in NHP research generally, but here we specifically focus on the development and interpretation of functional magnetic resonance imaging (fMRI), deep brain stimulation (DBS), the understanding of neural oscillations and memory, and investigation of the neural control of movement and of vision/binocular rivalry. The increasing power of human-specific methods, including advances in fMRI and invasive techniques such as electrocorticography and single-unit recordings, is discussed. These methods serve to render NHP approaches redundant. We conclude that the defence of NHP use is groundless, and that neuroscience would be more relevant and successful for humans, if it were conducted with a direct human focus. We have confidence in opposing NHP neuroscience, both on scientific as well as on ethical grounds. 2016 FRAME.

  1. A Quantitative Proteomic Analysis of Urine from Gamma-Irradiated Non-Human Primates

    PubMed Central

    Byrum, Stephanie D; Burdine, Marie S; Orr, Lisa; Moreland, Linley; Mackintosh, Samuel G; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin; Tackett, Alan J

    2016-01-01

    The molecular effects of total body gamma-irradiation exposure are of critical importance as large populations of people could be exposed either by terrorists, nuclear blast, or medical therapy. In this study, we aimed to identify changes in the urine proteome using a non-human primate model system, Rhesus macaque, in order to characterize effects of acute radiation syndrome following whole body irradiation (Co-60) at 6.7 Gy and 7.4 Gy with a twelve day observation period. The urine proteome is potentially a valuable and non-invasive diagnostic for radiation exposure. Using high-resolution mass spectrometry, we identified 2346 proteins in the urine proteome. We show proteins involved in disease, cell adhesion, and metabolic pathway were significantly changed upon exposure to differing levels and durations of radiation exposure. Cell damage increased at a faster rate at 7.4 Gy compared with 6.7 Gy exposures. We report sets of proteins that are putative biomarkers of time- and dose-dependent radiation exposure. The proteomic study presented here is a comprehensive analysis of the urine proteome following radiation exposure. PMID:26962295

  2. A non-human primate model of radiation-induced cachexia

    PubMed Central

    Cui, Wanchang; Bennett, Alexander W.; Zhang, Pei; Barrow, Kory R.; Kearney, Sean R.; Hankey, Kim G.; Taylor-Howell, Cheryl; Gibbs, Allison M.; Smith, Cassandra P.; MacVittie, Thomas J.

    2016-01-01

    Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20–25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease. PMID:27029502

  3. A non-human primate model of radiation-induced cachexia.

    PubMed

    Cui, Wanchang; Bennett, Alexander W; Zhang, Pei; Barrow, Kory R; Kearney, Sean R; Hankey, Kim G; Taylor-Howell, Cheryl; Gibbs, Allison M; Smith, Cassandra P; MacVittie, Thomas J

    2016-03-31

    Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.

  4. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration.

    PubMed

    Freeman, Willard M; Vanguilder, Heather D; Guidone, Elizabeth; Krystal, John H; Grant, Kathleen A; Vrana, Kent E

    2011-08-01

    Objective diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. Two-dimensional difference in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within-subject samples collected before exposure to ethanol and after 3 months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of serum amyloid A4 (SAA4), retinol-binding protein, inter-alpha inhibitor H4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption.

  5. A Microneedle Patch Containing Measles Vaccine is Immunogenic in Non-human Primates

    PubMed Central

    Edens, Chris; Collins, Marcus L.; Goodson, James L.; Rota, Paul A.; Prausnitz, Mark R.

    2015-01-01

    Very high vaccination coverage is required to eliminate measles, but achieving high coverage can be constrained by the logistical challenges associated with subcutaneous injection. To simplify logistics of vaccine delivery, a patch containing micron-scale polymeric needles was formulated to encapsulate the standard dose of measles vaccine (1000 TCID50) and the immunogenicity of the microneedle patch was compared with subcutaneous injection in rhesus macaques. The microneedle patch was administered without reconstitution with diluent, dissolved in skin within 10 minutes, and caused only mild, transient skin erythema. Both groups of rhesus macaques generated neutralizing antibody responses to measles that were consistent with protection and the neutralizing antibody titers were equivalent. In addition, the microneedle patches maintained an acceptable level of potency after storage at elevated temperature suggesting improved thermostability compared to standard lyophilized vaccine. In conclusion, a measles microneedle patch vaccine was immunogenic in non-human primates, and this approach offers a promising delivery method that could help increase vaccination coverage. PMID:25770786

  6. Blood microsampling from the ear capillary in non-human primates.

    PubMed

    Lefevre, Arthur; Ballesta, Sébastien; Pozzobon, Mathieu; Charieau, Jean-Luc; Duperrier, Sandra; Sirigu, Angela; Duhamel, Jean-René

    2015-10-01

    Blood sampling from awake non-human primates (NHPs) is classically performed under constraint in the cephalic or saphenous vein. It is a challenging, potentially harmful and stressful procedure which may lead to biased results and raises ethical concerns. Laboratory NHPs undergo a head-restrained procedure allowing for a safer procedure of collecting blood from their ears. Using regular capillary blood collection devices 500 µL of blood can be easily withdrawn per puncture point, which is sufficient for performing most of the usual modern biological assays. This procedure has been validated by measuring total proteins, cortisol and vasopressin concentrations from concomitant blood samples taken from the saphenous vein and the ear capillary vessels of macaques (n = 16). We observed strong correlations between the blood concentrations of total proteins, cortisol and vasopressin (r = 0.72, r = 0.63, r = 0.83, respectively; all P values <0.01) taken from the saphenous vein and from the ear capillary. There were no significant differences between blood concentrations taken from the saphenous vein and the ear capillary. Our alternative to the classical blood collection procedure is harmless and can be routinely performed, which can therefore improve scientific results while increasing animal welfare in accordance with the 3R (replacement, reduction and refinement) principles.

  7. Isolation of Anti-Ricin Protective Antibodies Exhibiting High Affinity from Immunized Non-Human Primates.

    PubMed

    Noy-Porat, Tal; Rosenfeld, Ronit; Ariel, Naomi; Epstein, Eyal; Alcalay, Ron; Zvi, Anat; Kronman, Chanoch; Ordentlich, Arie; Mazor, Ohad

    2016-03-03

    Ricin, derived from the castor bean plant Ricinus communis, is one of the most potent and lethal toxins known, against which there is no available antidote. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this study was to isolate high affinity anti-ricin antibodies that possess potent toxin-neutralization capabilities. Two non-human primates were immunized with either a ricin-holotoxin- or subunit-based vaccine, to ensure the elicitation of diverse high affinity antibodies. By using a comprehensive set of primers, immune scFv phage-displayed libraries were constructed and panned. A panel of 10 antibodies (five directed against the A subunit of ricin and five against the B subunit) was isolated and reformatted into a full-length chimeric IgG. All of these antibodies were found to neutralize ricin in vitro, and several conferred full protection to ricin-intoxicated mice when given six hours after exposure. Six antibodies were found to possess exceptionally high affinity toward the toxin, with KD values below pM (k(off )< 1 × 10(-7) s(-1)) that were well correlated with their ability to neutralize ricin. These antibodies, alone or in combination, could be used for the development of a highly-effective therapeutic preparation for post-exposure treatment of ricin intoxication.

  8. Protection of non-human primates against glanders with a gold nanoparticle glycoconjugate vaccine

    PubMed Central

    Torres, Alfredo G.; Gregory, Anthony E.; Hatcher, Christopher L.; Vinet-Oliphant, Heather; Morici, Lisa A.; Titball, Richard W.; Roy, Chad J.

    2014-01-01

    The Gram-negative Burkholderia mallei is a zoonotic pathogen and the causative agent of glanders disease. Because the bacteria maintain the potential to be used as a biothreat agent, vaccine strategies are required for human glanders prophylaxis. A rhesus macaque (Macaca mulatta) model of pneumonic (inhalational) glanders was established and the protective properties of a nanoparticle glycoconjugate vaccine composed of B. thailandensis LPS conjugated to FliC was evaluated. An aerosol challenge dose of ~1×104 CFU B. mallei produced mortality in 50% of naïve animals (n = 2/4), 2–3 days post-exposure. Although survival benefit was not observed by vaccination with a glycoconjugate glanders vaccine (p=0.42), serum LPS-specific IgG titres were significantly higher on day 80 in 3 vaccinated animals who survived compared with 3 vaccinated animals who died. Furthermore, B. mallei was isolated from multiple organs of both non-vaccinated survivors, but not from any organs of 3 vaccinated survivors at 30 days post-challenge. Taken together, this is the first time a candidate vaccine has been evaluated in a non-human primate aerosol model of glanders and represents the initial step for consideration in pre-clinical studies. PMID:25533326

  9. Hominin geographical range dynamics and relative brain size: Do non-human primates provide a good analogy?

    PubMed

    MacDonald, Katharine; Smaers, Jeroen B; Steele, James

    2015-10-01

    We use climatic and satellite remote sensing data to characterize environmental seasonality in the geographical ranges of extant non-human primates in order to assess the effect of relative brain size on tolerance of more seasonal habitats. Demonstration of such an effect in living non-human primates could provide a comparative framework for modeling hominin dispersals and geographical range dynamics in the Pliocene and Pleistocene. Our analyses found no such effect: there are neither positive nor negative correlations between relative brain size and either geographical range size or the average and range of values for environmental seasonality, whether analysed at the level of all primates, or within parvorders (strepsirrhine, catarrhine, platyrrhine). Independent analyses by other researchers comparing feeding behaviour and ecology at individual primate study sites demonstrate that in seasonal environments, the year-round metabolic costs of maintaining a relatively large brain are met by adaptive behavioural/dietary strategies. However, consistent with our own results, those comparative studies found that there was no overall association, whether positive or negative, between 'raw' environmental seasonality and primate relative brain size. We must therefore look elsewhere for a comparative model of hominin geographical range dynamics in the Pleistocene.

  10. Spatial Overlap Between People and Non-human Primates in a Fragmented Landscape.

    PubMed

    Paige, Sarah B; Bleecker, Johanna; Mayer, Jonathan; Goldberg, Tony

    2017-03-01

    In western Uganda, the landscape surrounding Kibale National Park (KNP) contains households, trading centers, roads, fields, and forest fragments. The mosaic arrangement of these landscape features is thought to enhance human-primate interaction, leading to primate population declines and increased bi-directional disease transmission. Using a social-ecological systems research framework that captures the complexity of interaction among people, wildlife, and environment, we studied five forest fragments near KNP and conducted intensive on-the-ground mapping to identify locations of human-primate spatial overlap. Primate locations and human activities were distributed within, on the edges, and far beyond fragment borders. Analysis of shared spaces indicated that 5.5% of human space overlapped with primate spaces, while 69.5% of primate spaces overlapped with human spaces. Nearest neighbor analysis indicated that human activities were significantly spatially clustered within and around individual fragments, as were primate locations. Getis-Ord statistics revealed statistically significant "hotspots" of human activity and primate activity, but only one location where spatial overlap between humans and primates was statistically significant. Human activities associated with collecting fuelwood and other forest products were the primary drivers of human-primate overlap; however, primates also spent time outside of forest fragments in agricultural spaces. These results demonstrate that fragmented landscapes are not uniform with respect to human-primate overlap, and that the implications of human-primate interaction, such as primate population declines and possible cross-species disease transmission, are spatially aggregated.

  11. Multi-atlas Library for Eliminating Normalization Failures in Non-Human Primates

    PubMed Central

    Maldjian, Joseph A.; Shively, Carol A.; Nader, Michael A.; Friedman, David P.; Whitlow, Christopher T.

    2015-01-01

    Introduction Current tools for automated skull stripping, normalization, and segmentation of non-human primate (NHP) brain MRI studies typically demonstrate high failure rates. Many of these failures are due to a poor initial estimate for the affine component of the transformation. The purpose of this study is to introduce a multi-atlas approach to overcome these limitations and drive the failure rate to near zero. Materials and Methods A library of study-specific templates (SST) spanning three Old World primate species (Macaca fascicularis, M. mulatta, Chlorocebus aethiops) was created using a previously described unbiased automated approach. Several modifications were introduced to the methodology to improve initial affine estimation at the study-specific template level, and at the individual subject level. These involve performing multiple separate normalizations to a multi-atlas library of templates and selecting the best performing template on the basis of a covariance similarity metric. This template was then used as an initialization for the affine component of subsequent skull stripping and normalization procedures. Normalization failure rate for SST generation and individual-subject segmentation on a set of 150 NHP was evaluated on the basis of visual inspection. Results The previous automated template creation procedure results in excellent skull stripping, segmentation, and atlas labeling across species. Failure rate at the individual-subject level was approximately 1%, however at the SST generation level it was 17%. Using the new multi-atlas approach, failure rate was further reduced to zero for both SST generation and individual subject processing. Conclusions We describe a multi-atlas library registration approach for driving normalization failures in NHP to zero. It is straightforward to implement, and can have application to a wide variety of existing tools, as well as in difficult populations including neonates and the elderly. This approach is

  12. Preventive immunization of aged and juvenile non-human primates to beta-amyloid

    PubMed Central

    2012-01-01

    Background Immunization against beta-amyloid (Aβ) is a promising approach for the treatment of Alzheimer’s disease, but the optimal timing for the vaccination remains to be determined. Preventive immunization approaches may be more efficacious and associated with fewer side-effects; however, there is only limited information available from primate models about the effects of preclinical vaccination on brain amyloid composition and the neuroinflammatory milieu. Methods Ten non-human primates (NHP) of advanced age (18–26 years) and eight 2-year-old juvenile NHPs were immunized at 0, 2, 6, 10 and 14 weeks with aggregated Aβ42 admixed with monophosphoryl lipid A as adjuvant, and monitored for up to 6 months. Anti-Aβ antibody levels and immune activation markers were assessed in plasma and cerebrospinal fluid samples before and at several time-points after immunization. Microglial activity was determined by [11C]PK11195 PET scans acquired before and after immunization, and by post-mortem immunohistochemical and real-time PCR evaluation. Aβ oligomer composition was assessed by immunoblot analysis in the frontal cortex of aged immunized and non-immunized control animals. Results All juvenile animals developed a strong and sustained serum anti-Aβ IgG antibody response, whereas only 80 % of aged animals developed detectable antibodies. The immune response in aged monkeys was more delayed and significantly weaker, and was also more variable between animals. Pre- and post-immunization [11C]PK11195 PET scans showed no evidence of vaccine-related microglial activation. Post-mortem brain tissue analysis indicated a low overall amyloid burden, but revealed a significant shift in oligomer size with an increase in the dimer:pentamer ratio in aged immunized animals compared with non-immunized controls (P < 0.01). No differences were seen in microglial density or expression of classical and alternative microglial activation markers between immunized and control

  13. Preference and consequences: A preliminary look at whether preference impacts oral processing in non-human primates.

    PubMed

    Vinyard, Christopher J; Thompson, Cynthia L; Doherty, Alison; Robl, Nicholas

    2016-09-01

    Non-human primates demonstrate food preferences much like humans. We have little insight, however, into how those preferences impact oral processing in primates. To begin describing this relationship, we conducted a preliminary analysis measuring food preference in two tufted capuchins (Cebus apella) and comparing ranked preference to physiological variables during chewing of these foods. Food preference was assessed for each monkey across 12 foods, including monkey biscuits and 11 foods consumed by humans (e.g., various fruits and nuts). Animals chose from randomized pairs of foods to generate a ranked scale across the 12 foods. Contemporaneous with preference testing, electromyographic (EMG) activity was measured for the jaw-closing muscles to assess oral physiology during chewing of these foods. As expected, these capuchins exhibited clear preferences among these 12 foods. Based on their preferences, we identified sets of preferred and non-preferred brittle (i.e., almond versus monkey chow) and ductile (i.e., dates and prunes versus apricots) foods for physiological comparisons that broadly control variation in food mechanical properties (FMPs). As expected, oral physiology varied with FMPs in each animal. Within brittle and ductile groupings, we observed several significant differences in chewing cycle length and relative muscle activation levels that are likely related to food preference. These differences tended to be complex and individual specific. The two capuchins chewed non-preferred apricots significantly faster than preferred dates and prunes. Effect sizes for preference were smaller than those for FMPs, supporting the previous focus on FMPs in primate dietary research. Although preliminary, these results suggest that food preference may influence oral physiology in non-human primates. The prospect that this relationship exists in monkeys raises the possibility that a link between food preference and oral processing in humans may be based on shared

  14. Viral Kinetics of Primary Dengue Virus Infection in Non-Human Primates: A Systematic Review and Individual Pooled Analysis

    PubMed Central

    Althouse, Benjamin M.; Durbin, Anna P.; Hanley, Kathryn A.; Halstead, Scott B.; Weaver, Scott C.; Cummings, Derek A. T.

    2014-01-01

    Viremia kinetics directly influence the clinical course and transmission dynamics of DENV, but many aspects of viral dynamics remain unknown. Non-human primates (NHP) have been used as a model system for DENV infection for decades. Here, we identify papers with experimentally-infected NHP and estimate the time to- and duration of viremia as well as estimate associations between these and serotype, inoculating dose, viremia assay, and species of NHP. We estimate the time to viremia in rhesus macaques to range from 2.63 to 3.32 days for DENV-2 and -1 and the duration to range from 3.13 to 5.13 days for DENV-4 and -2. We find no differences between non-human primates for time to viremia or duration, and a significant negative relationship between inoculating dose and duration of viremia. These results aide in understanding the transmission dynamics of sylvatic DENV non-human primates, an issue of growing importance as dengue vaccines become available. PMID:24606701

  15. Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates.

    PubMed

    Wang, Qidi; Zhang, Lianfeng; Kuwahara, Kazuhiko; Li, Li; Liu, Zijie; Li, Taisheng; Zhu, Hua; Liu, Jiangning; Xu, Yanfeng; Xie, Jing; Morioka, Hiroshi; Sakaguchi, Nobuo; Qin, Chuan; Liu, Gang

    2016-05-13

    Severe acute respiratory syndrome (SARS) is caused by a coronavirus (SARS-CoV) and has the potential to threaten global public health and socioeconomic stability. Evidence of antibody-dependent enhancement (ADE) of SARS-CoV infection in vitro and in non-human primates clouds the prospects for a safe vaccine. Using antibodies from SARS patients, we identified and characterized SARS-CoV B-cell peptide epitopes with disparate functions. In rhesus macaques, the spike glycoprotein peptides S471-503, S604-625, and S1164-1191 elicited antibodies that efficiently prevented infection in non-human primates. In contrast, peptide S597-603 induced antibodies that enhanced infection both in vitro and in non-human primates by using an epitope sequence-dependent (ESD) mechanism. This peptide exhibited a high level of serological reactivity (64%), which resulted from the additive responses of two tandem epitopes (S597-603 and S604-625) and a long-term human B-cell memory response with antisera from convalescent SARS patients. Thus, peptide-based vaccines against SARS-CoV could be engineered to avoid ADE via elimination of the S597-603 epitope. We provide herein an alternative strategy to prepare a safe and effective vaccine for ADE of viral infection by identifying and eliminating epitope sequence-dependent enhancement of viral infection.

  16. Consensus-degenerate hybrid oligonucleotide primers (CODEHOPs) for the detection of novel viruses in non-human primates.

    PubMed

    Staheli, Jeannette P; Ryan, Jonathan T; Bruce, A Gregory; Boyce, Richard; Rose, Timothy M

    2009-09-01

    Consensus-degenerate hybrid oligonucleotide primers (CODEHOPs) have proven to be a powerful tool for the identification of novel genes. CODEHOPs are designed from highly-conserved regions of multiply-aligned protein sequences from members of a gene family and are used in PCR amplification to identify distantly-related genes. The CODEHOP approach has been used to identify novel pathogens by targeting amino acid motifs conserved in specific pathogen families. We initiated a program utilizing the CODEHOP approach to develop PCR-based assays targeting a variety of viral families that are pathogens in non-human primates. We have also developed and further improved a computer program and website to facilitate the design of CODEHOP PCR primers. Here, we detail the method for the development of pathogen-specific CODEHOP PCR assays using the papillomavirus family as a target. Papillomaviruses constitute a diverse virus family infecting a wide variety of mammalian species, including humans and non-human primates. We demonstrate that our pan-papillomavirus CODEHOP assay is broadly reactive with all major branches of the virus family and show its utility in identifying a novel non-human primate papillomavirus in cynomolgus macaques.

  17. Mean Organ Doses Resulting From Non-Human Primate Whole Thorax Lung Irradiation Prescribed to Mid-Line Tissue.

    PubMed

    Prado, Charlotte; Kazi, Abdul; Bennett, Alexander; MacVittie, Thomas; Prado, Karl

    2015-11-01

    Multi-organ dose evaluations and the effects of heterogeneous tissue dose calculations have been retrospectively evaluated following irradiation to the whole thorax and lung in non-human primates (NHP). A clinical-based approach was established to evaluate actual doses received in the heart and lungs during whole thorax lung irradiation. Anatomical structure and organ densities have been introduced in the calculations to show the effects of dose distribution through heterogeneous tissue. Mean organ doses received by non-human primates undergoing whole thorax lung irradiations were calculated using a treatment planning system that is routinely used in clinical radiation oncology. The doses received by non-human primates irradiated following conventional dose calculations have been retrospectively reconstructed using computerized tomography-based, heterogeneity-corrected dose calculations. The use of dose volume descriptors for irradiation to organs at risk and tissue exposed to radiation is introduced. Mean and partial-volume doses to lung and heart are presented and contrasted. The importance of exact dose definitions is highlighted, and the relevance of precise dosimetry to establish organ-specific dose response relationships in NHP models of acute and delayed effects of acute radiation exposure is emphasized.

  18. Morphine Produces Immunosuppressive Effects in Non-human Primates at the Proteomic and Cellular Levels

    SciTech Connect

    Brown, Joseph N.; Ortiz, Gabriel M.; Angel, Thomas E.; Jacobs, Jon M.; Gritsenko, Marina A.; Chan, Eric Y.; Purdy, David E.; Murnane, Robert D.; Larsen, Kay; Palermo, Robert E.; Shukla, Anil K.; Clauss, Therese RW; Katze, Michael G.; McCune, Joseph M.; Smith, Richard D.

    2012-05-11

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. As a prelude to understanding how these changes might interact with lentiviral infection in vivo, animals from two non-human primate (NHP) species [African green monkey (AGMs) and pigtailed macaque (PTs)] were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g., lymph node, colon, cerebrospinal fluid (CSF), and peripheral blood) before and after the administration of morphine (titrated up to a maximum dose of 5 mg/kg over a period of 20 days). Cellular immune, plasma cytokine, and proteome changes were measured and morphine-induced changes in these parameters were assessed on an inter-organ, inter-individual, and inter-species basis. In both species, morphine was associated with decreased levels of (Ki-67+) T cell activation but with only minimal changes in overall T cell counts, neutrophil counts, and NK cells counts. While changes in T cell maturation were observed, these varied across the various tissue/fluid compartments studied. Proteomic analysis revealed a morphine-induced suppressive effect in the lymph node, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the interplay between opioid abuse and the response to infection with agents such as the human immunodeficiency virus, type 1 (HIV).

  19. Do robots have goals? How agent cues influence action understanding in non-human primates.

    PubMed

    Kupferberg, Aleksandra; Glasauer, Stefan; Burkart, Judith M

    2013-06-01

    The capacity to understand goals and intentions emerges early and universally in humans and is a basic precondition for the interpretation and prediction of others' actions, be it other humans, animals, or even robots. It is unclear, however, how this goal attribution system is acquired, in particular with regard to the role of prior experience with the actor and visual characteristics that are necessary. In four preferential looking time experiments we examined how familiarity, appearance, and movement of different agents influence the capability of marmosets to perceive the behavior of these agents as goal directed. To this end we compared the monkeys' reactions to the same goal-directed actions performed by four different agents: a human actor, a conspecific, a monkey-like small robot, and a black box. The results showed that monkeys attributed goals to the human actor, the conspecific, and the robot, but not the box. Thus, the monkeys extended their capacity for goal attribution not only to familiar agents, but also to agents not previously encountered, provided that they had some conspecific-like features. Our results suggest that in non-human primates, the system for goal attribution does not require previous experience with a specific agent or agent-category, as long as it exhibits certain visual characteristics like face, body or legs. Furthermore, the results suggest that the capacity to attribute goals emerged very early during evolution and, at least in marmoset monkeys, does not necessarily require pre-learned associations in order to fulfill its function when dealing with unfamiliar agents.

  20. Multisensory Integration in Non-Human Primates during a Sensory-Motor Task.

    PubMed

    Lanz, Florian; Moret, Véronique; Rouiller, Eric Michel; Loquet, Gérard

    2013-01-01

    Daily our central nervous system receives inputs via several sensory modalities, processes them and integrates information in order to produce a suitable behavior. The amazing part is that such a multisensory integration brings all information into a unified percept. An approach to start investigating this property is to show that perception is better and faster when multimodal stimuli are used as compared to unimodal stimuli. This forms the first part of the present study conducted in a non-human primate's model (n = 2) engaged in a detection sensory-motor task where visual and auditory stimuli were displayed individually or simultaneously. The measured parameters were the reaction time (RT) between stimulus and onset of arm movement, successes and errors percentages, as well as the evolution as a function of time of these parameters with training. As expected, RTs were shorter when the subjects were exposed to combined stimuli. The gains for both subjects were around 20 and 40 ms, as compared with the auditory and visual stimulus alone, respectively. Moreover the number of correct responses increased in response to bimodal stimuli. We interpreted such multisensory advantage through redundant signal effect which decreases perceptual ambiguity, increases speed of stimulus detection, and improves performance accuracy. The second part of the study presents single-unit recordings derived from the premotor cortex (PM) of the same subjects during the sensory-motor task. Response patterns to sensory/multisensory stimulation are documented and specific type proportions are reported. Characterization of bimodal neurons indicates a mechanism of audio-visual integration possibly through a decrease of inhibition. Nevertheless the neural processing leading to faster motor response from PM as a polysensory association cortical area remains still unclear.

  1. Cortico-basal ganglia circuits involved in different motivation disorders in non-human primates.

    PubMed

    Sgambato-Faure, Véronique; Worbe, Yulia; Epinat, Justine; Féger, Jean; Tremblay, Léon

    2016-01-01

    The ventral striatum (VS) is of particular interest in the study of neuropsychiatric disorders. In this study, performed on non-human primates, we associated local perturbation with monosynaptic axonal tracer injection into medial, central and lateral VS to characterize anatomo-functional circuits underlying the respective expression of sexual manifestations, stereotyped behaviors and hypoactive state associated with loss of food motivation. For the three behavioral effects, we demonstrated the existence of three distinct cortico-basal ganglia (BG) circuits that were topographically organized and overlapping at some cortical (orbitofrontal cortex, anterior cingulate cortex) and subcortical (caudal levels of BG) levels, suggesting interactions between motivation domains. Briefly, erection was associated with a circuit involving the orbitofrontal cortex, medial prefrontal cortex (areas 10, 11) and limbic parts of BG, i.e. medial parts of the pallidal complex and the substantia nigra pars reticulata (SNr). Stereotyped behavior was linked to a circuit involving the lateral orbitofrontal cortex (area 12/47) and limbic parts of the pallidal complex and of the SNr, while the apathetic state was underlined by a circuit involving not only the orbital and medial prefrontal cortex but also the lateral prefrontal cortex (area 8, 45), the anterior insula and the lateral parts of the medial pallidal complex and of the ventro-medial SNr. For the three behavioral effects, the cortico-BG circuits mainly involved limbic regions of the external and internal pallidum, as well as the limbic part of the substantia nigra pars reticulata (SNr), suggesting the involvement of both direct and indirect striatal pathways and both output BG structures. As these motivation disorders could still be induced in dopamine (DA)-depleted monkeys, we suggest that DA issued from the substantia nigra pars compacta (SNc) modulates their expression rather than causes them. Finally, this study may give some

  2. Inverse zonation of hepatocyte transduction with AAV vectors between mice and non-human primates

    PubMed Central

    Bell, Peter; Wang, Lili; Gao, Guangping; Haskins, Mark E.; Tarantal, Alice F.; McCarter, Robert J.; Zhu, Yanqing; Yu, Hongwei; Wilson, James M.

    2011-01-01

    Gene transfer vectors based on adeno-associated virus 8 (AAV8) are highly efficient in liver transduction and can be easily administered by intravenous injection. In mice, AAV8 transduces predominantly hepatocytes near central veins and yields lower transduction levels in hepatocytes in periportal regions. This transduction bias has important implications for gene therapy that aims to correct metabolic liver enzymes because metabolic zonation along the porto-central axis requires the expression of therapeutic proteins within the zone where they are normally localized. In the present study we compared the expression pattern of AAV8 expressing green fluorescent protein (GFP) in liver between mice, dogs, and non-human primates. We confirmed the pericentral dominance in transgene expression in mice with AAV8 when the liver-specific thyroid hormone-binding globulin (TBG) promoter was used but also observed the same expression pattern with the ubiquitous chicken β-actin (CB) and cytomegalovirus (CMV) promoters, suggesting that transduction zonation is not caused by promoter specificity. Predominantly pericentral expression was also found in dogs injected with AAV8. In contrast, in cynomolgus and rhesus macaques the expression pattern from AAV vectors was reversed, i.e. transgene expression was most intense around portal areas and less intense or absent around central veins. Infant rhesus macaques as well as newborn mice injected with AAV8 however showed a random distribution of transgene expression with neither portal nor central transduction bias. Based on the data in monkeys, adult humans treated with AAV vectors are predicted to also express transgenes predominantly in periportal regions whereas infants are likely to show a uniform transduction pattern in liver. PMID:21778099

  3. Mapping orbitofrontal-limbic maturation in non-human primates: A longitudinal magnetic resonance imaging study.

    PubMed

    Uematsu, Akiko; Hata, Junichi; Komaki, Yuji; Seki, Fumiko; Yamada, Chihoko; Okahara, Norio; Kurotaki, Yoko; Sasaki, Erika; Okano, Hideyuki

    2017-09-18

    Brain development involves spatiotemporally complex microstructural changes. A number of neuropsychiatric disorders are linked to the neural processes of development and aging. Thus, it is important to understanding the typical developmental patterns of various brain structures, which will help to define critical periods of vulnerability for neural maturation, as well as anatomical mechanisms of brain structure-related neuropathology. In this study, we used magnetic resonance imaging to assess development of the orbitofrontal cortex, cingulate cortex, amygdala, and hippocampus in a non-human primate species, the common marmoset (Callithrix jacchus). We collected a total of 114 T2-weighted and 91 diffusion-weighted scans from 23 animals from infancy to early adulthood. Quantitative and qualitative evaluation of age-related brain growth patterns showed non-linear structural developmental changes in all measured brain regions, consistent with reported human data. Overall, robust volumetric growth was observed from 1 to 3 months of age (from infancy to the early juvenile period). This rapid brain growth was associated with the largest decrease in mean, axial, and radial diffusivities of diffusion tensor imaging in all brain regions, suggesting an increase in the number and size of cells, dendrites, and spines during this period. After this developmental period, the volume of various brain regions steadily increased until adolescence (7-13 months of age, depending on the region). Further, structural connectivity derived from tractography data in various brain regions continuously changed from infancy to adolescence, suggesting that the increase in brain volume was related to continued axonal myelination during adolescence. Thereafter, the volume of the cortical regions decreased considerably, while there was no change in subcortical regions. Familial factors, rather than sex, contributed the development of the front-limbic brain regions. Overall, this study provides

  4. Non-human primate models of PD to test novel therapies.

    PubMed

    Morissette, Marc; Di Paolo, Thérèse

    2017-04-08

    Non-human primate (NHP) models of Parkinson disease show many similarities with the human disease. They are very useful to test novel pharmacotherapies as reviewed here. The various NHP models of this disease are described with their characteristics including the macaque, the marmoset, and the squirrel monkey models. Lesion-induced and genetic models are described. There is no drug to slow, delay, stop, or cure Parkinson disease; available treatments are symptomatic. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-Dopa) still remains the gold standard symptomatic treatment of Parkinson. However, involuntary movements termed L-Dopa-induced dyskinesias appear in most patients after chronic treatment and may become disabling. Dyskinesias are very difficult to manage and there is only amantadine approved providing only a modest benefit. In this respect, NHP models have been useful to seek new drug targets, since they reproduce motor complications observed in parkinsonian patients. Therapies to treat motor symptoms in NHP models are reviewed with a discussion of their translational value to humans. Disease-modifying treatments tested in NHP are reviewed as well as surgical treatments. Many biochemical changes in the brain of post-mortem Parkinson disease patients with dyskinesias are reviewed and compare well with those observed in NHP models. Non-motor symptoms can be categorized into psychiatric, autonomic, and sensory symptoms. These symptoms are present in most parkinsonian patients and are already installed many years before the pre-motor phase of the disease. The translational usefulness of NHP models of Parkinson is discussed for non-motor symptoms.

  5. Cryptosporidium spp., Giardia intestinalis, and Enterocytozoon bieneusi in Captive Non-Human Primates in Qinling Mountains

    PubMed Central

    Du, Shuai-Zhi; Zhao, Guang-Hui; Shao, Jun-Feng; Fang, Yan-Qin; Tian, Ge-Ru; Zhang, Long-Xian; Wang, Rong-Jun; Wang, Hai-Yan; Qi, Meng; Yu, San-Ke

    2015-01-01

    Non-human primates (NHPs) are confirmed as reservoirs of Cryptosporidium spp., Giardia intestinalis, and Enterocytozoon bieneusi. In this study, 197 fresh fecal samples from 8 NHP species in Qinling Mountains, northwestern China, were collected and examined using multilocus sequence typing (MLST) method. The results showed that 35 (17.8%) samples were positive for tested parasites, including Cryptosporidium spp. (3.0%), G. intestinalis (2.0%), and E. bieneusi (12.7%). Cryptosporidium spp. were detected in 6 fecal samples of Macaca mulatta, and were identified as C. parvum (n=1) and C. andersoni (n=5). Subtyping analysis showed Cryptosporidium spp. belonged to the C. andersoni MLST subtype (A4, A4, A4, and A1) and C. parvum 60 kDa glycoprotein (gp60) subtype IId A15G2R1. G. intestinalis assemblage E was detected in 3 M. mulatta and 1 Saimiri sciureus. Intra-variations were observed at the triose phosphate isomerase (tpi), beta giardin (bg), and glutamate dehydrogenase (gdh) loci, with 3, 1, and 2 new subtypes found in respective locus. E. bieneusi was found in Cercopithecus neglectus (25.0%), Papio hamadrayas (16.7%), M. mulatta (16.3%), S. sciureus (10%), and Rhinopithecus roxellana (9.5%), with 5 ribosomal internal transcribed spacer (ITS) genotypes: 2 known genotypes (D and BEB6) and 3 novel genotypes (MH, XH, and BSH). These findings indicated the presence of zoonotic potential of Cryptosporidium spp. and E. bieneusi in NHPs in Qinling Mountains. This is the first report of C. andersoni in NHPs. The present study provided basic information for control of cryptosporidiosis, giardiasis, and microsporidiosis in human and animals in this area. PMID:26323837

  6. Borrelia burgdorferi transcriptome in the central nervous system of non-human primates.

    PubMed

    Narasimhan, Sukanya; Caimano, Melissa J; Liang, Fang Ting; Santiago, Felix; Laskowski, Michelle; Philipp, Mario T; Pachner, Andrew R; Radolf, Justin D; Fikrig, Erol; Camaino, Melissa J

    2003-12-23

    Neurological symptoms are common manifestations of Lyme disease; however, the paucibacillary nature of the spirochete in this environment has precluded a molecular analysis of the spirochete in the CNS. We have now adapted differential expression analysis by using a custom-amplified library (DECAL) in conjunction with Borrelia burgdorferi whole-genome and subgenome arrays to examine in vivo gene expression by B. burgdorferi in a non-human primate (NHP) model of neuroborreliosis. The expression profile of B. burgdorferi was examined in the CNS and heart of steroid-treated and immunocompetent NHPs. Eighty-six chromosomal genes and 80 plasmid-encoded genes were expressed at similar levels in the CNS and heart tissue of both immunocompetent and steroid-treated NHPs. The expression of 66 chromosomal genes and 32 plasmid-encoded genes was increased in the CNS of both immunocompetent and steroid-treated NHPs. It is likely that the expression of these genes is governed by physiological factors specific to the CNS milieu. However, 83 chromosomal and 114 plasmid-encoded genes showed contrasting expression profiles in steroid-treated and immunocompetent NHPs. The effect of dexamethasone on the immune status of the host as well as on the host metabolic pathways could contribute to these differences in the B. burgdorferi transcriptome. Results obtained herein underscore the complex interplay of host factors on B. burgdorferi gene expression in vivo. The results provide a global snapshot of the spirochetal transcriptome in the CNS and should spur the design of experiments aimed at understanding the molecular basis of neuroborreliosis.

  7. Evolutionarily conserved serum microRNAs predict radiation-induced fatality in non-human primates

    PubMed Central

    Fendler, Wojciech; Malachowska, Beata; Meghani, Khyati; Konstantinopoulos, Panagiotis A.; Guha, Chandan; Singh, Vijay K.; Chowdhury, Dipanjan

    2017-01-01

    Effective planning for the medical response to a radiologic or nuclear accident is complex. Due to limited resources for medical countermeasures, the key would be to accurately triage and identify victims most likely to benefit from treatment. We had used a mouse model system to provide evidence that serum microRNAs (miRNAs) may effectively predict the impact of radiation on long-term viability of animals. Here we use non-human primates (NHPs) to demonstrate that this concept is conserved and serum miRNA signatures have the potential to serve as prediction biomarkers for radiation-induced fatality in a human population. We identified a signature of seven miRNAs that are altered by irradiation in both mice and NHPs. Genomic analysis of these conserved miRNAs revealed that there is a combination of seven transcription factors that are predicted to regulate these miRNAs in human, mice, and NHPs. Moreover, a combination of three miRNAs (miR-133b, miR-215, and miR-375) can identify, with nearly complete accuracy, NHPs exposed to radiation versus unexposed NHPs. Consistent with historical data, female macaques appeared to be more sensitive to radiation, but the difference was not significant. Sex-based stratification allowed us to identify an interaction between gender and miR-16-2 expression, which affected the outcome of radiation exposure. Moreover, we developed a classifier based on two miRNAs (miR-30a and miR-126) that can reproducibly predict radiation-induced mortality. Altogether, we have obtained a 5-miRNA composite signature that can identify irradiated macaques and predict their probability of survival. PMID:28251902

  8. A wireless transmission neural interface system for unconstrained non-human primates.

    PubMed

    Fernandez-Leon, Jose A; Parajuli, Arun; Franklin, Robert; Sorenson, Michael; Felleman, Daniel J; Hansen, Bryan J; Hu, Ming; Dragoi, Valentin

    2015-10-01

    Studying the brain in large animal models in a restrained laboratory rig severely limits our capacity to examine brain circuits in experimental and clinical applications. To overcome these limitations, we developed a high-fidelity 96-channel wireless system to record extracellular spikes and local field potentials from the neocortex. A removable, external case of the wireless device is attached to a titanium pedestal placed in the animal skull. Broadband neural signals are amplified, multiplexed, and continuously transmitted as TCP/IP data at a sustained rate of 24 Mbps. A Xilinx Spartan 6 FPGA assembles the digital signals into serial data frames for transmission at 20 kHz though an 802.11n wireless data link on a frequency-shift key-modulated signal at 5.7-5.8 GHz to a receiver up to 10 m away. The system is powered by two CR123A, 3 V batteries for 2 h of operation. We implanted a multi-electrode array in visual area V4 of one anesthetized monkey (Macaca fascicularis) and in the dorsolateral prefrontal cortex (dlPFC) of a freely moving monkey (Macaca mulatta). The implanted recording arrays were electrically stable and delivered broadband neural data over a year of testing. For the first time, we compared dlPFC neuronal responses to the same set of stimuli (food reward) in restrained and freely moving conditions. Although we did not find differences in neuronal responses as a function of reward type in the restrained and unrestrained conditions, there were significant differences in correlated activity. This demonstrates that measuring neural responses in freely moving animals can capture phenomena that are absent in the traditional head-fixed paradigm. We implemented a wireless neural interface for multi-electrode recordings in freely moving non-human primates, which can potentially move systems neuroscience to a new direction by allowing one to record neural signals while animals interact with their environment.

  9. A wireless transmission neural interface system for unconstrained non-human primates

    NASA Astrophysics Data System (ADS)

    Fernandez-Leon, Jose A.; Parajuli, Arun; Franklin, Robert; Sorenson, Michael; Felleman, Daniel J.; Hansen, Bryan J.; Hu, Ming; Dragoi, Valentin

    2015-10-01

    Objective. Studying the brain in large animal models in a restrained laboratory rig severely limits our capacity to examine brain circuits in experimental and clinical applications. Approach. To overcome these limitations, we developed a high-fidelity 96-channel wireless system to record extracellular spikes and local field potentials from the neocortex. A removable, external case of the wireless device is attached to a titanium pedestal placed in the animal skull. Broadband neural signals are amplified, multiplexed, and continuously transmitted as TCP/IP data at a sustained rate of 24 Mbps. A Xilinx Spartan 6 FPGA assembles the digital signals into serial data frames for transmission at 20 kHz though an 802.11n wireless data link on a frequency-shift key-modulated signal at 5.7-5.8 GHz to a receiver up to 10 m away. The system is powered by two CR123A, 3 V batteries for 2 h of operation. Main results. We implanted a multi-electrode array in visual area V4 of one anesthetized monkey (Macaca fascicularis) and in the dorsolateral prefrontal cortex (dlPFC) of a freely moving monkey (Macaca mulatta). The implanted recording arrays were electrically stable and delivered broadband neural data over a year of testing. For the first time, we compared dlPFC neuronal responses to the same set of stimuli (food reward) in restrained and freely moving conditions. Although we did not find differences in neuronal responses as a function of reward type in the restrained and unrestrained conditions, there were significant differences in correlated activity. This demonstrates that measuring neural responses in freely moving animals can capture phenomena that are absent in the traditional head-fixed paradigm. Significance. We implemented a wireless neural interface for multi-electrode recordings in freely moving non-human primates, which can potentially move systems neuroscience to a new direction by allowing one to record neural signals while animals interact with their environment.

  10. The genetic toxicology of methylphenidate hydrochloride in non-human primates.

    PubMed

    Morris, Suzanne M; Dobrovolsky, Vasily N; Shaddock, Joseph G; Mittelstaedt, Roberta A; Bishop, Michelle E; Manjanatha, Mugimane G; Shelton, Sharon D; Doerge, Daniel R; Twaddle, Nathan C; Chen, James J; Lin, Chien-Ju; Paule, Merle G; Slikker, William; Hotchkiss, Charlotte E; Petibone, Dayton; Tucker, James D; Mattison, Donald R

    2009-02-19

    The studies presented in this work were designed to evaluate the genetic toxicity of methylphenidate hydrochloride (MPH) in non-human primates (NHP) using a long-term, chronic dosing regimen. Thus, approximately two-year old, male rhesus monkeys of Indian origin were orally exposed to MPH diluted in the electrolyte replenisher, Prang, five days per week over a 20-month period. There were 10 animals per dose group and the doses were (1) control, Prang only, (2) low, 0.15 mg/kg of MPH twice per day increased to 2.5mg/kg twice per day and (3) high, 1.5 mg/kg of MPH twice per day increased to 12.5 mg/kg twice per day. Blood samples were obtained from each animal to determine the base-line serum levels of MPH and the major metabolite of MPH in NHP, ritalinic acid (RA). In addition, the base-line frequency of micronucleated erythrocytes (MN-RETs) by flow cytometry, HPRT mutants by a lymphocyte cloning assay, and chromosome aberrations by FISH painting were determined from peripheral blood samples. Once dosing began, the serum levels of MPH and its major metabolite, RA, were determined monthly. The MN-RET frequency and health parameters (CBC, serum chemistries) were also determined monthly. HPRT mutant and chromosome aberration frequencies were measured every three months. CBC values and serum chemistries, with the exception of alanine amino transferase, were within normal limits over the course of drug exposure. The final plasma levels of MPH were similar to those produced by the pediatric dose of 0.3 microg/ml. No significant increases in the frequencies of MN-RETs, HPRT mutants, or chromosome aberrations were detected in the treated animals compared to the control animals over the 20-month exposure period.

  11. Biophysical and neural basis of resting state functional connectivity: Evidence from non-human primates.

    PubMed

    Chen, Li Min; Yang, Pai-Feng; Wang, Feng; Mishra, Arabinda; Shi, Zhaoyue; Wu, Ruiqi; Wu, Tung-Lin; Wilson, George H; Ding, Zhaohua; Gore, John C

    2017-06-01

    Functional MRI (fMRI) has evolved from simple observations of regional changes in MRI signals caused by cortical activity induced by a task or stimulus, to task-free acquisitions of images in a resting state. Such resting state signals contain low frequency fluctuations which may be correlated between voxels, and strongly correlated regions are deemed to reflect functional connectivity within synchronized circuits. Resting state functional connectivity (rsFC) measures have been widely adopted by the neuroscience community, and are being used and interpreted as indicators of intrinsic neural circuits and their functional states in a broad range of applications, both basic and clinical. However, there has been relatively little work reported that validates whether inter-regional correlations in resting state fluctuations of fMRI (rsfMRI) signals actually measure functional connectivity between brain regions, or to establish how MRI data correlate with other metrics of functional connectivity. In this mini-review, we summarize recent studies of rsFC within mesoscopic scale cortical networks (100μm-10mm) within a well defined functional region of primary somatosensory cortex (S1), as well as spinal cord and brain white matter in non-human primates, in which we have measured spatial patterns of resting state correlations and validated their interpretation with electrophysiological signals and anatomic connections. Moreover, we emphasize that low frequency correlations are a general feature of neural systems, as evidenced by their presence in the spinal cord as well as white matter. These studies demonstrate the valuable role of high field MRI and invasive measurements in an animal model to inform the interpretation of human imaging studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Social complexity parallels vocal complexity: a comparison of three non-human primate species

    PubMed Central

    Bouchet, Hélène; Blois-Heulin, Catherine; Lemasson, Alban

    2013-01-01

    Social factors play a key role in the structuring of vocal repertoires at the individual level, notably in non-human primates. Some authors suggested that, at the species level too, social life may have driven the evolution of communicative complexity, but this has rarely been empirically tested. Here, we use a comparative approach to address this issue. We investigated vocal variability, at both the call type and the repertoire levels, in three forest-dwelling species of Cercopithecinae presenting striking differences in their social systems, in terms of social organization as well as social structure. We collected female call recordings from twelve De Brazza's monkeys (Cercopithecus neglectus), six Campbell's monkeys (Cercopithecus campbelli) and seven red-capped mangabeys (Cercocebus torquatus) housed in similar conditions. First, we noted that the level of acoustic variability and individual distinctiveness found in several call types was related to their importance in social functioning. Contact calls, essential to intra-group cohesion, were the most individually distinctive regardless of the species, while threat calls were more structurally variable in mangabeys, the most “despotic” of our three species. Second, we found a parallel between the degree of complexity of the species' social structure and the size, diversity, and usage of its vocal repertoire. Mangabeys (most complex social structure) called twice as often as guenons and displayed the largest and most complex repertoire. De Brazza's monkeys (simplest social structure) displayed the smallest and simplest repertoire. Campbell's monkeys displayed an intermediate pattern. Providing evidence of higher levels of vocal variability in species presenting a more complex social system, our results are in line with the theory of a social-vocal coevolution of communicative abilities, opening new perspectives for comparative research on the evolution of communication systems in different animal taxa. PMID

  13. Social complexity parallels vocal complexity: a comparison of three non-human primate species.

    PubMed

    Bouchet, Hélène; Blois-Heulin, Catherine; Lemasson, Alban

    2013-01-01

    Social factors play a key role in the structuring of vocal repertoires at the individual level, notably in non-human primates. Some authors suggested that, at the species level too, social life may have driven the evolution of communicative complexity, but this has rarely been empirically tested. Here, we use a comparative approach to address this issue. We investigated vocal variability, at both the call type and the repertoire levels, in three forest-dwelling species of Cercopithecinae presenting striking differences in their social systems, in terms of social organization as well as social structure. We collected female call recordings from twelve De Brazza's monkeys (Cercopithecus neglectus), six Campbell's monkeys (Cercopithecus campbelli) and seven red-capped mangabeys (Cercocebus torquatus) housed in similar conditions. First, we noted that the level of acoustic variability and individual distinctiveness found in several call types was related to their importance in social functioning. Contact calls, essential to intra-group cohesion, were the most individually distinctive regardless of the species, while threat calls were more structurally variable in mangabeys, the most "despotic" of our three species. Second, we found a parallel between the degree of complexity of the species' social structure and the size, diversity, and usage of its vocal repertoire. Mangabeys (most complex social structure) called twice as often as guenons and displayed the largest and most complex repertoire. De Brazza's monkeys (simplest social structure) displayed the smallest and simplest repertoire. Campbell's monkeys displayed an intermediate pattern. Providing evidence of higher levels of vocal variability in species presenting a more complex social system, our results are in line with the theory of a social-vocal coevolution of communicative abilities, opening new perspectives for comparative research on the evolution of communication systems in different animal taxa.

  14. Cryptosporidium spp., Giardia intestinalis, and Enterocytozoon bieneusi in Captive Non-Human Primates in Qinling Mountains.

    PubMed

    Du, Shuai-Zhi; Zhao, Guang-Hui; Shao, Jun-Feng; Fang, Yan-Qin; Tian, Ge-Ru; Zhang, Long-Xian; Wang, Rong-Jun; Wang, Hai-Yan; Qi, Meng; Yu, San-Ke

    2015-08-01

    Non-human primates (NHPs) are confirmed as reservoirs of Cryptosporidium spp., Giardia intestinalis, and Enterocytozoon bieneusi. In this study, 197 fresh fecal samples from 8 NHP species in Qinling Mountains, northwestern China, were collected and examined using multilocus sequence typing (MLST) method. The results showed that 35 (17.8%) samples were positive for tested parasites, including Cryptosporidium spp. (3.0%), G. intestinalis (2.0%), and E. bieneusi (12.7%). Cryptosporidium spp. were detected in 6 fecal samples of Macaca mulatta, and were identified as C. parvum (n=1) and C. andersoni (n=5). Subtyping analysis showed Cryptosporidium spp. belonged to the C. andersoni MLST subtype (A4, A4, A4, and A1) and C. parvum 60 kDa glycoprotein (gp60) subtype IId A15G2R1. G. intestinalis assemblage E was detected in 3 M. mulatta and 1 Saimiri sciureus. Intra-variations were observed at the triose phosphate isomerase (tpi), beta giardin (bg), and glutamate dehydrogenase (gdh) loci, with 3, 1, and 2 new subtypes found in respective locus. E. bieneusi was found in Cercopithecus neglectus (25.0%), Papio hamadrayas (16.7%), M. mulatta (16.3%), S. sciureus (10%), and Rhinopithecus roxellana (9.5%), with 5 ribosomal internal transcribed spacer (ITS) genotypes: 2 known genotypes (D and BEB6) and 3 novel genotypes (MH, XH, and BSH). These findings indicated the presence of zoonotic potential of Cryptosporidium spp. and E. bieneusi in NHPs in Qinling Mountains. This is the first report of C. andersoni in NHPs. The present study provided basic information for control of cryptosporidiosis, giardiasis, and microsporidiosis in human and animals in this area.

  15. Anatomical, BOLD, blood-flow MRI of non-human primate (baboon) retina

    PubMed Central

    Zhang, Yi; Wey, Hsiao-Ying; Nateras, Oscar San Emeterio; Peng, Qi; De La Garza, Bryan H.; Duong, Timothy Q

    2011-01-01

    The goal of this study was to demonstrate high-resolution anatomical, BOLD (blood-oxygenation-level-dependent), and blood-flow (BF) MRI on large non-human primate (NHP) retinas using a 3-Tesla clinical scanner as a first step toward translation. Baboon was chosen because of its evolutionary similarity to human. Anesthetized preparation, free of eye-movement artifacts, was used to evaluate clinical scanner hardware feasibility. Anatomical MRI (0.1×0.2×2.0 mm) before contrast-agent injection detected three alternating bright-dark-bright layers. The hyperintense inner strip nearest to the vitreous was enhanced by an intravascular contrast agent, likely included the ganglion and bipolar cell layer and the embedded retinal vessels. The hypointense middle strip showed no contrast enhancement, likely included the avascular outer unclear layer and photoreceptor segments. The hyperintense outer strip showed contrast enhancement, likely corresponded to the choroid vascular layer. In the posterior retina, the total thickness including the choroid was 617±101µm (±SD, n=7). BOLD fMRI (0.3×0.6×2.0 mm) of oxygen inhalation relative to air increased 6.5±1.4%. Basal BF (2×2×2mm) was 83±30mL/100g/min (air), and hypercapnia increased BF by 25±9% (P<0.05). This study demonstrates multimodal MRI to image anatomy, physiology and function on large NHP retinas using a clinical scanner, offering encouraging data to explore human applications. PMID:21360746

  16. Scanning electron microscopy of chronically implanted intracortical microelectrode arrays in non-human primates

    NASA Astrophysics Data System (ADS)

    Barrese, James C.; Aceros, Juan; Donoghue, John P.

    2016-04-01

    Objective. Signal attenuation is a major problem facing intracortical sensors for chronic neuroprosthetic applications. Many studies suggest that failure is due to gliosis around the electrode tips, however, mechanical and material causes of failure are often overlooked. The purpose of this study was to investigate the factors contributing to progressive signal decline by using scanning electron microscopy (SEM) to visualize structural changes in chronically implanted arrays and histology to examine the tissue response at corresponding implant sites. Approach. We examined eight chronically implanted intracortical microelectrode arrays (MEAs) explanted from non-human primates at times ranging from 37 to 1051 days post-implant. We used SEM, in vivo neural recordings, and histology (GFAP, Iba-1, NeuN). Three MEAs that were never implanted were also imaged as controls. Main results. SEM revealed progressive corrosion of the platinum electrode tips and changes to the underlying silicon. The parylene insulation was prone to cracking and delamination, and in some instances the silicone elastomer also delaminated from the edges of the MEA. Substantial tissue encapsulation was observed and was often seen growing into defects in the platinum and parylene. These material defects became more common as the time in vivo increased. Histology at 37 and 1051 days post-implant showed gliosis, disruption of normal cortical architecture with minimal neuronal loss, and high Iba-1 reactivity, especially within the arachnoid and dura. Electrode tracts were either absent or barely visible in the cortex at 1051 days, but were seen in the fibrotic encapsulation material suggesting that the MEAs were lifted out of the brain. Neural recordings showed a progressive drop in impedance, signal amplitude, and viable channels over time. Significance. These results provide evidence that signal loss in MEAs is truly multifactorial. Gliosis occurs in the first few months after implantation but does

  17. Scanning electron microscopy of chronically implanted intracortical microelectrode arrays in non-human primates.

    PubMed

    Barrese, James C; Aceros, Juan; Donoghue, John P

    2016-04-01

    Signal attenuation is a major problem facing intracortical sensors for chronic neuroprosthetic applications. Many studies suggest that failure is due to gliosis around the electrode tips, however, mechanical and material causes of failure are often overlooked. The purpose of this study was to investigate the factors contributing to progressive signal decline by using scanning electron microscopy (SEM) to visualize structural changes in chronically implanted arrays and histology to examine the tissue response at corresponding implant sites. We examined eight chronically implanted intracortical microelectrode arrays (MEAs) explanted from non-human primates at times ranging from 37 to 1051 days post-implant. We used SEM, in vivo neural recordings, and histology (GFAP, Iba-1, NeuN). Three MEAs that were never implanted were also imaged as controls. SEM revealed progressive corrosion of the platinum electrode tips and changes to the underlying silicon. The parylene insulation was prone to cracking and delamination, and in some instances the silicone elastomer also delaminated from the edges of the MEA. Substantial tissue encapsulation was observed and was often seen growing into defects in the platinum and parylene. These material defects became more common as the time in vivo increased. Histology at 37 and 1051 days post-implant showed gliosis, disruption of normal cortical architecture with minimal neuronal loss, and high Iba-1 reactivity, especially within the arachnoid and dura. Electrode tracts were either absent or barely visible in the cortex at 1051 days, but were seen in the fibrotic encapsulation material suggesting that the MEAs were lifted out of the brain. Neural recordings showed a progressive drop in impedance, signal amplitude, and viable channels over time. These results provide evidence that signal loss in MEAs is truly multifactorial. Gliosis occurs in the first few months after implantation but does not prevent useful recordings for several years

  18. Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates

    NASA Astrophysics Data System (ADS)

    Barrese, James C.; Rao, Naveen; Paroo, Kaivon; Triebwasser, Corey; Vargas-Irwin, Carlos; Franquemont, Lachlan; Donoghue, John P.

    2013-12-01

    systematic early increases, which did not appear to affect recording quality, followed by a slow decline over years. The combination of slowly falling impedance and signal quality in these arrays indicates that insulating material failure is the most significant factor. Significance. This is the first long-term failure mode analysis of an emerging BCI technology in a large series of non-human primates. The classification system introduced here may be used to standardize how neuroprosthetic failure modes are evaluated. The results demonstrate the potential for these arrays to record for many years, but achieving reliable sensors will require replacing connectors with implantable wireless systems, controlling the meningeal reaction, and improving insulation materials. These results will focus future research in order to create clinical neuroprosthetic sensors, as well as valuable research tools, that are able to safely provide reliable neural signals for over a decade.

  19. Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43

    PubMed Central

    Uchida, Azusa; Sasaguri, Hiroki; Kimura, Nobuyuki; Tajiri, Mio; Ohkubo, Takuya; Ono, Fumiko; Sakaue, Fumika; Kanai, Kazuaki; Hirai, Takashi; Sano, Tatsuhiko; Shibuya, Kazumoto; Kobayashi, Masaki; Yamamoto, Mariko; Yokota, Shigefumi; Kubodera, Takayuki; Tomori, Masaki; Sakaki, Kyohei; Enomoto, Mitsuhiro; Hirai, Yukihiko; Kumagai, Jiro; Yasutomi, Yasuhiro; Mochizuki, Hideki; Kuwabara, Satoshi; Uchihara, Toshiki; Mizusawa, Hidehiro

    2012-01-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and

  20. Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates.

    PubMed

    Barrese, James C; Rao, Naveen; Paroo, Kaivon; Triebwasser, Corey; Vargas-Irwin, Carlos; Franquemont, Lachlan; Donoghue, John P

    2013-12-01

    not appear to affect recording quality, followed by a slow decline over years. The combination of slowly falling impedance and signal quality in these arrays indicates that insulating material failure is the most significant factor. This is the first long-term failure mode analysis of an emerging BCI technology in a large series of non-human primates. The classification system introduced here may be used to standardize how neuroprosthetic failure modes are evaluated. The results demonstrate the potential for these arrays to record for many years, but achieving reliable sensors will require replacing connectors with implantable wireless systems, controlling the meningeal reaction, and improving insulation materials. These results will focus future research in order to create clinical neuroprosthetic sensors, as well as valuable research tools, that are able to safely provide reliable neural signals for over a decade.

  1. Scanning electron microscopy of chronically implanted intracortical microelectrode arrays in non-human primates

    PubMed Central

    Barrese, James C; Aceros, Juan; Donoghue, John P

    2016-01-01

    Objective Signal attenuation is a major problem facing intracortical sensors for chronic neuroprosthetic applications. Many studies suggest that failure is due to gliosis around the electrode tips, however, mechanical and material causes of failure are often overlooked. The purpose of this study was to investigate the factors contributing to progressive signal decline by using scanning electron microscopy (SEM) to visualize structural changes in chronically implanted arrays and histology to examine the tissue response at corresponding implant sites. Approach We examined eight chronically implanted intracortical microelectrode arrays (MEAs) explanted from non-human primates at times ranging from 37 to 1051 days post-implant. We used SEM, in vivo neural recordings, and histology (GFAP, Iba-1, NeuN). Three MEAs that were never implanted were also imaged as controls. Main results SEM revealed progressive corrosion of the platinum electrode tips and changes to the underlying silicon. The parylene insulation was prone to cracking and delamination, and in some instances the silicone elastomer also delaminated from the edges of the MEA. Substantial tissue encapsulation was observed and was often seen growing into defects in the platinum and parylene. These material defects became more common as the time in vivo increased. Histology at 37 and 1051 days post-implant showed gliosis, disruption of normal cortical architecture with minimal neuronal loss, and high Iba-1 reactivity, especially within the arachnoid and dura. Electrode tracts were either absent or barely visible in the cortex at 1051 days, but were seen in the fibrotic encapsulation material suggesting that the MEAs were lifted out of the brain. Neural recordings showed a progressive drop in impedance, signal amplitude, and viable channels over time. Significance These results provide evidence that signal loss in MEAs is truly multifactorial. Gliosis occurs in the first few months after implantation but does not

  2. Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43.

    PubMed

    Uchida, Azusa; Sasaguri, Hiroki; Kimura, Nobuyuki; Tajiri, Mio; Ohkubo, Takuya; Ono, Fumiko; Sakaue, Fumika; Kanai, Kazuaki; Hirai, Takashi; Sano, Tatsuhiko; Shibuya, Kazumoto; Kobayashi, Masaki; Yamamoto, Mariko; Yokota, Shigefumi; Kubodera, Takayuki; Tomori, Masaki; Sakaki, Kyohei; Enomoto, Mitsuhiro; Hirai, Yukihiko; Kumagai, Jiro; Yasutomi, Yasuhiro; Mochizuki, Hideki; Kuwabara, Satoshi; Uchihara, Toshiki; Mizusawa, Hidehiro; Yokota, Takanori

    2012-03-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and

  3. Distinct Expression Patterns Of Causative Genes Responsible For Hereditary Progressive Hearing Loss In Non-Human Primate Cochlea.

    PubMed

    Hosoya, Makoto; Fujioka, Masato; Ogawa, Kaoru; Okano, Hideyuki

    2016-02-26

    Hearing impairment is the most frequent sensory deficit in humans. Deafness genes, which harbor pathogenic mutations that have been identified in families with hereditary hearing loss, are commonly expressed in the auditory end organ or the cochlea and may contribute to normal hearing function, yet some of the mouse models carrying these mutations fail to recapitulate the hearing loss phenotype. In this study, we find that distinct expression patterns of those deafness genes in the cochlea of a non-human primate, the common marmoset (Callithrix jacchus). We examined 20 genes whose expression in the cochlea has already been reported. The deafness genes GJB3, CRYM, GRHL2, DFNA5, and ATP6B1 were expressed in marmoset cochleae in patterns different from those in mouse cochleae. Of note, all those genes are causative for progressive hearing loss in humans, but not in mice. The other tested genes, including the deafness gene COCH, in which mutation recapitulates deafness in mice, were expressed in a similar manner in both species. The result suggests that the discrepancy in the expression between rodents and primates may account for the phenotypic difference. This limitation of the rodent models can be bypassed by using non-human primate models such as the marmoset.

  4. An autonomous, automated and mobile device to concurrently assess several cognitive functions in group-living non-human primates.

    PubMed

    Fizet, Jonas; Rimele, Adam; Pebayle, Thierry; Cassel, Jean-Christophe; Kelche, Christian; Meunier, Hélène

    2017-07-31

    Research methods in cognitive neuroscience using non-human primates have undergone notable changes over the last decades. Recently, several research groups have described freely accessible devices equipped with a touchscreen interface. Two characteristics of such systems are of particular interest: some apparatuses include automated identification of subjects, while others are mobile. Here, we designed, tested and validated an experimental system that, for the first time, combine automatization and mobility. Moreover, our system allows autonomous learning and testing of cognitive performance in group-living subjects, including follow-up assessments. The mobile apparatus is designed to be available 24h a day, 7days a week, in a typical confined primate breeding and housing facility. Here we present as proof of concept, the results of two pilot studies. We report that rhesus macaques (Macaca mulatta) learned the tasks rapidly and achieved high-level of stable performance. Approaches of this kind should be developed for future pharmacological and biomedical studies in non-human primates. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Intravenously injected Newcastle disease virus in non-human primates is safe to use for oncolytic virotherapy.

    PubMed

    Buijs, P R A; van Amerongen, G; van Nieuwkoop, S; Bestebroer, T M; van Run, P R W A; Kuiken, T; Fouchier, R A M; van Eijck, C H J; van den Hoogen, B G

    2014-11-01

    Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic potential. Detailed preclinical information regarding the safety of oncolytic NDV is scarce. In this study, we evaluated the toxicity, biodistribution and shedding of intravenously injected oncolytic NDVs in non-human primates (Macaca fascicularis). Two animals were injected with escalating doses of a non-recombinant vaccine strain, a recombinant lentogenic strain or a recombinant mesogenic strain. To study transmission, naive animals were co-housed with the injected animals. Injection with NDV did not lead to severe illness in the animals or abnormalities in hematologic or biochemistry measurements. Injected animals shed low amounts of virus, but this did not lead to seroconversion of the contact animals. Postmortem evaluation demonstrated no pathological changes or evidence of virus replication. This study demonstrates that NDV generated in embryonated chicken eggs is safe for intravenous administration to non-human primates. In addition, our study confirmed results from a previous report that naïve primate and human sera are able to neutralize egg-generated NDV. We discuss the implications of these results for our study and the use of NDV for virotherapy.

  6. Distinct Expression Patterns Of Causative Genes Responsible For Hereditary Progressive Hearing Loss In Non-Human Primate Cochlea

    PubMed Central

    Hosoya, Makoto; Fujioka, Masato; Ogawa, Kaoru; Okano, Hideyuki

    2016-01-01

    Hearing impairment is the most frequent sensory deficit in humans. Deafness genes, which harbor pathogenic mutations that have been identified in families with hereditary hearing loss, are commonly expressed in the auditory end organ or the cochlea and may contribute to normal hearing function, yet some of the mouse models carrying these mutations fail to recapitulate the hearing loss phenotype. In this study, we find that distinct expression patterns of those deafness genes in the cochlea of a non-human primate, the common marmoset (Callithrix jacchus). We examined 20 genes whose expression in the cochlea has already been reported. The deafness genes GJB3, CRYM, GRHL2, DFNA5, and ATP6B1 were expressed in marmoset cochleae in patterns different from those in mouse cochleae. Of note, all those genes are causative for progressive hearing loss in humans, but not in mice. The other tested genes, including the deafness gene COCH, in which mutation recapitulates deafness in mice, were expressed in a similar manner in both species. The result suggests that the discrepancy in the expression between rodents and primates may account for the phenotypic difference. This limitation of the rodent models can be bypassed by using non-human primate models such as the marmoset. PMID:26915689

  7. A sexually dimorphic peptidergic system in the lower spinal cord controlling penile function in non-human primates.

    PubMed

    Ito, T; Oti, T; Takanami, K; Satoh, K; Ueda, Y; Sakamoto, T; Sakamoto, H

    2017-09-12

    Experimental animal study. Although a population of gastrin-releasing peptide (GRP) neurons in the lumbar spinal cord has an important role in erection and ejaculation in rats, little information exists on this GRP system in primates. To identify the male-specific GRP system in the primate spinal cord, we studied the lumbosacral cord in macaque monkeys as a non-human primate model. University laboratory in Japan. To determine the gene sequence of GRP precursors, the rhesus macaque monkey genomic sequence data were searched, followed by phylogenetic analysis. Subsequently, immunocytochemical analysis for GRP was performed in the monkey spinal cord. We have used bioinformatics to identify the ortholog gene for GRP precursor in macaque monkeys. Phylogenetic analysis suggested that primate prepro-GRP is separated from that of other mammalian species and clustered to an independent branch as primates. Immunocytochemistry for GRP further demonstrated that male-dominant sexual dimorphism was found in the spinal GRP system in monkeys as in rodents. We have demonstrated in macaque monkeys that the GRP system in the lower spinal cord shows male-specific dimorphism and may have an important role in penile functions not only in rodents but also in primates. Tissues of Nihonzaru (Japanese macaque monkeys) were provided in part by National Institutes of Natural Sciences (NINS) through the National Bio-Resource Project (NBRP) of the MEXT, Japan. This work was supported in part by KAKENHI from the Japan Society for the Promotion of Science (JSPS) (to KT; 15KK0343, 15J40220 and HS; 15K15202, 15KK0257, 15H05724).Spinal Cord advance online publication, 12 September 2017; doi:10.1038/sc.2017.105.

  8. A comparative study of the trabecular bony architecture of the talus in humans, non-human primates, and Australopithecus.

    PubMed

    DeSilva, Jeremy M; Devlin, Maureen J

    2012-09-01

    This study tested the hypothesis that talar trabecular microarchitecture reflects the loading patterns in the primate ankle joint, to determine whether talar trabecular morphology might be useful for inferring locomotor behavior in fossil hominins. Trabecular microarchitecture was quantified in the anteromedial, anterolateral, posteromedial, and posterolateral quadrants of the talar body in humans and non-human primates using micro-computed tomography. Trabecular bone parameters, including bone volume fraction, trabecular number and thickness, and degree of anisotropy differed between primates, but not in a manner entirely consistent with hypotheses derived from locomotor kinematics. Humans have highly organized trabecular struts across the entirety of the talus, consistent with the compressive loads incurred during bipedal walking. Chimpanzees possess a high bone volume fraction, consisting of plate-like trabecular struts. Orangutan tali are filled with a high number of thin, connected trabeculae, particularly in the anterior portion of the talus. Gorillas and baboons have strikingly similar internal architecture of the talus. Intraspecific analyses revealed no regional differences in trabecular architecture unique to bipedal humans. Of the 22 statistically significant regional differences in the human talus, all can also be found in other primates. Trabecular thickness, number, spacing, and connectivity density had the same regional relationship in the talus of humans, chimpanzees, gorillas, and baboons, suggesting a deeply conserved architecture in the primate talus. Australopithecus tali are human-like in most respects, differing most notably in having more oriented struts in the posteromedial quadrant of the body compared with the posterolateral quadrant. Though this result could mean that australopiths loaded their ankles in a unique manner during bipedal gait, the regional variation in degree of anisotropy was similar in humans, chimpanzees, and gorillas

  9. Application of the genome editing tool CRISPR/Cas9 in non-human primates

    PubMed Central

    LUO, Xin; LI, Min; SU, Bing

    2016-01-01

    In the past three years, RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system has been used to facilitate efficient genome editing in many model and non-model animals. However, its application in nonhuman primates is still at the early stage, though in view of the similarities in anatomy, physiology, behavior and genetics, closely related nonhuman primates serve as optimal models for human biology and disease studies. In this review, we summarize the current proceedings of gene editing using CRISPR/Cas9 in nonhuman primates. PMID:27469252

  10. Plasma sphingolipids are biomarkers of metabolic syndrome in non-human primates maintained on a Western-style diet.

    PubMed

    Brozinick, J T; Hawkins, E; Hoang Bui, H; Kuo, M-S; Tan, B; Kievit, P; Grove, K

    2013-08-01

    The intake of a Western diet enriched in animal fat has been shown to be a major risk factor for Type 2 diabetes and obesity. Previous rodent studies have indicated that these conditions may be triggered by the accumulation of the sphingolipid ceramide in insulin-sensitive tissues. However, data are lacking in this regard from both humans and non-human primates. Here we have investigated the relationship between plasma ceramides and metabolic syndrome in Rhesus macaques fed a high-fat and high-fructose (HFFD) 'western' diet. We investigated this relationship in cohorts of monkeys fed a HFFD for a period of 8 months to 5 years. Animals were classified as control, pre-diabetic or diabetic based on fasting plasma parameters and insulin sensitivity. HFFD treatment produced significant increases in body weight and body fat and also resulted in a decline in insulin sensitivity. In parallel to the reduction in insulin sensitivity, significant increases in both plasma ceramide and dihydroceramide levels were observed, which further increased as animals progressed to the diabetic state. Plasma levels of the rare sphingolipid C18:0 deoxysphinganine, a marker of increased metabolic flux through serine palmitoyl transferase (SPT), were also elevated in both pre- and diabetic animals. Furthermore, plasma serine levels were significantly elevated in diabetic monkeys, which may indicate a shift in SPT substrate selectivity from serine to alanine or glycine. In contrast, branch chain amino acids were unchanged in pre-diabetic non-human primates, and only plasma valine levels were elevated in diabetic animals. Together, these data indicate that HFFD induces de novo synthesis of ceramides in non-human primates, and that increased production of plasma ceramides is significantly correlated with the decline in insulin sensitivity.

  11. Is Alpha-Synuclein Loss-of-Function a Contributor to Parkinsonian Pathology? Evidence from Non-human Primates

    PubMed Central

    Collier, Timothy J.; Redmond, D. Eugene; Steece-Collier, Kathy; Lipton, Jack W.; Manfredsson, Fredric P.

    2016-01-01

    Accumulation of alpha-synuclein (α-syn) in Lewy bodies and neurites of midbrain dopamine neurons is diagnostic for Parkinson's disease (PD), leading to the proposal that PD is a toxic gain-of-function synucleinopathy. Here we discuss the alternative viewpoint that α-syn displacement from synapses by misfolding and aggregation results in a toxic loss-of-function. In support of this hypothesis we provide evidence from our pilot study demonstrating that knockdown of endogenous α-syn in dopamine neurons of non-human primates reproduces the pattern of nigrostriatal degeneration characteristic of PD. PMID:26858591

  12. First report of yellow fever virus in non-human primates in the State of Paraná, Brazil.

    PubMed

    Tranquilin, Marcos Vinícius; Lehmkuhl, Ricardo Coelho; Maron, Angela; Silva, Lineu Roberto da; Ziliotto, Liane; Seki, Meire Christina; Salomon, Gabriela Ronchi; Carrasco, Adriano de Oliveira Torres

    2013-01-01

    Sylvatic yellow fever is a zoonosis associated mainly with wild animals, especially those in the genus Alouatta, that act as the source of infection. Once infected, these animals pass the disease on to humans by way of an infected mosquito belonging to the genera Aedes, Haemagogus, or Sabethes. The present study is the first report of a case of yellow fever in non-human primates (NHP) in the State of Paraná, Brazil. After the case was diagnosed, several prophylactic measures were adopted to prevent outbreaks of the disease in humans.

  13. Magnetic resonance imaging of perfusion–diffusion mismatch in rodent and non-human primate stroke models

    PubMed Central

    Duong, Timothy Q.

    2013-01-01

    Stroke is a leading cause of death and long-term disability. Non-invasive magnetic resonance imaging (MRI) has been widely used for the early detection of ischemic stroke and the longitudinal monitoring of novel treatment strategies. Recent advances in MRI techniques have enabled improved sensitivity and specificity to detecting ischemic brain injury and monitoring functional recovery. This review describes recent progresses in the development and application of multimodal MRI and image analysis techniques to study experimental stroke in rats and non-human primates. PMID:23594679

  14. Magnetic resonance imaging of perfusion-diffusion mismatch in rodent and non-human primate stroke models.

    PubMed

    Duong, Timothy Q

    2013-06-01

    Stroke is a leading cause of death and long-term disability. Non-invasive magnetic resonance imaging (MRI) has been widely used for the early detection of ischemic stroke and the longitudinal monitoring of novel treatment strategies. Recent advances in MRI techniques have enabled improved sensitivity and specificity to detecting ischemic brain injury and monitoring functional recovery. This review describes recent progresses in the development and application of multimodal MRI and image analysis techniques to study experimental stroke in rats and non-human primates.

  15. Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates

    PubMed Central

    Barrese, James C; Rao, Naveen; Paroo, Kaivon; Triebwasser, Corey; Vargas-Irwin, Carlos; Franquemont, Lachlan; Donoghue, John P

    2016-01-01

    systematic early increases, which did not appear to affect recording quality, followed by a slow decline over years. The combination of slowly falling impedance and signal quality in these arrays indicate that insulating material failure is the most significant factor. Significance This is the first long-term failure mode analysis of an emerging BCI technology in a large series of non-human primates. The classification system introduced here may be used to standardize how neuroprosthetic failure modes are evaluated. The results demonstrate the potential for these arrays to record for many years, but achieving reliable sensors will require replacing connectors with implantable wireless systems, controlling the meningeal reaction, and improving insulation materials. These results will focus future research in order to create clinical neuroprosthetic sensors, as well as valuable research tools, that are able to safely provide reliable neural signals for over a decade. PMID:24216311

  16. Using naturalistic utterances to investigate vocal communication processing and development in human and non-human primates

    PubMed Central

    Talkington, William J.; Taglialatela, Jared P.; Lewis, James W.

    2013-01-01

    Humans and several non-human primates possess cortical regions that are most sensitive to vocalizations produced by their own kind (conspecifics). However, the use of speech and other broadly defined categories of behaviorally relevant natural sounds has led to many discrepancies regarding where voice-sensitivity occurs, and more generally the identification of cortical networks, “proto-networks” or protolanguage networks, and pathways that may be sensitive or selective for certain aspects of vocalization processing. In this prospective review we examine different approaches for exploring vocal communication processing, including pathways that may be, or become, specialized for conspecific utterances. In particular, we address the use of naturally produced non-stereotypical vocalizations (mimicry of other animal calls) as another category of vocalization for use with human and non-human primate auditory systems. We focus this review on two main themes, including progress and future ideas for studying vocalization processing in great apes (chimpanzees) and in very early stages of human development, including infants and fetuses. Advancing our understanding of the fundamental principles that govern the evolution and early development of cortical pathways for processing non-verbal communication utterances is expected to lead to better diagnoses and early intervention strategies in children with communication disorders, improve rehabilitation of communication disorders resulting from brain injury, and develop new strategies for intelligent hearing aid and implant design that can better enhance speech signals in noisy environments. PMID:23994296

  17. Good gibbons and evil macaques: a historical review on cognitive features of non-human primates in Chinese traditional culture.

    PubMed

    Zhang, Peng

    2015-07-01

    For several thousand years the ancient Chinese have accumulated rich knowledge, in the form of written literature and folklore, on the non-human primates widely distributed in China. I have used critical text analysis and discourse analysis to clarify when and how ancient Chinese distinguished gibbons from macaques. I divided the progress into four main stages, the Pre-Shang to Shang dynasty (before 1046 BC), the Zhou to Han dynasty (1046 BC-220 AD), the six dynasties to Song dynasty (220-1279 AD), and the Yuan to Qing dynasties (1279-1840 AD). I found that China's traditional cognition of gibbons and macaques emphasized the appearance of animals, organoleptic performance, or even whether or not their behavior was "moral". They described them as human-like animals by ethical standards but ignored the species itself. This kind of cognitive style actually embodies the "pursuit of goodness", which is the feature of Chinese traditional culture. This study presents some original views on Chinese traditional knowledge of non-human primates.

  18. Biocompatibility Assessment of Detonation Nanodiamond in Non-Human Primates and Rats Using Histological, Hematologic, and Urine Analysis.

    PubMed

    Moore, Laura; Yang, Junyu; Lan, Thanh T Ha; Osawa, Eiji; Lee, Dong-Keun; Johnson, William D; Xi, Jianzhong; Chow, Edward Kai-Hua; Ho, Dean

    2016-08-23

    Detonation nanodiamonds (DNDs) have been widely explored for biomedical applications ranging from cancer therapy to magnetic resonance imaging due to several promising properties. These include faceted surfaces that mediate potent drug binding and water coordination that have resulted in marked enhancements to the efficacy and safety of drug delivery and imaging. In addition, scalable processing of DNDs yields uniform particles. Furthermore, a broad spectrum of biocompatibility studies has shown that DNDs appear to be well-tolerated. Prior to the clinical translation of DNDs for indications that are addressed via intravenous administration, comprehensive assessment of DND safety in both small and large animal preclinical models is needed. This article reports the results of a DND biocompatibility study in both non-human primates and rats. The rat study was performed as a multiple dose subacute investigation in two cohorts that lasted for 2 weeks and included histological, serum, and urine analysis. The non-human primate study was performed as a dual gender, multiple dose, and long-term investigation in both standard/clinically relevant and elevated dosing cohorts that lasted for 6 months and included comprehensive serum, urine, histological, and body weight analysis. The results from these studies indicate that NDs are well-tolerated at clinically relevant doses. Examination of dose-dependent changes in biomarker levels provides important guidance for the downstream in-human validation of DNDs for clinical drug delivery and imaging.

  19. Using naturalistic utterances to investigate vocal communication processing and development in human and non-human primates.

    PubMed

    Talkington, William J; Taglialatela, Jared P; Lewis, James W

    2013-11-01

    Humans and several non-human primates possess cortical regions that are most sensitive to vocalizations produced by their own kind (conspecifics). However, the use of speech and other broadly defined categories of behaviorally relevant natural sounds has led to many discrepancies regarding where voice-sensitivity occurs, and more generally the identification of cortical networks, "proto-networks" or protolanguage networks, and pathways that may be sensitive or selective for certain aspects of vocalization processing. In this prospective review we examine different approaches for exploring vocal communication processing, including pathways that may be, or become, specialized for conspecific utterances. In particular, we address the use of naturally produced non-stereotypical vocalizations (mimicry of other animal calls) as another category of vocalization for use with human and non-human primate auditory systems. We focus this review on two main themes, including progress and future ideas for studying vocalization processing in great apes (chimpanzees) and in very early stages of human development, including infants and fetuses. Advancing our understanding of the fundamental principles that govern the evolution and early development of cortical pathways for processing non-verbal communication utterances is expected to lead to better diagnoses and early intervention strategies in children with communication disorders, improve rehabilitation of communication disorders resulting from brain injury, and develop new strategies for intelligent hearing aid and implant design that can better enhance speech signals in noisy environments. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives".

  20. Molecular Detection of Plasmodium malariae/Plasmodium brasilianum in Non-Human Primates in Captivity in Costa Rica.

    PubMed

    Fuentes-Ramírez, Alicia; Jiménez-Soto, Mauricio; Castro, Ruth; Romero-Zuñiga, Juan José; Dolz, Gaby

    2017-01-01

    One hundred and fifty-two blood samples of non-human primates of thirteen rescue centers in Costa Rica were analyzed to determine the presence of species of Plasmodium using thick blood smears, semi-nested multiplex polymerase chain reaction (SnM-PCR) for species differentiation, cloning and sequencing for confirmation. Using thick blood smears, two samples were determined to contain the Plasmodium malariae parasite, with SnM-PCR, a total of five (3.3%) samples were positive to P. malariae, cloning and sequencing confirmed both smear samples as P. malariae. One sample amplified a larger and conserved region of 18S rDNA for the genus Plasmodium and sequencing confirmed the results obtained microscopically and through SnM-PCR tests. Sequencing and construction of a phylogenetic tree of this sample revealed that the P. malariae/P. brasilianum parasite (GenBank KU999995) found in a howler monkey (Alouatta palliata) is identical to that recently reported in humans in Costa Rica. The SnM-PCR detected P. malariae/P. brasilianum parasite in different non-human primate species in captivity and in various regions of the southern Atlantic and Pacific coast of Costa Rica. The similarity of the sequences of parasites found in humans and a monkey suggests that monkeys may be acting as reservoirs of P.malariae/P. brasilianum, for which reason it is important, to include them in control and eradication programs.

  1. Molecular Detection of Plasmodium malariae/Plasmodium brasilianum in Non-Human Primates in Captivity in Costa Rica

    PubMed Central

    Fuentes-Ramírez, Alicia; Jiménez-Soto, Mauricio; Castro, Ruth; Romero-Zuñiga, Juan José

    2017-01-01

    One hundred and fifty-two blood samples of non-human primates of thirteen rescue centers in Costa Rica were analyzed to determine the presence of species of Plasmodium using thick blood smears, semi-nested multiplex polymerase chain reaction (SnM-PCR) for species differentiation, cloning and sequencing for confirmation. Using thick blood smears, two samples were determined to contain the Plasmodium malariae parasite, with SnM-PCR, a total of five (3.3%) samples were positive to P. malariae, cloning and sequencing confirmed both smear samples as P. malariae. One sample amplified a larger and conserved region of 18S rDNA for the genus Plasmodium and sequencing confirmed the results obtained microscopically and through SnM-PCR tests. Sequencing and construction of a phylogenetic tree of this sample revealed that the P. malariae/P. brasilianum parasite (GenBank KU999995) found in a howler monkey (Alouatta palliata) is identical to that recently reported in humans in Costa Rica. The SnM-PCR detected P. malariae/P. brasilianum parasite in different non-human primate species in captivity and in various regions of the southern Atlantic and Pacific coast of Costa Rica. The similarity of the sequences of parasites found in humans and a monkey suggests that monkeys may be acting as reservoirs of P.malariae/P. brasilianum, for which reason it is important, to include them in control and eradication programs. PMID:28125696

  2. Encapsulating Non-Human Primate Multipotent Stromal Cells in Alginate via High Voltage for Cell-Based Therapies and Cryopreservation

    PubMed Central

    Gryshkov, Oleksandr; Pogozhykh, Denys; Hofmann, Nicola; Pogozhykh, Olena; Mueller, Thomas; Glasmacher, Birgit

    2014-01-01

    Alginate cell-based therapy requires further development focused on clinical application. To assess engraftment, risk of mutations and therapeutic benefit studies should be performed in an appropriate non-human primate model, such as the common marmoset (Callithrix jacchus). In this work we encapsulated amnion derived multipotent stromal cells (MSCs) from Callithrix jacchus in defined size alginate beads using a high voltage technique. Our results indicate that i) alginate-cell mixing procedure and cell concentration do not affect the diameter of alginate beads, ii) encapsulation of high cell numbers (up to 10×106 cells/ml) can be performed in alginate beads utilizing high voltage and iii) high voltage (15–30 kV) does not alter the viability, proliferation and differentiation capacity of MSCs post-encapsulation compared with alginate encapsulated cells produced by the traditional air-flow method. The consistent results were obtained over the period of 7 days of encapsulated MSCs culture and after cryopreservation utilizing a slow cooling procedure (1 K/min). The results of this work show that high voltage encapsulation can further be maximized to develop cell-based therapies with alginate beads in a non-human primate model towards human application. PMID:25259731

  3. Evolution of the sweetness receptor in primates. II. Gustatory responses of non-human primates to nine compounds known to be sweet in man.

    PubMed

    Nofre, C; Tinti, J M; Glaser, D

    1996-12-01

    The gustatory responses of nine compounds, namely glycine, D-phenylalanine, D-tryptophan, cyanosuosan, magapame, sucrononate, campame, cyclamate and superaspartame, all known as sweet in man, were studied in 41 species or subspecies of non-human primates, selected among Prosimii (Lemuridae and Lorisidae), Platyrrhini (Callitrichidae and Cebidae) and Catarrhini (Cercopithecidae, Hylobatidae and Pongidae). The first six compounds are generally sweet to all primates, which implies that they interact with the primate sweetness receptors essentially through constant recognition sites. Campame is sweet only to Cebidae and Catarrhini, cyclamate only to Catarrhini, superaspartame principally to Callitrichidae and Catarrhini, which implies that all these compounds interact with the receptors partly through variable recognition sites. From the present work, from other previous results (where notably it was observed that alitame is sweet to all primates, ampame only to Prosimii and Catarrhini, and aspartame only to Catarrhini), and from the multipoint attachment (MPA) theory of sweetness reception (as elaborated by Nofre and Tinti from a detailed study of structure-activity relationships of various sweeteners in man), it is inferred that the primate sweetness receptors are very likely made up of eight recognition sites, of which the first, second, third, fourth, seventh and eighth are constant, and the fifth and sixth variable. From these results and from the MPA theory, it is also inferred that the recognition sites of the primate sweetness receptors could be: Asp-1 or Glu-1, Lys-2, Asp-3 or Glu-3, Thr-4, X-5, X-6, Thr-7, Ser-8, where the variable recognition sites X-5 and X-6 would be: Ala-5 and Ala-6 for Callitrichidae, Ser-5 and Ala-6 for Cebidae, Ala-5 and Thr-6 for Prosimii, and Thr-5 and Thr-6 for Catarrhini. By using Tupaiidae (tree shrews) as a reference outgroup and by means of other structural and functional molecular considerations, it appears that Callitrichidae

  4. High-resolution imaging of the large non-human primate brain using microPET: a feasibility study

    NASA Astrophysics Data System (ADS)

    Naidoo-Variawa, S.; Hey-Cunningham, A. J.; Lehnert, W.; Kench, P. L.; Kassiou, M.; Banati, R.; Meikle, S. R.

    2007-11-01

    The neuroanatomy and physiology of the baboon brain closely resembles that of the human brain and is well suited for evaluating promising new radioligands in non-human primates by PET and SPECT prior to their use in humans. These studies are commonly performed on clinical scanners with 5 mm spatial resolution at best, resulting in sub-optimal images for quantitative analysis. This study assessed the feasibility of using a microPET animal scanner to image the brains of large non-human primates, i.e. papio hamadryas (baboon) at high resolution. Factors affecting image accuracy, including scatter, attenuation and spatial resolution, were measured under conditions approximating a baboon brain and using different reconstruction strategies. Scatter fraction measured 32% at the centre of a 10 cm diameter phantom. Scatter correction increased image contrast by up to 21% but reduced the signal-to-noise ratio. Volume resolution was superior and more uniform using maximum a posteriori (MAP) reconstructed images (3.2-3.6 mm3 FWHM from centre to 4 cm offset) compared to both 3D ordered subsets expectation maximization (OSEM) (5.6-8.3 mm3) and 3D reprojection (3DRP) (5.9-9.1 mm3). A pilot 18F-2-fluoro-2-deoxy-d-glucose ([18F]FDG) scan was performed on a healthy female adult baboon. The pilot study demonstrated the ability to adequately resolve cortical and sub-cortical grey matter structures in the baboon brain and improved contrast when images were corrected for attenuation and scatter and reconstructed by MAP. We conclude that high resolution imaging of the baboon brain with microPET is feasible with appropriate choices of reconstruction strategy and corrections for degrading physical effects. Further work to develop suitable correction algorithms for high-resolution large primate imaging is warranted.

  5. Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates.

    PubMed

    Elsworth, John D; Jentsch, J David; Vandevoort, Catherine A; Roth, Robert H; Redmond, D Eugene; Leranth, Csaba

    2013-03-01

    Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor. Some rodent studies have suggested that BPA can exert detrimental effects on brain development. However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development. Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates. Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus. Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus. In contrast, administration of BPA to juvenile vervet monkeys (14-18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity. These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA.

  6. Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates

    PubMed Central

    Elsworth, John D.; Jentsch, J. David; VandeVoort, Catherine A.; Roth, Robert H.; Redmond, D. Eugene; Leranth, Csaba

    2013-01-01

    Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor. Some rodent studies have suggested that BPA can exert detrimental effects on brain development. However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development. Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates. Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus. Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus. In contrast, administration of BPA to juvenile vervet monkeys (14–18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity. These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA. PMID:23337607

  7. An Evaluation of 20 Years of EU Framework Programme-Funded Immune-Mediated Inflammatory Translational Research in Non-Human Primates

    PubMed Central

    Haanstra, Krista G.; Jonker, Margreet; ‘t Hart, Bert A.

    2016-01-01

    Aging western societies are facing an increasing prevalence of chronic inflammatory and degenerative diseases for which often no effective treatments exist, resulting in increasing health-care expenditure. Despite high investments in drug development, the number of promising new drug candidates decreases. We propose that preclinical research in non-human primates can help to bridge the gap between drug discovery and drug prescription. Translational research covers various stages of drug development of which preclinical efficacy tests in valid animal models is usually the last stage. Preclinical research in non-human primates may be essential in the evaluation of new drugs or therapies when a relevant rodent model is not available. Non-human primate models for life-threatening or severely debilitating diseases in humans are available at the Biomedical Primate Research Centre (BPRC). These have been instrumental in translational research for several decades. In order to stimulate European health research and innovation from bench to bedside, the European Commission has invested heavily in access to non-human primate research for more than 20 years. BPRC has hosted European users in a series of transnational access programs covering a wide range of research areas with the common theme being immune-mediated inflammatory disorders. We present an overview of the results and give an account of the studies performed as part of European Union Framework Programme (EU FP)-funded translational non-human primate research performed at the BPRC. These data illustrate the value of translational non-human primate research for the development of new therapies and emphasize the importance of EU FP funding in drug development. PMID:27872622

  8. Detection of optogenetic stimulation in somatosensory cortex by non-human primates--towards artificial tactile sensation.

    PubMed

    May, Travis; Ozden, Ilker; Brush, Benjamin; Borton, David; Wagner, Fabien; Agha, Naubahar; Sheinberg, David L; Nurmikko, Arto V

    2014-01-01

    Neuroprosthesis research aims to enable communication between the brain and external assistive devices while restoring lost functionality such as occurs from stroke, spinal cord injury or neurodegenerative diseases. In future closed-loop sensorimotor prostheses, one approach is to use neuromodulation as direct stimulus to the brain to compensate for a lost sensory function and help the brain to integrate relevant information for commanding external devices via, e.g. movement intention. Current neuromodulation techniques rely mainly of electrical stimulation. Here we focus specifically on the question of eliciting a biomimetically relevant sense of touch by direct stimulus of the somatosensory cortex by introducing optogenetic techniques as an alternative to electrical stimulation. We demonstrate that light activated opsins can be introduced to target neurons in the somatosensory cortex of non-human primates and be optically activated to create a reliably detected sensation which the animal learns to interpret as a tactile sensation localized within the hand. The accomplishment highlighted here shows how optical stimulation of a relatively small group of mostly excitatory somatosensory neurons in the nonhuman primate brain is sufficient for eliciting a useful sensation from data acquired by simultaneous electrophysiology and from behavioral metrics. In this first report to date on optically neuromodulated behavior in the somatosensory cortex of nonhuman primates we do not yet dissect the details of the sensation the animals exerience or contrast it to those evoked by electrical stimulation, issues of considerable future interest.

  9. Long-Term Two-Photon Calcium Imaging of Neuronal Populations with Subcellular Resolution in Adult Non-human Primates.

    PubMed

    Sadakane, Osamu; Masamizu, Yoshito; Watakabe, Akiya; Terada, Shin-Ichiro; Ohtsuka, Masanari; Takaji, Masafumi; Mizukami, Hiroaki; Ozawa, Keiya; Kawasaki, Hiroshi; Matsuzaki, Masanori; Yamamori, Tetsuo

    2015-12-01

    Two-photon imaging with genetically encoded calcium indicators (GECIs) enables long-term observation of neuronal activity in vivo. However, there are very few studies of GECIs in primates. Here, we report a method for long-term imaging of a GECI, GCaMP6f, expressed from adeno-associated virus vectors in cortical neurons of the adult common marmoset (Callithrix jacchus), a small New World primate. We used a tetracycline-inducible expression system to robustly amplify neuronal GCaMP6f expression and up- and downregulate it for more than 100 days. We succeeded in monitoring spontaneous activity not only from hundreds of neurons three-dimensionally distributed in layers 2 and 3 but also from single dendrites and axons in layer 1. Furthermore, we detected selective activities from somata, dendrites, and axons in the somatosensory cortex responding to specific tactile stimuli. Our results provide a way to investigate the organization and plasticity of cortical microcircuits at subcellular resolution in non-human primates.

  10. Morphometric and Statistical Analysis of the Palmaris Longus Muscle in Human and Non-Human Primates

    PubMed Central

    Aversi-Ferreira, Roqueline A. G. M. F.; Bretas, Rafael Vieira; Maior, Rafael Souto; Davaasuren, Munkhzul; Paraguassú-Chaves, Carlos Alberto; Nishijo, Hisao; Aversi-Ferreira, Tales Alexandre

    2014-01-01

    The palmaris longus is considered a phylogenetic degenerate metacarpophalangeal joint flexor muscle in humans, a small vestigial forearm muscle; it is the most variable muscle in humans, showing variation in position, duplication, slips and could be reverted. It is frequently studied in papers about human anatomical variations in cadavers and in vivo, its variation has importance in medical clinic, surgery, radiological analysis, in studies about high-performance athletes, in genetics and anthropologic studies. Most studies about palmaris longus in humans are associated to frequency or case studies, but comparative anatomy in primates and comparative morphometry were not found in scientific literature. Comparative anatomy associated to morphometry of palmaris longus could explain the degeneration observed in this muscle in two of three of the great apes. Hypothetically, the comparison of the relative length of tendons and belly could indicate the pathway of the degeneration of this muscle, that is, the degeneration could be associated to increased tendon length and decreased belly from more primitive primates to those most derivate, that is, great apes to modern humans. In conclusion, in primates, the tendon of the palmaris longus increase from Lemuriformes to modern humans, that is, from arboreal to terrestrial primates and the muscle became weaker and tending to be missing. PMID:24860810

  11. Sources of variation in hair cortisol in wild and captive non-human primates.

    PubMed

    Fourie, Nicolaas H; Brown, Janine L; Jolly, Clifford J; Phillips-Conroy, Jane E; Rogers, Jeffrey; Bernstein, Robin M

    2016-04-01

    Hair cortisol analysis is a potentially powerful tool for evaluating adrenal function and chronic stress. However, the technique has only recently been applied widely to studies of wildlife, including primates, and there are numerous practical and technical factors that should be considered to ensure good quality data and the validity of results and conclusions. Here we report on various intrinsic and extrinsic sources of variation in hair cortisol measurements in wild and captive primates. Hair samples from both wild and captive primates revealed that age and sex can affect hair cortisol concentrations; these effects need to be controlled for when making comparisons between individual animals or populations. Hair growth rates also showed considerable inter-specific variation among a number of primate species. We describe technical limitations of hair analyses and variation in cortisol concentrations as a function of asynchronous hair growth, anatomical site of collection, and the amount and numbers of hair/s used for cortisol extraction. We discuss these sources of variation and their implications for proper study design and interpretation of results.

  12. Non-human Primate Schlafen11 Inhibits Production of Both Host and Viral Proteins.

    PubMed

    Stabell, Alex C; Hawkins, John; Li, Manqing; Gao, Xia; David, Michael; Press, William H; Sawyer, Sara L

    2016-12-01

    Schlafen11 (encoded by the SLFN11 gene) has been shown to inhibit the accumulation of HIV-1 proteins. We show that the SLFN11 gene is under positive selection in simian primates and is species-specific in its activity against HIV-1. The activity of human Schlafen11 is relatively weak compared to that of some other primate versions of this protein, with the versions encoded by chimpanzee, orangutan, gibbon, and marmoset being particularly potent inhibitors of HIV-1 protein production. Interestingly, we find that Schlafen11 is functional in the absence of infection and reduces protein production from certain non-viral (GFP) and even host (Vinculin and GAPDH) transcripts. This suggests that Schlafen11 may just generally block protein production from non-codon optimized transcripts. Because Schlafen11 is an interferon-stimulated gene with a broad ability to inhibit protein production from many host and viral transcripts, its role may be to create a general antiviral state in the cell. Interestingly, the strong inhibitors such as marmoset Schlafen11 consistently block protein production better than weak primate Schlafen11 proteins, regardless of the virus or host target being analyzed. Further, we show that the residues to which species-specific differences in Schlafen11 potency map are distinct from residues that have been targeted by positive selection. We speculate that the positive selection of SLFN11 could have been driven by a number of different factors, including interaction with one or more viral antagonists that have yet to be identified.

  13. Total Body Irradiation in the "Hematopoietic" Dose Range Induces Substantial Intestinal Injury in Non-Human Primates.

    PubMed

    Wang, Junru; Shao, Lijian; Hendrickson, Howard P; Liu, Liya; Chang, Jianhui; Luo, Yi; Seng, John; Pouliot, Mylene; Authier, Simon; Zhou, Daohong; Allaben, William; Hauer-Jensen, Martin

    2015-11-01

    The non-human primate has been a useful model for studies of human acute radiation syndrome (ARS). However, to date structural changes in various parts of the intestine after total body irradiation (TBI) have not been systematically studied in this model. Here we report on our current study of TBI-induced intestinal structural injury in the non-human primate after doses typically associated with hematopoietic ARS. Twenty-four non-human primates were divided into three groups: sham-irradiated control group; and total body cobalt-60 (60Co) 6.7 Gy gamma-irradiated group; and total body 60Co 7.4 Gy gamma-irradiated group. After animals were euthanized at day 4, 7 and 12 postirradiation, sections of small intestine (duodenum, proximal jejunum, distal jejunum and ileum) were collected and fixed in 10% formalin. The intestinal mucosal surface length, villus height and crypt depths were assessed by computer-assisted image analysis. Plasma citrulline levels were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total bone marrow cells were counted and hematopoietic stem/progenitor cells in bone marrow were analyzed by flow cytometer. Histopathologically, all segments exhibited conspicuous disappearance of plicae circulares and prominent atrophy of crypts and villi. Intestinal mucosal surface length was significantly decreased in all intestinal segments on day 4, 7 and 12 after irradiation (P < 0.02-P < 0.001). Villus height was significantly reduced in all segments on day 4 and 7 (P = 0.02-0.005), whereas it had recovered by day 12 (P > 0.05). Crypt depth was also significantly reduced in all segments on day 4, 7 and 12 after irradiation (P < 0.04-P < 0.001). Plasma citrulline levels were dramatically reduced after irradiation, consistent with intestinal mucosal injury. Both 6.7 and 7.4 Gy TBI reduced total number of bone marrow cells. And further analysis showed that the number and function of CD45(+)CD34(+) hematopoietic stem/progenitors in bone

  14. Perception and description of New World non-human primates in the travel literature of the fifteenth and sixteenth centuries: a critical review.

    PubMed

    Veracini, Cecilia; Teixeira, Dante Martins

    2017-01-01

    The current work presents the results of a review of most of the European diaries and travel chronicles containing reports of New World non-human primates dating from the discovery of America in 1492 until the end of the sixteenth century. We report the integral texts translated into English of these literary sources, giving a critical interpretation from a historical and scientific point of view. We note the ways these primates were perceived and described, with attention to the most important characteristics that were highlighted by the first explorers. Ethnotaxonomy and vernacular names used to designate non-human primates are also provided. This new body of knowledge, based largely on empirical reports full of details and first-hand observations, emerged as the first nucleus in the natural history of Neotropical Primates.

  15. Safety, immunogenicity, and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primates.

    PubMed

    Lukashevich, Igor S; Carrion, Ricardo; Salvato, Maria S; Mansfield, Keith; Brasky, Kathleen; Zapata, Juan; Cairo, Cristiana; Goicochea, Marco; Hoosien, Gia E; Ticer, Anysha; Bryant, Joseph; Davis, Harry; Hammamieh, Rasha; Mayda, Maria; Jett, Marti; Patterson, Jean

    2008-09-26

    A single injection of ML29 reassortant vaccine for Lassa fever induces low, transient viremia, and low or moderate levels of ML29 replication in tissues of common marmosets depending on the dose of the vaccination. The vaccination elicits specific immune responses and completely protects marmosets against fatal disease by induction of sterilizing cell-mediated immunity. DNA array analysis of human peripheral blood mononuclear cells from healthy donors exposed to ML29 revealed that gene expression patterns in ML29-exposed PBMC and control, media-exposed PBMC, clustered together confirming safety profile of the ML29 in non-human primates. The ML29 reassortant is a promising vaccine candidate for Lassa fever.

  16. Diffeomorphic registration with self-adaptive spatial regularization for the segmentation of non-human primate brains.

    PubMed

    Risser, Laurent; Dolius, Lionel; Fonta, Caroline; Mescam, Muriel

    2014-01-01

    Cerebral aging has been linked to structural and functional changes in the brain throughout life. Here, we study the marmoset, a small non-human primate, in order to get insights into the mechanisms of brain aging in normal and pathological conditions. Imaging the brain of small animals with techniques such as MRI, quickly becomes a challenging task when compared with human brain imaging. Very often, a simple pre-processing step such as brain extraction cannot be achieved with classical tools. In this paper, we propose a diffeomorphic registration algorithm, which makes use of learned constraints to propagate the manual segmentation of a marmoset brain template to other MR images of marmoset brains. The main methological contribution of our paper is to explore a new strategy to automatically tune the spatial regularization of the deformations. Results show that we obtain a robust segmentation of the brain, even for images with a low contrast.

  17. Route and method of delivery of DNA vaccine influence immune responses in mice and non-human primates.

    PubMed Central

    McCluskie, M. J.; Brazolot Millan, C. L.; Gramzinski, R. A.; Robinson, H. L.; Santoro, J. C.; Fuller, J. T.; Widera, G.; Haynes, J. R.; Purcell, R. H.; Davis, H. L.

    1999-01-01

    BACKGROUND: In spite of the large number of studies that have evaluated DNA-based immunization, few have directly compared the immune responses generated by different routes of immunization, particularly in non-human primates. Here we examine the ability of a hepatitis B surface antigen (HBsAg)-encoding plasmid to induce immune responses in mice and non-human primates (rhesus monkeys: Macaca mulatta) after delivery by a number of routes. MATERIALS AND METHODS: Eight different injected [intraperitoneal (IP), intradermal (ID), intravenous (IV), intramuscular (IM), intraperineal (IPER), subcutaneous (SC), sublingual (SL), vaginal wall (VW)] and six noninjected [intranasal inhalation (INH), intranasal instillation (INS), intrarectal (IR), intravaginal (IVAG), ocular (Oc), oral feeding (oral)] routes and the gene gun (GG) were used to deliver HBsAg-expressing plasmid DNA to BALB/c mice. Sera were assessed for HBsAg-specific antibodies (anti-HBs, IgG, IgG1, IgG2a) and cytotoxic T lymphocyte (CTL) activity measured. Three of the most commonly used routes (IM, ID, GG) were compared in rhesus monkeys, also using HBsAg-expressing vectors. Monkeys were immunized with short (0-, 4- and 8-week) or long (0-, 12- and 24-week) intervals between boosts, and in the case of GG, also with different doses, and their sera were assessed for anti-HBs. RESULTS: In one study, anti-HBs were detected in plasma of mice treated by five of eight of the injected and none of the six noninjected routes. The highest levels of anti-HBs were induced by IM and IV injections, although significant titers were also obtained with SL and ID. Each of these routes also induced CTL, as did IPER and VW and one noninjected route (INH) that failed to induce antibodies. In a second study, GG (1.6 microg) was compared to ID and IM (100 microg) delivery. Significant titers were obtained by all routes after only one boost, with the highest levels detected by IM. Delivery to the skin by GG induced exclusively IgG1

  18. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates

    NASA Astrophysics Data System (ADS)

    Veiseh, Omid; Doloff, Joshua C.; Ma, Minglin; Vegas, Arturo J.; Tam, Hok Hei; Bader, Andrew R.; Li, Jie; Langan, Erin; Wyckoff, Jeffrey; Loo, Whitney S.; Jhunjhunwala, Siddharth; Chiu, Alan; Siebert, Sean; Tang, Katherine; Hollister-Lock, Jennifer; Aresta-Dasilva, Stephanie; Bochenek, Matthew; Mendoza-Elias, Joshua; Wang, Yong; Qi, Merigeng; Lavin, Danya M.; Chen, Michael; Dholakia, Nimit; Thakrar, Raj; Lacík, Igor; Weir, Gordon C.; Oberholzer, Jose; Greiner, Dale L.; Langer, Robert; Anderson, Daniel G.

    2015-06-01

    The efficacy of implanted biomedical devices is often compromised by host recognition and subsequent foreign body responses. Here, we demonstrate the role of the geometry of implanted materials on their biocompatibility in vivo. In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals and plastics, significantly abrogated foreign body reactions and fibrosis when compared with smaller spheres. We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5-mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than five times longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules. Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved simply by tuning their spherical dimensions.

  19. Ageing as a primary risk factor for Parkinson’s disease: evidence from studies of non-human primates

    PubMed Central

    Collier, Timothy J.; Kanaan, Nicholas M.; Kordower, Jeffrey H.

    2012-01-01

    Ageing is the greatest risk factor for the development of Parkinson’s disease. However, the current dogma holds that cellular mechanisms that are associated with ageing of midbrain dopamine neurons and those that are related to dopamine neuron degeneration in Parkinson’s disease are unrelated. We propose, based on evidence from studies of non-human primates, that normal ageing and the degeneration of dopamine neurons in Parkinson’s disease are linked by the same cellular mechanisms and, therefore, that markers of cellular risk factors accumulate with age in a pattern that mimics the pattern of degeneration observed in Parkinson’s disease. We contend that ageing induces a pre-parkinsonian state, and that the cellular mechanisms of dopamine neuron demise during normal ageing are accelerated or exaggerated in Parkinson’s disease through a combination of genetic and environmental factors. PMID:21587290

  20. Non-human Primate Schlafen11 Inhibits Production of Both Host and Viral Proteins

    PubMed Central

    Stabell, Alex C.; Hawkins, John; Li, Manqing; Gao, Xia; David, Michael; Press, William H.; Sawyer, Sara L.

    2016-01-01

    Schlafen11 (encoded by the SLFN11 gene) has been shown to inhibit the accumulation of HIV-1 proteins. We show that the SLFN11 gene is under positive selection in simian primates and is species-specific in its activity against HIV-1. The activity of human Schlafen11 is relatively weak compared to that of some other primate versions of this protein, with the versions encoded by chimpanzee, orangutan, gibbon, and marmoset being particularly potent inhibitors of HIV-1 protein production. Interestingly, we find that Schlafen11 is functional in the absence of infection and reduces protein production from certain non-viral (GFP) and even host (Vinculin and GAPDH) transcripts. This suggests that Schlafen11 may just generally block protein production from non-codon optimized transcripts. Because Schlafen11 is an interferon-stimulated gene with a broad ability to inhibit protein production from many host and viral transcripts, its role may be to create a general antiviral state in the cell. Interestingly, the strong inhibitors such as marmoset Schlafen11 consistently block protein production better than weak primate Schlafen11 proteins, regardless of the virus or host target being analyzed. Further, we show that the residues to which species-specific differences in Schlafen11 potency map are distinct from residues that have been targeted by positive selection. We speculate that the positive selection of SLFN11 could have been driven by a number of different factors, including interaction with one or more viral antagonists that have yet to be identified. PMID:28027315

  1. The Contribution of Non-human Primate Models to the Development of Human Vaccines

    PubMed Central

    Rivera-Hernandez, Tania; Carnathan, Diane G.; Moyle, Peter M.; Toth, Istvan; West, Nicholas P.; Young, Paul L.; Silvestri, Guido; Walker, Mark J.

    2015-01-01

    The nonhuman primates (NHPs) model in biomedical research has contributed to the study of human infectious, autoimmune, oncogenic, and neurological diseases. This review focuses on the importance of NHP models in vaccine development for tuberculosis, pertussis, Dengue, group A streptococcus (Streptococcus pyogenes) infection, HIV infection, and certain diseases in the elderly (influenza, for example). From understanding disease pathogenesis and mechanisms of protection, to assessing vaccine safety and efficacy, we discuss selected cases where the importance of the use of NHP models is highlighted. PMID:25549702

  2. The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates

    PubMed Central

    Krivokrysenko, Vadim I.; Toshkov, Ilia A.; Gleiberman, Anatoli S.; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K.; Narizhneva, Natalya V.; Singh, Vijay K.; Whitnall, Mark H.; Purmal, Andrei A.; Shakhov, Alexander N.; Gudkov, Andrei V.; Feinstein, Elena

    2015-01-01

    There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1–48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40–60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters. PMID:26367124

  3. A multi-site array for combined local electrochemistry and electrophysiology in the non-human primate brain.

    PubMed

    Disney, Anita A; McKinney, Collin; Grissom, Larry; Lu, Xuekun; Reynolds, John H

    2015-11-30

    Currently, the primary technique employed in circuit-level study of the brain is electrophysiology, recording local field or action potentials (LFPs or APs). However most communication between neurons is chemical and the relationship between electrical activity within neurons and chemical signaling between them is not well understood in vivo, particularly for molecules that signal at least in part by non-synaptic transmission. We describe a multi-contact array and accompanying head stage circuit that together enable concurrent electrophysiological and electrochemical recording. The array is small (<200 μm) and can be assembled into a device of arbitrary length. It is therefore well-suited for use in all major in vivo model systems in neuroscience, including non-human primates where the large brain and need for daily insertion and removal of recording devices places particularly strict demands on design. We present a protocol for array fabrication. We then show that a device built in the manner described can record LFPs and perform enzyme-based amperometric detection of choline in the awake macaque monkey. Comparison with existing methods Existing methods allow single mode (electrophysiology or electrochemistry) recording. This system is designed for concurrent, dual-mode recording. It is also the only system designed explicitly to meet the challenges of recording in non-human primates. Our system offers the possibility for conducting in vivo studies in a range of species that examine the relationship between the electrical activity of neurons and their chemical environment, with exquisite spatial and temporal precision. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  4. A multi-site array for combined local electrochemistry and electrophysiology in the non-human primate brain

    PubMed Central

    Disney, Anita A; McKinney, Collin; Grissom, Larry; Lu, Xuekun; Reynolds, John H

    2015-01-01

    Background Currently, the primary technique employed in circuit-level study of the brain is electrophysiology, recording local field or action potentials (LFPs or APs). However most communication between neurons is chemical and the relationship between electrical activity within neurons and chemical signaling between them is not well understood in vivo, particularly for molecules that signal at least in part by non-synaptic transmission. New Method We describe a multi-contact array and accompanying head stage circuit that together enable concurrent electrophysiological and electrochemical recording. The array is small (<200μm) and can be assembled into a device of arbitrary length. It is therefore well-suited for use in all major in vivo model systems in neuroscience, including non-human primates where the large brain and need for daily insertion and removal of recording devices places particularly strict demands on design. Results We present a protocol for array fabrication. We then show that a device built in the manner described can record LFPs and perform enzyme-based amperometric detection of choline in the awake macaque monkey. Comparison with existing methods Existing methods allow single mode (electrophysiology or electrochemistry) recording. This system is designed for concurrent, dual-mode recording. It is also the only system designed explicitly to meet the challenges of recording in non-human primates. Conclusions Our system offers the possibility for conducting in vivo studies in a range of species that examine the relationship between the electrical activity of neurons and their chemical environment, with exquisite spatial and temporal precision. PMID:26226654

  5. The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.

    PubMed

    Krivokrysenko, Vadim I; Toshkov, Ilia A; Gleiberman, Anatoli S; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K; Narizhneva, Natalya V; Singh, Vijay K; Whitnall, Mark H; Purmal, Andrei A; Shakhov, Alexander N; Gudkov, Andrei V; Feinstein, Elena

    2015-01-01

    There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1-48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40-60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

  6. Home cage locomotor changes in non-human primates after prolonged welding-fume exposure.

    PubMed

    Kim, Choong Yong; Sung, Jae Hyuck; Chung, Yong Hyun; Park, Jung Duck; Han, Jeong Hee; Lee, Jong Seong; Heo, Jeong Doo; Yu, Il Je

    2013-12-01

    To define the relationship between the brain concentration of manganese and neurological signs, such as locomotion, after prolonged welding-fume exposure, cynomolgus monkeys were acclimated for 1 month and then divided into three concentration groups: unexposed, low concentration (31 mg/m(3) total suspended particulate (TSP), 0.9 mg/m(3) of Mn), and high concentration (62 mg/m(3) TSP, 1.95 mg/m(3) of Mn) of TSP. The monkeys were exposed to manual metal-arc stainless steel (MMA-SS) welding fumes for 2 h per day over 8 months in an inhalation chamber system equipped with an automatic fume generator. The home cage locomotor activity and patterns were determined using a camera system over 2-4 consecutive days. After 25 and 32 weeks of exposure, the home cage locomotor activity of the high-concentration primates was found to be 5-6 times higher than that of the unexposed primates, and this increased locomotor activity was maintained for 7 weeks after ceasing the welding-fume exposure, eventually subsiding to three times higher after 13 weeks of recovery. Therefore, the present results, along with our previous observations of a high magnetic resonance imaging (MRI) T1 signal in the globus pallidus and increased blood Mn concentration, indicate that prolonged welding-fume exposure can cause neurobehavioral changes in cynomolgus monkeys.

  7. Diet Synergistically Affects Helicobacter pylori-Induced Gastric Carcinogenesis in Non-human Primates

    PubMed Central

    Liu, Hui; Merrell, D. Scott; Semino-Mora, Cristina; Goldman, Matthew; Rahman, Arifur; Mog, Steven; Dubois, Andre

    2009-01-01

    Background and Aims Gastric cancer results from a combination of H. pylori infection, exposure to dietary carcinogens, and predisposing genetic makeup. Because the role of these factors in gastric carcinogenesis cannot be readily determined in humans, the present study examined the role of an oral carcinogen and H. pylori infection in Rhesus monkeys. Methods Gastroscopies were performed in 23 monkeys assigned to four groups: controls (C); nitrosating carcinogen ethyl-nitro-nitrosoguanidine (ENNG) administration alone (E); inoculation of a virulent H. pylori strain, alone (H); and ethyl-nitro-nitrosoguanidine in combination with H. pylori (EH). Follow-up gastroscopies and biopsies were performed at 3-month intervals for five years for pathological and molecular studies. Results Postinoculation, H and EH groups exhibited persistent infection and antral gastritis. Starting at two- and five-year, respectively, gastric intestinal metaplasia and intraepithelial neoplasia developed in three EH monkeys but in no other groups. Transcriptional analysis of biopsy specimens at five-year revealed group-specific expression profiles, with striking changes in EH monkeys, plus a neoplasia-specific expression profile characterized by changes in multiple cancer-associated genes. Importantly, this neoplastic profile was evident in non-neoplastic mucosa, suggesting that the identified genes may represent markers preceding cancer. Conclusions Gastric intraglandular neoplasia is induced in primates when H. pylori infection is associated with consumption of a carcinogen similar to the nitrosamines found in pickled vegetables, suggesting that H. pylori and the carcinogen synergistically induce gastric neoplasia in primates. PMID:19622359

  8. The 'other faunivory' revisited: Insectivory in human and non-human primates and the evolution of human diet.

    PubMed

    McGrew, William C

    2014-06-01

    The role of invertebrates in the evolution of human diet has been under-studied by comparison with vertebrates and plants. This persists despite substantial knowledge of the importance of the 'other faunivory', especially insect-eating, in the daily lives of non-human primates and traditional human societies, especially hunters and gatherers. Most primates concentrate on two phyla, Mollusca and Arthropoda, but of the latter's classes, insects (especially five orders: Coleoptera, Hymenoptera, Isoptera, Lepidoptera, Orthoptera) are paramount. An insect product, bees' honey, is particularly important, and its collection shows a reversal of the usual sexual division of labor. Human entomophagy involves advanced technology (fire, containers) and sometimes domestication. Insectivory provides comparable calorific and nutritional benefits to carnivory, but with different costs. Much insectivory in hominoids entails elementary technology used in extractive foraging, such as termite fishing by chimpanzees. Elucidating insectivory in the fossil and paleontological record is challenging, but at least nine avenues are available: remains, lithics, residues, DNA, coprolites, dental microwear, stable isotopes, osteology, and depictions. All are in play, but some have been more successful so far than others. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Effects of Caloric Restriction on Cardiovascular Aging in Non-human Primates and Humans

    PubMed Central

    Cruzen, Christina; Colman, Ricki J.

    2009-01-01

    Synopsis Approximately one in three Americans has some form of cardiovascular disease (CVD), accounting for one of every 2.8 deaths in the United States in 2004. Two of the major risk factors for CVD are advancing age and obesity. An intervention able to positively impact both aging and obesity, such as caloric restriction (CR), may prove extremely useful in the fight against CVD. CR is the only environmental or lifestyle intervention that has repeatedly been shown to increase maximum life span and to retard aging in laboratory rodents. In this article, we review evidence that CR in nonhuman primates and humans has a positive effect on risk factors for CVD. PMID:19944270

  10. Evidence for coordinated functional activity within the extended amygdala of non-human and human primates

    PubMed Central

    Oler, Jonathan A.; Birn, Rasmus M.; Patriat, Rémi; Fox, Andrew S.; Shelton, Steven E.; Burghy, Cory A.; Stodola, Diane E.; Essex, Marilyn J.; Davidson, Richard J.; Kalin, Ned H.

    2012-01-01

    Neuroanatomists posit that the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST) comprise two major nodes of a macrostructural forebrain entity termed the extended amygdala. The extended amygdala is thought to play a critical role in adaptive motivational behavior and is implicated in the pathophysiology of maladaptive fear and anxiety. Resting functional connectivity of the Ce was examined in 107 young anesthetized rhesus monkeys and 105 young humans using standard resting-state functional magnetic resonance imaging (fMRI) methods to assess temporal correlations across the brain. The data expand the neuroanatomical concept of the extended amygdala by finding, in both species, highly significant functional coupling between the Ce and the BST. These results support the use of in vivo functional imaging methods in nonhuman and human primates to probe the functional anatomy of major brain networks such as the extended amygdala. PMID:22465841

  11. Grooming-at-a-distance by exchanging calls in non-human primates

    PubMed Central

    Arlet, Malgorzata; Jubin, Ronan; Masataka, Nobuo; Lemasson, Alban

    2015-01-01

    The ‘social bonding hypothesis' predicts that, in large social groups, functions of gestural grooming should be partially transferred to vocal interactions. Hence, vocal exchanges would have evolved in primates to play the role of grooming-at-a-distance in order to facilitate the maintenance of social cohesion. However, there are few empirical studies testing this hypothesis. To address this point, we compared the rate of contact call exchanges between females in two captive groups of Japanese macaques as a function of female age, dominance rank, genetic relatedness and social affinity measured by spatial proximity and grooming interactions. We found a significant positive relationship between the time spent on grooming by two females and the frequency with which they exchanged calls. Our results conform to the predictions of the social bonding hypothesis, i.e. vocal exchanges can be interpreted as grooming-at-a-distance. PMID:26510675

  12. Transmission of Ebola virus from pigs to non-human primates

    PubMed Central

    Weingartl, Hana M.; Embury-Hyatt, Carissa; Nfon, Charles; Leung, Anders; Smith, Greg; Kobinger, Gary

    2012-01-01

    Ebola viruses (EBOV) cause often fatal hemorrhagic fever in several species of simian primates including human. While fruit bats are considered natural reservoir, involvement of other species in EBOV transmission is unclear. In 2009, Reston-EBOV was the first EBOV detected in swine with indicated transmission to humans. In-contact transmission of Zaire-EBOV (ZEBOV) between pigs was demonstrated experimentally. Here we show ZEBOV transmission from pigs to cynomolgus macaques without direct contact. Interestingly, transmission between macaques in similar housing conditions was never observed. Piglets inoculated oro-nasally with ZEBOV were transferred to the room housing macaques in an open inaccessible cage system. All macaques became infected. Infectious virus was detected in oro-nasal swabs of piglets, and in blood, swabs, and tissues of macaques. This is the first report of experimental interspecies virus transmission, with the macaques also used as a human surrogate. Our finding may influence prevention and control measures during EBOV outbreaks. PMID:23155478

  13. Neuroendocrine control in social relationships in non-human primates: Field based evidence.

    PubMed

    Ziegler, Toni E; Crockford, Catherine

    2017-03-11

    Primates maintain a variety of social relationships and these can have fitness consequences. Research has established that different types of social relationships are unpinned by different or interacting hormonal systems, for example, the neuropeptide oxytocin influences social bonding, the steroid hormone testosterone influences dominance relationships, and paternal care is characterized by high oxytocin and low testosterone. Although the oxytocinergic system influences social bonding, it can support different types of social bonds in different species, whether pair bonds, parent-offspring bonds or friendships. It seems that selection processes shape social and mating systems and their interactions with neuroendocrine pathways. Within species, there are individual differences in the development of the neuroendocrine system: the social environment individuals are exposed to during ontogeny alters their neuroendocrine and socio-cognitive development, and later, their social interactions as adults. Within individuals, neuroendocrine systems can also have short-term effects, impacting on social interactions, such as those during hunting, intergroup encounters or food sharing, or the likelihood of cooperating, winning or losing. To understand these highly dynamic processes, extending research beyond animals in laboratory settings to wild animals living within their natural social and ecological setting may bring insights that are otherwise unreachable. Field endocrinology with neuropeptides is still emerging. We review the current status of this research, informed by laboratory studies, and identify questions particularly suited to future field studies. We focus on primate social relationships, specifically social bonds (mother-offspring, father-offspring, cooperative breeders, pair bonds and adult platonic friendships), dominance, cooperation and in-group/out-group relationships, and examine evidence with respect to the 'tend and defend' hypothesis.

  14. Immunological competence in non-human primates: differences observed in four species

    PubMed Central

    Harvey, J. S.; Felsburg, P. J.; Heberling, R. L.; Kniker, W. T.; Kalter, S. S.

    1974-01-01

    Previous studies have shown that the baboon and squirrel monkey are resistant to certain herpesviruses that cause serious infection or induce tumours in the cebus monkey and marmoset. This study was undertaken to evaluate the immunological competence of the four species of nonhuman primates. A variety of clinical immunological techniques were employed to evaluate the bursal, thymicdependent and phagocytic systems of immunity in these species. No primate was found to demonstrate immune competence of the same magnitude observed in normal humans. The baboon manifested immune responsiveness most closely resembling that of man. These animals displayed no abnormalities in circulating white blood cell populations, ability to form antibody, delayed skin response to mitogens or lymphocyte transformation in vitro. Rebuck skin window (RSW) findings closely resembled those observed in humans. While the squirrel monkey also appeared to be relatively competent, antibody formation, skin test reactivity and RSW responses were slightly less than those observed in the baboon. Cebus monkeys showed several abnormalities which included significant leukopenia, very low serum alpha-1 globulin levels, cutaneous anergy and a poor RSW response. The most marked abnormalities were found in the marmosets that had persistent leucocytosis, absent to poor antibody responses to immunogens, weak responses to phytohaemagglutinin in vivo and in vitro, with a uniquely greater response to pokeweed mitogen in vitro. The poor RSW response was similar to that observed in the squirrel monkey and cebus. While these studies suggest that baboons and squirrel monkeys are relatively intact immunologically, the marmoset and cebus monkey species appear to have significant manifestations of immunological incompetence in association with susceptibility to a variety of infectious and oncogenic agents. ImagesFIG. 4 PMID:4219764

  15. Research involving anxiety in non-human primates has potential implications for the assessment and treatment of anxiety in autism spectrum disorder: A translational literature review.

    PubMed

    Gonzales, Heather K; O'Reilly, Mark; Lang, Russell; Sigafoos, Jeff; Lancioni, Giulio; Kajian, Mandana; Kuhn, Michelle; Longino, Deanna; Rojeski, Laura; Watkins, Laci

    2016-06-01

    The purpose of this translational review (i.e. moving from basic primate research toward possible human applications) was to summarize non-human primate literature on anxiety to inform the development of future assessments of anxiety in non-verbal individuals with autism spectrum disorder (ASD). Systematic searches of databases identified 67 studies that met inclusion criteria. Each study was analysed and summarised in terms of (a) strategies used to evoke anxiety, (b) non-verbal behavioural indicators of anxiety and (c) physiological indicators of anxiety. Eighteen strategies were used to evoke anxiety, 48 non-verbal behavioural indicators and 17 physiological indicators of anxiety were measured. A number of the strategies used with non-human primates, if modified carefully, could be considered in the ongoing effort to study anxiety in individuals with ASD. Potential applications to the assessment of anxiety in humans with ASD are discussed.

  16. Approaches to optical neuromodulation from rodents to non-human primates by integrated optoelectronic devices.

    PubMed

    Wang, Jing; Ozden, Ilker; Diagne, Mohamed; Wagner, Fabien; Borton, David; Brush, Benjamin; Agha, Naubahar; Burwell, Rebecca; Sheinberg, David; Diester, Ilka; Deisseroth, Karl; Nurmikko, Arto

    2011-01-01

    Methods on rendering neurons in the central nervous system to be light responsive has led to a boom in using optical neuromodulation as a new approach for controlling brain states and understanding neural circuits. In addition to the developing versatility to "optogenetically" labeling of neural cells and their subtypes by microbiological methods, parallel efforts are under way to design and implement optoelectronic devices to achieve simultaneous optical neuromodulation and electrophysiological recording with high spatial and temporal resolution. Such new device-based technologies need to be developed for full exploitation of the promise of optogenetics. In this paper we present single- and multi-element optoelectronic devices developed in our laboratories. The single-unit element, namely the coaxial optrode, was utilized to characterize the neural responses in optogenetically modified rodent and primate models. Furthermore, the multi-element device, integrating the optrode with a 6×6 microelectrode array, was used to characterize the spatiotemporal spread of neural activity in response to single-site optical stimulation in freely moving rats. We suggest that the particular approaches we employed can lead to the emergence of methods where spatio-temporal optical modulation is integrated with real-time read out from neural populations.

  17. Cultural evolution of systematically structured behaviour in a non-human primate.

    PubMed

    Claidière, Nicolas; Smith, Kenny; Kirby, Simon; Fagot, Joël

    2014-12-22

    Culture pervades human life and is at the origin of the success of our species. A wide range of other animals have culture too, but often in a limited form that does not complexify through the gradual accumulation of innovations. We developed a new paradigm to study cultural evolution in primates in order to better evaluate our closest relatives' cultural capacities. Previous studies using transmission chain experimental paradigms, in which the behavioural output of one individual becomes the target behaviour for the next individual in the chain, show that cultural transmission can lead to the progressive emergence of systematically structured behaviours in humans. Inspired by this work, we combined a pattern reproduction task on touch screens with an iterated learning procedure to develop transmission chains of baboons (Papio papio). Using this procedure, we show that baboons can exhibit three fundamental aspects of human cultural evolution: a progressive increase in performance, the emergence of systematic structure and the presence of lineage specificity. Our results shed new light on human uniqueness: we share with our closest relatives essential capacities to produce human-like cultural evolution.

  18. Cultural evolution of systematically structured behaviour in a non-human primate

    PubMed Central

    Claidière, Nicolas; Smith, Kenny; Kirby, Simon; Fagot, Joël

    2014-01-01

    Culture pervades human life and is at the origin of the success of our species. A wide range of other animals have culture too, but often in a limited form that does not complexify through the gradual accumulation of innovations. We developed a new paradigm to study cultural evolution in primates in order to better evaluate our closest relatives' cultural capacities. Previous studies using transmission chain experimental paradigms, in which the behavioural output of one individual becomes the target behaviour for the next individual in the chain, show that cultural transmission can lead to the progressive emergence of systematically structured behaviours in humans. Inspired by this work, we combined a pattern reproduction task on touch screens with an iterated learning procedure to develop transmission chains of baboons (Papio papio). Using this procedure, we show that baboons can exhibit three fundamental aspects of human cultural evolution: a progressive increase in performance, the emergence of systematic structure and the presence of lineage specificity. Our results shed new light on human uniqueness: we share with our closest relatives essential capacities to produce human-like cultural evolution. PMID:25377450

  19. Baby on board: olfactory cues indicate pregnancy and fetal sex in a non-human primate

    PubMed Central

    Crawford, Jeremy Chase; Drea, Christine M.

    2015-01-01

    Olfactory cues play an integral, albeit underappreciated, role in mediating vertebrate social and reproductive behaviour. These cues fluctuate with the signaller's hormonal condition, coincident with and informative about relevant aspects of its reproductive state, such as pubertal onset, change in season and, in females, timing of ovulation. Although pregnancy dramatically alters a female's endocrine profiles, which can be further influenced by fetal sex, the relationship between gestation and olfactory cues is poorly understood. We therefore examined the effects of pregnancy and fetal sex on volatile genital secretions in the ring-tailed lemur (Lemur catta), a strepsirrhine primate possessing complex olfactory mechanisms of reproductive signalling. While pregnant, dams altered and dampened their expression of volatile chemicals, with compound richness being particularly reduced in dams bearing sons. These changes were comparable in magnitude with other, published chemical differences among lemurs that are salient to conspecifics. Such olfactory ‘signatures’ of pregnancy may help guide social interactions, potentially promoting mother–infant recognition, reducing intragroup conflict or counteracting behavioural mechanisms of paternity confusion; cues that also advertise fetal sex may additionally facilitate differential sex allocation. PMID:25716086

  20. Non human primate models for Alzheimer's disease-related research and drug discovery.

    PubMed

    Van Dam, Debby; De Deyn, Peter Paul

    2017-02-01

    Pathophysiological mechanisms underlying Alzheimer's disease (AD) remain insufficiently documented for the identification of accurate diagnostic markers and purposeful target discovery and development. Nonhuman primates (NHPs) have important translational value given their close phylogenetic relationship to humans and similar developmental paths in (neuro)anatomy, physiology, genetics, and neural functions, as well as cognition, emotion, and social behavior. Areas covered: This review deals with the past and future role of NHP-based research in AD pathophysiology, diagnosis and drug discovery, and touches upon ethical and legal aspects. Expert opinion: Aging NHPs are not complete phenocopies of human AD. Conceivably, no other species or experimental model will ever develop the full spectrum of AD-typical alterations. Nevertheless, partial - and even negative - models can increase knowledge of disease mechanisms. Modeling complex brain disorders should not be based on a single model or species. Understanding brain diseases relies on knowledge of healthy brain functioning, and given their close phylogenetic relationship to humans, NHPs serve excellent tools in this respect. NHP-based studies remain essential in the development and validation of radiopharmaceuticals for early diagnostic imaging biomarkers, as well as in the efficacy and safety evaluation of new therapeutic approaches, with active immunization or vaccination approaches as front runners.

  1. The importance of surface-based cues for face discrimination in non-human primates

    PubMed Central

    Parr, Lisa A.; Taubert, Jessica

    2011-01-01

    Understanding how individual identity is processed from faces remains a complex problem. Contrast reversal, showing faces in photographic negative, impairs face recognition in humans and demonstrates the importance of surface-based information (shading and pigmentation) in face recognition. We tested the importance of contrast information for face encoding in chimpanzees and rhesus monkeys using a computerized face-matching task. Results showed that contrast reversal (positive to negative) selectively impaired face processing in these two species, although the impairment was greater for chimpanzees. Unlike chimpanzees, however, monkeys performed just as well matching negative to positive faces, suggesting that they retained some ability to extract identity information from negative faces. A control task showed that chimpanzees, but not rhesus monkeys, performed significantly better matching face parts compared with whole faces after a contrast reversal, suggesting that contrast reversal acts selectively on face processing, rather than general visual-processing mechanisms. These results confirm the importance of surface-based cues for face processing in chimpanzees and humans, while the results were less salient for rhesus monkeys. These findings make a significant contribution to understanding the evolution of cognitive specializations for face processing among primates, and suggest potential differences between monkeys and apes. PMID:21123266

  2. Novel serum proteomic signatures in a non-human primate model of retinal injury

    PubMed Central

    Dunmire, Jeffrey J.; Bouhenni, Rachida; Hart, Michael L.; Wakim, Bassam T.; Chomyk, Anthony M.; Scott, Sarah E.; Nakamura, Hiroshi

    2011-01-01

    Purpose To identify candidate protein biomarkers in sera indicative of acute retinal injury. Methods We used laser photocoagulation as a model of acute retinal injury in Rhesus macaques. In a paired-control study design, we collected serum from each animal (n=6) at 4 h, 1 day, and 3 days following a mock procedure and then again following retinal laser treatment that produced mild lesions. Samples were fractionated by isoelectric focusing, digested with trypsin, and analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Spectral counting was used to determine relative protein abundances and identify proteins with statistically significant differences between control and treated sera. Results Mild retinal injury was confirmed by fundus photography and histological examination. The average number of total proteins detected by LC-MS/MS was 908±82 among samples from all three time points. Following statistical analysis and employing stringent filtering criteria, a total of 19 proteins were identified as being significantly more abundant in sera following laser-induced retinal injury, relative to control sera. Many of the proteins detected were unique to one time point. However, four proteins (phosphoglycerate kinase 1, keratin 18, Lewis alpha-3-fucosyltransferase, and ephrin receptor A2) showed differences that were significant at both 4 h and 1 day after laser treatment, followed by a decrease to baseline levels by day 3. Conclusions A serum biomarker response to mild retinal laser injury was demonstrated in a primate model. Among the proteins detected with highest significant differences, most are upregulated within 24 h, and their appearance in the serum is transient. It is conceivable that a panel of these proteins could provide a means for detecting the acute-phase response to retinal injury. Further investigation of these candidate biomarkers and their correlation to retinal damage is warranted. PMID:21527995

  3. Oesophagostomiasis in non-human primates of Gombe National Park, Tanzania.

    PubMed

    Terio, Karen A; Lonsdorf, Elizabeth V; Kinsel, Michael J; Raphael, Jane; Lipende, Iddi; Collins, Anthony; Li, Yingying; Hahn, Beatrice H; Travis, Dominic A; Gillespie, Thomas R

    2016-06-16

    Oesophagostomum sp. is a parasitic nematode that frequently infects wild chimpanzees. Although nodular lesions are commonly associated with infection, some wild chimpanzee populations seem to tolerate Oesophagostomum nodular lesions while those at Gombe and other sites suffer from associated morbidity and mortality. From August 2004 to December 2013, we examined demographic (i.e., age, sex) and individual correlates (i.e., fecal consistency, Oesophagostomum egg production) to Oesophagostomum-associated pathology in 14 individually recognized chimpanzees at Gombe Stream National Park, Tanzania. In addition, we characterized Oesophagostomum-associated pathology in 14 individual sympatric primates including baboons, colobus, and cercopithecid monkeys. In five chimpanzees, there was no evidence of any significant underlying disease aside from oesophagostomiasis to explain the thin condition or diarrhea. All five of these chimpanzees had moderate to numerous parasitic nodules. In general, nodules were more numerous in older chimpanzees. Three of four chimpanzees with the highest average Oesophagostomum egg counts in feces collected during the year prior to their death had numerous parasitic nodules at necropsy. In contrast, the four chimpanzees with the lowest egg counts had only moderate numbers of nodules. No association (P = 0.74) was noted between frequency of diarrhea in the year prior to death and the number of nodules noted at necropsy. Nodules were also present in all baboons examined documenting pathology associated with Oesophagostomum infection in wild baboons. In contrast, no lesions were noted in colobus or cercopithecid monkeys, although it is uncertain if they are infected as no fecal studies have been completed in these species to date at Gombe. Sequence of DNA isolated from nodules in chimpanzees matched (99%) Oesophagostomum stephanostomum. Further research is needed to identify the types of Oesophagostomum causing lesions in baboons and to

  4. Infrared neural stimulation of primary visual cortex in non-human primates

    PubMed Central

    Cayce, Jonathan M.; Friedman, Robert M.; Chen, Gang; Jansen, E. Duco; Mahadevan-Jansen, Anita; Roe, Anna W.

    2014-01-01

    Infrared neural stimulation (INS) is an alternative neurostimulation modality that uses pulsed infrared light to evoke spatially precise neural activity that does not require direct contact with neural tissue. With these advantages INS has the potential to increase our understanding of specific neural pathways and impact current diagnostic and therapeutic clinical applications. In order to develop this technique, we investigate the feasibility of INS (λ = 1.875 μm, fiber diameter = 100–400 μm) to activate and modulate neural activity in primary visual cortex (V1) of Macaque monkeys. Infrared neural stimulation was found to evoke localized neural responses as evidenced by both electrophysiology and intrinsic signal optical imaging (OIS). Single unit recordings acquired during INS indicated statistically significant increases in neuron firing rates that demonstrate INS evoked excitatory neural activity. Consistent with this, INS stimulation led to focal intensity-dependent reflectance changes recorded with OIS. We also asked whether INS is capable of stimulating functionally specific domains in visual cortex and of modulating visually evoked activity in visual cortex. We found that application of INS via 100 μm or 200 μm fiber optics produced enhancement of visually evoked OIS response confined to the eye column where INS was applied and relative suppression of the other eye column. Stimulating the cortex with a 400 μm fiber, exceeding the ocular dominance width, led to relative suppression, consistent with involvement of inhibitory surrounds. This study is the first to demonstrate that INS can be used to either enhance or diminish visual cortical response and that this can be done in a functional domain specific manner. INS thus holds great potential for use as a safe, non-contact, focally specific brain stimulation technology in primate brains. PMID:23994125

  5. A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates

    PubMed Central

    Hjorth, Stephan; Karlsson, Cecilia; Jucaite, Aurelija; Varnäs, Katarina; Hamrén, Ulrika Wählby; Johnström, Peter; Gulyás, Balázs; Donohue, Sean R; Pike, Victor W; Halldin, Christer; Farde, Lars

    2015-01-01

    There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization. Thus, as part of a compound differentiation effort, three novel selective CB1 receptor (CB1R) antagonists, developed by AstraZeneca (AZ) for the treatment of obesity, were compared with two clinically tested reference compounds, rimonabant and taranabant, with regard to receptor occupancy relative to dose and exposure. A total of 42 PET measurements were performed in 6 non-human primates using the novel CB1R antagonist radioligand [11C]SD5024. The AZ CB1R antagonists bound in a saturable manner to brain CB1R with in vivo affinities similar to that of rimonabant and taranabant, compounds with proven weight loss efficacy in clinical trials. Interestingly, it was found that exposures corresponding to those needed for optimal clinical efficacy of rimonabant and taranabant resulted in a CB1R occupancy typically around ~20–30%, thus much lower than what would be expected for classical G-protein coupled receptor (GPCR) antagonists in other therapeutic contexts. These findings are also discussed in relation to emerging literature on the potential usefulness of ‘neutral’ vs. ‘classical’ CB1R (inverse agonist) antagonists. The study additionally highlighted the usefulness of the radioligand [11C]SD5024 as a specific tracer for CB1R in the primate brain, though an arterial input function would ideally be required in future studies to further assure accurate quantitative analysis of specific binding. PMID:25791528

  6. FUNCTIONAL RECOVERY FOLLOWING MOTOR CORTEX LESIONS IN NON-HUMAN PRIMATES: EXPERIMENTAL IMPLICATIONS FOR HUMAN STROKE PATIENTS

    PubMed Central

    Darling, Warren G.; Pizzimenti, Marc A.; Morecraft, Robert J.

    2013-01-01

    This review discusses selected classical works and contemporary research on recovery of contralesional fine hand motor function following lesions to motor areas of the cerebral cortex in non-human primates. Findings from both the classical literature and contemporary studies show that lesions of cortical motor areas induce paresis initially, but are followed by remarkable recovery of fine hand/digit motor function that depends on lesion size and post-lesion training. Indeed, in recent work where considerable quantification of fine digit function associated with grasping and manipulating small objects has been observed, very favorable recovery is possible with minimal forced use of the contralesional limb. Studies of the mechanisms underlying recovery have shown that following small lesions of the digit areas of primary motor cortex (M1), there is expansion of the digit motor representations into areas of M1 that did not produce digit movements prior to the lesion. However, after larger lesions involving the elbow, wrist and digit areas of M1, no such expansion of the motor representation was observed, suggesting that recovery was due to other cortical or subcortical areas taking over control of hand/digit movements. Recently, we showed that one possible mechanism of recovery after lesion to the arm areas of M1 and lateral premotor cortex is enhancement of corticospinal projections from the medially located supplementary motor area (M2) to spinal cord laminae containing neurons which have lost substantial input from the lateral motor areas and play a critical role in reaching and digit movements. Because human stroke and brain injury patients show variable, and usually poorer, recovery of hand motor function than that of nonhuman primates after motor cortex damage, we conclude with a discussion of implications of this work for further experimentation to improve recovery of hand function in human stroke patients. PMID:21960307

  7. An implicit measure of olfactory performance for non-human primates reveals aversive and pleasant odor conditioning.

    PubMed

    Livneh, Uri; Paz, Rony

    2010-09-30

    We have little understanding of how odorants are processed in neural networks of the primate brain. Because chemo-stimuli are harder to control than physical stimuli (e.g. vision, audition), such research was limited by the temporal resolution, accuracy, and reliability of olfactometers (odor producing machines). Recent advances were able to create olfactometers that overcome these limitations, allowing their use together with neuroimaging techniques in humans. From the behavioral point of view, olfaction research requires a behavioral measure that can be used to quantify olfactory performance. This becomes a real problem when working with animals, where, unlike humans, explicit measures are harder to obtain. Furthermore, because odorants are powerful primitive reinforcers, such implicit measures can be beneficial to use in learning paradigms. Here we describe an olfactometer suitable for use in non-human primates, and an end-port design that allows the accurate measure of real-time respiratory modulations that are elicited in response to odor presentation. We demonstrate that this implicit measure is differentially modulated when experiencing pleasant or aversive odors. We then present an experimental paradigm in which monkeys learn to associate tones with odors, and show that the time delay from the conditioned stimuli to the next breath can be used to measure learning and memory expression in this paradigm. Using this construct, we reveal olfactory performance during acquisition and extinction of odor conditioning. These techniques can be used in electrophysiological recordings from relevant brain areas to shed light on neural networks involved in odor processing and reinforcement-learning.

  8. Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury.

    PubMed

    Slotkin, Jonathan R; Pritchard, Christopher D; Luque, Brian; Ye, Janice; Layer, Richard T; Lawrence, Mathew S; O'Shea, Timothy M; Roy, Roland R; Zhong, Hui; Vollenweider, Isabel; Edgerton, V Reggie; Courtine, Grégoire; Woodard, Eric J; Langer, Robert

    2017-04-01

    Tissue loss significantly reduces the potential for functional recovery after spinal cord injury. We previously showed that implantation of porous scaffolds composed of a biodegradable and biocompatible block copolymer of Poly-lactic-co-glycolic acid and Poly-l-lysine improves functional recovery and reduces spinal cord tissue injury after spinal cord hemisection injury in rats. Here, we evaluated the safety and efficacy of porous scaffolds in non-human Old-World primates (Chlorocebus sabaeus) after a partial and complete lateral hemisection of the thoracic spinal cord. Detailed analyses of kinematics and muscle activity revealed that by twelve weeks after injury fully hemisected monkeys implanted with scaffolds exhibited significantly improved recovery of locomotion compared to non-implanted control animals. Twelve weeks after injury, histological analysis demonstrated that the spinal cords of monkeys with a hemisection injury implanted with scaffolds underwent appositional healing characterized by a significant increase in remodeled tissue in the region of the hemisection compared to non-implanted controls. The number of glial fibrillary acidic protein immunopositive astrocytes was diminished within the inner regions of the remodeled tissue layer in treated animals. Activated macrophage and microglia were present diffusely throughout the remodeled tissue and concentrated at the interface between the preserved spinal cord tissue and the remodeled tissue layer. Numerous unphosphorylated neurofilament H and neuronal growth associated protein positive fibers and myelin basic protein positive cells may indicate neural sprouting inside the remodeled tissue layer of treated monkeys. These results support the safety and efficacy of polymer scaffolds in a primate model of acute spinal cord injury. A device substantially similar to the device described here is the subject of an ongoing human clinical trial.

  9. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation.

    PubMed

    Rose, Destanie R; Careaga, Milo; Van de Water, Judy; McAllister, Kim; Bauman, Melissa D; Ashwood, Paul

    2016-11-19

    Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing of MIA.An additional three non-treated animals were used as controls. The offspring were followed until 4 years of age, with blood collected at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function. Induced responses from peripheral immune cells were measured using multiplex assays.At one year of age, MIA exposed offspring displayed elevated production of innate inflammatory cytokines including: interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor (TNF)α at baseline and following stimulation. At four years of age, the MIA exposed offspring continued to display elevated IL-1β, and there was also a pattern of an increased production of T-cell helper type (TH)-2 cytokines, IL-4 and IL-13. Throughout this time period, the offspring of MIA treated dams exhibited altered behavioral phenotypes including increased stereotyped behaviors. During the first two years, stereotyped behaviors were associated with innate cytokine production

  10. Generation of a universal CD4 memory T cell recall peptide effective in humans, mice and non-human primates.

    PubMed

    Fraser, Christopher C; Altreuter, David H; Ilyinskii, Petr; Pittet, Lynnelle; LaMothe, Robert A; Keegan, Mark; Johnston, Lloyd; Kishimoto, Takashi Kei

    2014-05-19

    CD4T cells play a key role in humoral immunity by providing help to B cells, enabling effective antibody class switching and affinity maturation. Some vaccines may generate a poor response due to a lack of effective MHC class II epitopes, resulting in ineffective helper T cell activation and recall and consequently poor humoral immunity. It may be beneficial to provide a CD4T cell helper peptide with a vaccine particularly in the case of a poorly immunogenic antigen. Such a T cell helper peptide must be promiscuous in its ability to bind a broad range of MHC class II alleles due to broad allelic variation in the human population. We designed a chimeric MHC class II peptide (TpD) with epitopes from tetanus toxoid and diphtheria toxoid, separated by an internal cathepsin cleavage site. TpD was capable of inducing a memory recall response in peripheral blood mononuclear cells from 20/20 human donors. T cells responding to TpD showed a central memory phenotype. Immunization of mice with a synthetic nicotine nanoparticle vaccine containing TpD showed that the peptide was required for robust antibody production and resulted in a long term CD4 memory T cell recall response. As a pre-clinical model two non-human primate species, rhesus macaques and cynomolgus monkeys, were immunized with a nicotine nanoparticle vaccine and evaluated for an anti-nicotine antibody response and TpD specific memory T cells. We found that 4/4 rhesus monkeys had both sustained antibody production and TpD memory T cells for the duration of the experiment (119 days). In addition 30/30 cynomolgus monkeys dosed with nicotine vaccine nanoparticles showed dose-dependent antibody generation and T cell recall response compared to saline injected controls. In summary we have developed a potent universal memory T cell helper peptide (TpD) that is active in vitro in human PBMCs and in vivo in mice and non-human primates. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. The non-human primate striatum undergoes marked prolonged remodeling during postnatal development

    PubMed Central

    Martin, Lee J.; Cork, Linda C.

    2014-01-01

    was densely populated with LENK-immunoreactive neurons. The nucleus accumbens part of the ventral striatum also showed prominent differences in SP, LENK, and CAL immunoreactivities in shell and core territories. During 12 months of postnatal maturation salient changes occurred in neurotransmitter marker localization: TH-positive afferents densely innervated the matrix to exceed levels of immunoreactivity in the striosomes; SP immunoreactivity levels increased in the matrix; and LENK-immunoreactivity levels decreased in the matrix and increased in the striosomes. At 12 months of age, striatal chemoarchitecture was similar qualitatively to adult patterns, but quantitatively different in LENK and SP in caudate, putamen, and nucleus accumbens. This study shows for the first time that the rhesus monkey striatum requires more than 12 months after birth to develop an adult-like pattern of chemical neuroanatomy and that principal neurons within striosomes and matrix have different developmental programs for neuropeptide expression. We conclude that postnatal maturation of the striatal mosaic in primates is not static but, rather, is a protracted and dynamic process that requires many synchronous and compartment-selective changes in afferent innervation and in the expression of genes that regulate neuronal phenotypes. PMID:25294985

  12. NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure.

    PubMed

    Halene, Tobias B; Kozlenkov, Alexey; Jiang, Yan; Mitchell, Amanda C; Javidfar, Behnam; Dincer, Aslihan; Park, Royce; Wiseman, Jennifer; Croxson, Paula L; Giannaris, Eustathia Lela; Hof, Patrick R; Roussos, Panos; Dracheva, Stella; Hemby, Scott E; Akbarian, Schahram

    2016-02-01

    Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved. We exposed 26 young adult macaque monkeys for 6 months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts. After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups. Chronic clozapine exposure increases the proportion of NeuN+ nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted.

  13. NeuN+ Neuronal Nuclei in Non-Human Primate Prefrontal Cortex and Subcortical White Matter After Clozapine Exposure

    PubMed Central

    Halene, Tobias B.; Kozlenkov, Alexey; Jiang, Yan; Mitchell, Amanda; Javidfar, Behnam; Dincer, Aslihan; Park, Royce; Wiseman, Jennifer; Croxson, Paula; Giannaris, Eustathia Lela; Hof, Patrick R.; Roussos, Panos; Dracheva, Stella; Hemby, Scott E.; Akbarian, Schahram

    2016-01-01

    Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved. We exposed 26 young adult macaque monkeys for 6 months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts. After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups. Chronic clozapine exposure increases the proportion of NeuN+ nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted. PMID:26776227

  14. Immunogenicity of a peptide-based anti-IgE conjugate vaccine in non-human primates.

    PubMed

    Weeratna, Risini D; Chikh, Ghania; Zhang, Lu; Fraser, James D; Thorn, Jennifer M; Merson, James R; McCluskie, Michael J; Champion, Brian R; Davis, Heather L

    2016-06-01

    The anti-human immunoglobulin E (IgE) monoclonal antibody, omalizumab (Xolair®, Genentech, South San Fransisco, CA), is effective in the treatment of poorly controlled moderate to severe allergic asthma and chronic idiopathic urticaria. It acts by specifically binding to the constant domain (Cϵ3) of free human IgE in the blood and interstitial fluid. Although efficacious, use of omalizumab is limited due to restrictions on patient weight and pre-existing IgE levels, and frequent dosing (q2-4 weeks). A vaccine inducing anti-IgE antibodies has the potential for similar clinical benefits with less frequent dosing and relatively lower cost of goods. We developed a vaccine containing two IgE peptide-conjugates targeting the Cϵ3 domain of human IgE. As part of preclinical evaluation of the vaccine to optimize formulation and dose prior to initiating clinical studies, we evaluated the vaccine in non-human primates, and demonstrate the induction of anti-peptide antibodies that can bind to conformationally intact human IgE and are capable, at least in some animals, of substantial lowering circulating IgE levels.

  15. Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates

    PubMed Central

    Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne

    2017-01-01

    Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus, spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (rs=0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (rs=0.56) and hippocampus (rs=−0.62) or septum (rs=−0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes. PMID:28039490

  16. The high-affinity receptor for IgG, FcγRI, of humans and non-human primates.

    PubMed

    Chenoweth, Alicia M; Trist, Halina M; Tan, Peck-Szee; Wines, Bruce D; Hogarth, P Mark

    2015-11-01

    Non-human primate (NHP) models, especially involving macaques, are considered important models of human immunity and have been essential in preclinical testing for vaccines and therapeutics. Despite this, much less characterization of macaque Fc receptors has occurred compared to humans or mice. Much of the characterization of macaque Fc receptors so far has focused on the low-affinity Fc receptors, particularly FcγRIIIa. From these studies, it is clear that there are distinct differences between the human and macaque low-affinity receptors and their interaction with human IgG. Relatively little work has been performed on the high-affinity IgG receptor, FcγRI, especially in NHPs. This review will focus on what is currently known of how FcγRI interacts with IgG, from mutation studies and recent crystallographic studies of human FcγRI, and how amino acid sequence differences in the macaque FcγRI may affect this interaction. Additionally, this review will look at the functional consequences of differences in the amino acid sequences between humans and macaques. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Automated longitudinal registration of high resolution structural MRI brain sub-volumes in non-human primates

    PubMed Central

    Lecoeur, Jérémy; Wang, Feng; Chen, Li Min; Li, Rui; Avison, Malcolm J.; Dawant, Benoit M.

    2011-01-01

    Accurate anatomic co-registration is a prerequisite for identifying structural and functional changes in longitudinal studies of brain plasticity. Current MRI methods permit collection of brain images across multiple scales, ranging from whole brain at relatively low resolution (≥1 mm), to local brain areas at the level of cortical layers and columns (~100 µm) in the same session, allowing detection of subtle structural changes on a similar spatial scale. To measure these changes reliably, high resolution structural and functional images of local brain regions must be registered accurately across imaging sessions. The present study describes a robust fully automated strategy for the registration of high resolution structural images of brain sub-volumes to lower resolution whole brain images collected within a session, and the registration of partially overlapping high resolution MRI sub-volumes (“slabs”) across imaging sessions. In high field (9.4 T) reduced field-of-view high resolution structural imaging studies using a surface coil in an anesthetized non-human primate model, this fully automated coregistration pipeline was robust in the face of significant inhomogeneities in image intensity and tissue contrast arising from the spatially inhomogeneous transmit and receive properties of the surface coil, achieving a registration accuracy of 30 ± 15 µm between sessions. PMID:21920386

  18. Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles

    NASA Astrophysics Data System (ADS)

    Downs, Matthew E.; Buch, Amanda; Karakatsani, Maria Eleni; Konofagou, Elisa E.; Ferrera, Vincent P.

    2015-10-01

    Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.

  19. Manganese neurotoxicity: new perspectives from behavioral, neuroimaging, and neuropathological studies in humans and non-human primates

    PubMed Central

    Guilarte, Tomás R.

    2013-01-01

    Manganese (Mn) is an essential metal and has important physiological functions for human health. However, exposure to excess levels of Mn in occupational settings or from environmental sources has been associated with a neurological syndrome comprising cognitive deficits, neuropsychological abnormalities and parkinsonism. Historically, studies on the effects of Mn in humans and experimental animals have been concerned with effects on the basal ganglia and the dopaminergic system as it relates to movement abnormalities. However, emerging studies are beginning to provide significant evidence of Mn effects on cortical structures and cognitive function at lower levels than previously recognized. This review advances new knowledge of putative mechanisms by which exposure to excess levels of Mn alters neurobiological systems and produces neurological deficits not only in the basal ganglia but also in the cerebral cortex. The emerging evidence suggests that working memory is significantly affected by chronic Mn exposure and this may be mediated by alterations in brain structures associated with the working memory network including the caudate nucleus in the striatum, frontal cortex and parietal cortex. Dysregulation of the dopaminergic system may play an important role in both the movement abnormalities as well as the neuropsychiatric and cognitive function deficits that have been described in humans and non-human primates exposed to Mn. PMID:23805100

  20. Non-ABO blood group systems phenotyping in non-human primates for blood banking laboratory and xenotransplantation.

    PubMed

    Ramis, G; Martínez-Alarcon, L; Quereda, J J; Mrowiec, A; Funes, C; Ríos, A; Ramírez, P; Muñoz, A; Majado, M J

    2013-04-01

    Some biomedical research procedures, such as organ xenotransplantation, usually require intensive hemotherapy. Knowledge of the whole phenotype of blood donor and graft could be useful in the field of xenotransplantation. Human and simian-type categories of blood groups have been established and they can be tested by standard methods used for human blood grouping. The aim of this work was to study the incidence of non-ABO blood group systems in different species of non-human primates, which are employed in biomedical research. The phenotype of Rh, Lewis, Kidd, Kell, MNSs, Lutheran, P and Duffy antigens was investigated in olive baboon (n = 48), chacma baboon (n = 9), Guinea baboon (n = 14), Rhesus macaque (n = 38) and squirrel monkey (n = 30) by using commercial microtyping cards. Kell, Lutheran, Kidd and Duffy antigens have been detected in all species, Rh in squirrel monkey, MNSs in rhesus macaque and squirrel monkey, and Lewis in baboon and rhesus macaque. There were differences in frequency and haemagglutination scores between species regardless of their gender and age. The main differences were found in squirrel monkey when compared with baboons and macaques. This typing system provides a tool to assess the presence of antigens in animals used for experimental procedures, such as xenotransplantation and xenotransfusion.

  1. Could an experimental dengue virus infection fail to induce solid immunity against homologous viral challenge in non-human primates?

    PubMed

    Valdés, Iris; Gil, Lázaro; Lazo, Laura; Marcos, Ernesto; Martín, Jorge; Suzarte, Edith; Castro, Jorge; Romero, Yaremis; Guillén, Gerardo; Hermida, Lisset

    2016-02-01

    There are several dengue vaccine candidates at advanced stages of development, but none of them are licensed. Despite the reactogenicity and immunogenicity profile in humans of the tetravalent ChimeriVax™ dengue vaccine candidate, in efficacy trials, it has failed to confer complete protection against dengue virus (DENV)-1 and DENV-2. However, full protection against the four serotypes had been observed previously in monkeys immunized with this vaccine candidate. Some authors have tried to explain this contradiction by hypothesizing that protection rates in non-human primates (NHPs) are associated with a lack of post-challenge anamnestic immune responses. Here, we studied the protection and anamnestic response patterns after homologous challenge in NHPs previously infected with DENV-2. Two immunization schemes were used, varying the viral doses and the intervals between them. Animals developed immunity against DENV-2 that provided full protection against reinfection with a homologous virus. However, all monkeys showed a significant increase in antiviral and neutralizing antibody titers after challenge. Our results suggest that sterilizing immunity could not be induced by infection with the virus despite the lack of detectable viremia in some animals in which an increase in antibody titer was observed. For this reason, we propose that the lack of an anamnestic neutralizing antibody response after challenge, as suggested by some authors, should be carefully reviewed as a criterion for evaluating the functionality of vaccine candidates.

  2. Consequences of early adverse rearing experience(EARE) on development: insights from non-human primate studies.

    PubMed

    Zhang, Bo

    2017-01-18

    Early rearing experiences are important in one's whole life, whereas early adverse rearing experience(EARE) is usually related to various physical and mental disorders in later life. Although there were many studies on human and animals, regarding the effect of EARE on brain development, neuroendocrine systems, as well as the consequential mental disorders and behavioral abnormalities, the underlying mechanisms remain unclear. Due to the close genetic relationship and similarity in social organizations with humans, non-human primate(NHP) studies were performed for over 60 years. Various EARE models were developed to disrupt the early normal interactions between infants and mothers or peers. Those studies provided important insights of EARE induced effects on the physiological and behavioral systems of NHPs across life span, such as social behaviors(including disturbance behavior, social deficiency, sexual behavior, etc), learning and memory ability, brain structural and functional developments(including influences on neurons and glia cells, neuroendocrine systems, e.g., hypothalamic-pituitary-adrenal(HPA) axis, etc). In this review, the effects of EARE and the underlying epigenetic mechanisms were comprehensively summarized and the possibility of rehabilitation was discussed.

  3. Method validation and reference range values for a peripheral blood immunophenotyping assay in non-human primates.

    PubMed

    Caldwell, Robert G; Marshall, Peggy; Fishel, Jared

    2016-01-01

    A peripheral blood immunophenotyping assay was developed and validated for determination of total T-lymphocytes, helper T-lymphocytes, cytotoxic T-lymphocytes, B-lymphocytes, and natural killer cells in cynomolgus monkeys. Validation parameters included assessment of precision, linearity, antibody optimization, stability of peripheral blood samples, and stability of fixed immunophenotyping samples. Total lymphocyte populations were determined using a heterogeneous lymphocyte gating strategy consisting of CD45 fluorescent staining and side-scatter demarcation. Relative lymphocyte subset values were determined using antigen-specific gating strategies. Absolute subset concentrations for each lymphocyte subset were subsequently determined using a dual-platform methodology wherein relative lymphocyte subset values (via flow cytometry analyses) were multiplied by the absolute total lymphocyte (via hematology analyses) values. Reference ranges are presented for cynomolgus monkey, rhesus monkey, and baboon. Additional 1-year longitudinal immunophenotyping values are presented for the cynomolgus monkey. The method validation and reference ranges presented in this research provide a robust analytical methodology for determination of peripheral blood lymphocyte subsets in various non-human primate species.

  4. Isolation and maintenance of Balantidium coli (Malmsteim, 1857) cultured from fecal samples of pigs and non-human primates.

    PubMed

    Barbosa, Alynne da Silva; Bastos, Otilio Machado Pereira; Uchôa, Claudia M Antunes; Pissinatti, Alcides; Ferreira Filho, Paulo Ricardo; Dib, Lais Verdan; Azevedo, Eduarda Peixoto; de Siqueira, Mayara Perlingeiro; Cardozo, Matheus Lessa; Amendoeira, Maria Regina Reis

    2015-06-15

    Balantidium coli is a protozoa that can determine dysentery in humans, pigs and non-human primates having zoonotic potential. The lack of standardization in isolation and maintenance hinders the development of research on its biology and epidemiology. This study is aimed to standardize the isolation and maintenance of this parasite from animal feces, in culture medium, Pavlova modified. From 2012 to 2014, 1905 fecal samples were collected from captive animals of Rio de Janeiro. Were selected for isolation samples with a minimum of 10 trophozoites and/or 30 cysts of B. coli, totaling 88 pigs, 26 Cynomolgus and 90 rhesus macaques. In the presence of cysts, the sample was homogenized in saline solution, 500 μL was removed and inoculated into culture medium. The material that contained trophozoites the inoculum was made from 240 μL of fecal solution. All inoculate tubes with the subcultures were kept at 36°C, and sterile rice starch was always added to the medium. The parasites isolate from pigs, 34%, and from Cynomolgus 38.4% were maintained in vitro for a period of more than 24 months. These procedures proved to be adequate for isolation and maintenance of B. coli from different animals, they were found to be inexpensive and easy to perform.

  5. Future of liver transplantation: non-human primates for patient-specific organs from induced pluripotent stem cells.

    PubMed

    Sanal, Madhusudana Girija

    2011-08-28

    Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient's genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly.

  6. Establishment of a non-human primate Campylobacter disease model for the pre-clinical evaluation of Campylobacter vaccine formulations.

    PubMed

    Islam, Dilara; Lewis, Michael D; Srijan, Apichai; Bodhidatta, Ladaporn; Aksomboon, Ajchara; Gettayacamin, Montip; Baqar, Shahida; Scott, Daniel; Mason, Carl J

    2006-05-01

    Campylobacter jejuni is a common cause of enteritis worldwide. The mechanisms by which C. jejuni causes disease are unclear. Challenge studies in humans are currently considered unethical due to the possibility of severe complications, such as Guillain-Barré syndrome. Campylobacter infection in non-human primates closely mimics the disease and immune response, seen in humans. In this study, we attempted to determine the minimal dose of a pathogenic C. jejuni 81-176 strain required for clinical signs and symptoms of disease (> or = 80% attack rate) in Macaca mulatta monkeys using an escalating dosage (three doses for three monkey groups: 10(7), 10(9) and 10(11) cfu). Eighty percent of the monkeys challenged with highest dose (10(11) cfu) had mild disease, but the 80% attack rate (moderate diarrhea in 80% of the monkeys) was not achieved. However, 100% of monkeys showed IgA seroconversions (three-fold over pre-challenge titers). The elicited immune response was challenge dose-dependent. Campylobacter antigen specific fecal s-IgA responses were observed in all challenged groups but the response was not dose-dependent. Only IgM antibody secreting cells response was observed against Campylobacter antigens. The elicited immune response in three groups of rhesus monkeys was dose-dependent, indicating this monkey model can be used for pre-clinical evaluation of Campylobacter candidate vaccines, however these adult rhesus monkeys are less prone to Campylobacter infection.

  7. Oculomatic: High speed, reliable, and accurate open-source eye tracking for humans and non-human primates.

    PubMed

    Zimmermann, Jan; Vazquez, Yuriria; Glimcher, Paul W; Pesaran, Bijan; Louie, Kenway

    2016-09-01

    Video-based noninvasive eye trackers are an extremely useful tool for many areas of research. Many open-source eye trackers are available but current open-source systems are not designed to track eye movements with the temporal resolution required to investigate the mechanisms of oculomotor behavior. Commercial systems are available but employ closed source hardware and software and are relatively expensive, limiting wide-spread use. Here we present Oculomatic, an open-source software and modular hardware solution to eye tracking for use in humans and non-human primates. Oculomatic features high temporal resolution (up to 600Hz), real-time eye tracking with high spatial accuracy (<0.5°), and low system latency (∼1.8ms, 0.32ms STD) at a relatively low-cost. Oculomatic compares favorably to our existing scleral search-coil system while being fully non invasive. We propose that Oculomatic can support a wide range of research into the properties and neural mechanisms of oculomotor behavior. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Future of liver transplantation: Non-human primates for patient-specific organs from induced pluripotent stem cells

    PubMed Central

    Sanal, Madhusudana Girija

    2011-01-01

    Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient’s genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly. PMID:21990949

  9. Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1/CMAH/β4GalNT2 genes.

    PubMed

    Estrada, Jose L; Martens, Greg; Li, Ping; Adams, Andrew; Newell, Kenneth A; Ford, Mandy L; Butler, James R; Sidner, Richard; Tector, Matt; Tector, Joseph

    2015-01-01

    Simultaneous inactivation of pig GGTA1 and CMAH genes eliminates carbohydrate xenoantigens recognized by human antibodies. The β4GalNT2 glycosyltransferase may also synthesize xenoantigens. To further characterize glycan-based species incompatibilities, we examined human and non-human primate antibody binding to cells derived from genetically modified pigs lacking these carbohydrate-modifying genes. The Cas9 endonuclease and gRNA were used to create pigs lacking GGTA1, GGTA1/CMAH, or GGTA1/CMAH/β4GalNT2 genes. Peripheral blood mononuclear cells were isolated from these animals and examined for binding to IgM and IgG from humans, rhesus macaques, and baboons. Cells from GGTA1/CMAH/β4GalNT2 deficient pigs exhibited reduced human IgM and IgG binding compared to cells lacking both GGTA1 and CMAH. Non-human primate antibody reactivity with cells from the various pigs exhibited a slightly different pattern of reactivity than that seen in humans. Simultaneous inactivation of the GGTA1 and CMAH genes increased non-human primate antibody binding compared to cells lacking either GGTA1 only or to those deficient in GGTA1/CMAH/β4GalNT2. Inactivation of the β4GalNT2 gene reduces human and non-human primate antibody binding resulting in diminished porcine xenoantigenicity. The increased humoral immunity of non-human primates toward GGTA1-/CMAH-deficient cells compared to pigs lacking either GGTA1 or GGTA1/CMAH/β4GalNT2 highlights the complexities of carbohydrate xenoantigens and suggests potential limitations of the non-human primate model for examining some genetic modifications. The progressive reduction of swine xenoantigens recognized by human immunoglobulin through inactivation of pig GGTA1/CMAH/β4GalNT2 genes demonstrates that the antibody barrier to xenotransplantation can be minimized by genetic engineering. © 2015 The Authors. Xenotransplantation Published by John Wiley & Sons Ltd.

  10. HIV-1 Cross-reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Non-human Primate.

    PubMed

    Wang, Yimeng; O'Dell, Sijy; Turner, Hannah L; Chiang, Chi-I; Lei, Lin; Guenaga, Javier; Wilson, Richard; Martinez-Murillo, Paola; Doria-Rose, Nicole; Ward, Andrew B; Mascola, John R; Wyatt, Richard T; Karlsson Hedestam, Gunilla B; Li, Yuxing

    2017-08-23

    subset of individuals. To achieve this goal, an improved understanding of vaccine-elicited responses including at the monoclonal Ab level is essential. Here, we isolated and characterized a panel of vaccine-elicited cross-reactive neutralizing mAbs targeting Env V3 loop that moderately neutralized several primary viruses and recapitulated the serum neutralizing antibody response. Striking similarities between the cross-reactive V3 NAbs elicited by vaccination in macaques and natural infections in humans illustrate commonalities between the vaccine- and infection-induced responses to V3 and support the feasibility of exploring the V3 epitope as HIV-1 vaccine target in non-human primates. Copyright © 2017 American Society for Microbiology.

  11. Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in non-human primates

    PubMed Central

    Makris, Angela; Yeung, Kristen R; Lim, Shirlene M; Sunderland, Neroli; Heffernan, Scott; Thompson, John F; Iliopoulos, Jim; Killingsworth, Murray C; Yong, Jim; Xu, Bei; Ogle, Robert F; Thadhani, Ravi; Karumanchi, S. Ananth; Hennessy, Annemarie

    2016-01-01

    An imbalance in the angiogenesis axis during pregnancy manifests as clinical preeclampsia due to endothelial dysfunction. Circulating sFLT-1 (soluble fms-like tyrosine kinase 1) increases and PlGF (placental growth factor) reduces prior to and during disease. We investigated the clinical and biochemical effects of replenishing the reduced circulating PlGF with recombinant human PlGF (rhPlGF) and thus restoring the angiogenic balance. Hypertensive proteinuria was induced in a non-human primate (Papio hamadryas) by uterine artery ligation at 136 days gestation (of an 182 day pregnancy). Two weeks after uteroplacental ischemia (UPI), rhPlGF (rhPlGF, n=3) or normal saline (control, n=4) was administered by subcutaneous injection (100μg/kg/day) for 5 days. Blood pressure (BP) was monitored by intra-arterial radiotelemetry, sFLT-1 and PlGF by ELISA. UPI resulted in experimental preeclampsia evidenced by increased BP, proteinuria and endotheliosis on renal biopsy and elevated sFLT-1. PlGF significantly reduced after UPI. rhPlGF reduced SBP in the treated group (-5.2mmHg+0.8mmHg;from 132.6+6.6mmHg to 124.1+7.6mmHg) compared to an increase in SBP in controls (6.5mmHg+3mmHg; from 131.3+1.5mmHg to 138.6+1.5mmHg). Proteinuria reduced in the treated group (-72.7±55.7mg/mmol) but increased in the control group. Circulating sFLT-1 was not affected by the administration of PlGF, however a reduction in placental sFLT-1 mRNA expression was demonstrated. There was no significant difference in the weights or lengths of the neonates in the rhPlGF or control group, however, this study was not designed to assess fetal safety or outcomes. Increasing circulating PlGF by the administration of rhPlGF improves clinical parameters in a primate animal model of experimental preeclampsia. PMID:27091894

  12. On the pursuit of the brain network for proto-syntactic learning in non-human primates: conceptual issues and neurobiological hypotheses

    PubMed Central

    Petkov, Christopher I.; Wilson, Benjamin

    2012-01-01

    Songbirds have become impressive neurobiological models for aspects of human verbal communication because they learn to sequence their song elements, analogous, in some ways, to how humans learn to produce spoken sequences with syntactic structure. However, mammals such as non-human primates are considered to be at best limited-vocal learners and not able to sequence their vocalizations, although some of these animals can learn certain ‘artificial grammar’ sequences. Thus, conceptual issues have slowed the progress in exploring potential neurobiological homologues to language-related processes in species that are taxonomically closely related to humans. We consider some of the conceptual issues impeding a pursuit of, as we define them, ‘proto-syntactic’ capabilities and their neuronal substrates in non-human animals. We also discuss ways to better bridge comparative behavioural and neurobiological data between humans and other animals. Finally, we propose guiding neurobiological hypotheses with which we aim to facilitate the future testing of the level of correspondence between the human brain network for syntactic-learning and related neurobiological networks present in other primates. Insights from the study of non-human primates and other mammals are likely to complement those being obtained in birds to further our knowledge of the human language-related network at the cellular level. PMID:22688642

  13. Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3

    PubMed Central

    Maekawa, Tomoki; Briones, Ruel A.; Resuello, Ranillo R.G.; Tuplano, Joel V.; Hajishengallis, Evlambia; Kajikawa, Tetsuhiro; Koutsogiannaki, Sophia; Garcia, Cristina A.G.; Ricklin, Daniel; Lambris, John D.; Hajishengallis, George

    2016-01-01

    Aim Human periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system. We assessed whether the C3 inhibitor Cp40 inhibits naturally-occurring periodontitis in non-human primates. Materials and Methods Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for six weeks followed by a 6-week follow-up period. Clinical periodontal examinations and collection of gingival crevicular fluid and biopsies of gingiva and bone were performed at baseline and during the study. A one-way repeated measures ANOVA was used for data analysis. Results Whether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation (gingival index and bleeding on probing), tissue destruction (probing pocket depth and clinical attachment level) or tooth mobility. These clinical changes were associated with significantly reduced levels of pro-inflammatory mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least six weeks following drug discontinuation. Conclusion Cp40 inhibits pre-existing chronic periodontal inflammation and osteoclastogenesis in non-human primates, suggesting a novel adjunctive anti-inflammatory therapy for treating human periodontitis. PMID:26728318

  14. Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator

    PubMed Central

    Connolly, Allison T; Muralidharan, Abirami; Hendrix, Claudia; Johnson, Luke; Gupta, Rahul; Stanslaski, Scott; Denison, Tim; Baker, Kenneth B; Vitek, Jerrold L; Johnson, Matthew D

    2016-01-01

    Objective Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10–30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects’ limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30–60 s, but there was no correlation with beta band power. Significance This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject’s symptomatology. PMID:26469737

  15. Serial Multifocal Electroretinograms during Long-term Elevation and Reduction of Intraocular Pressure in Non-human Primates

    PubMed Central

    Nork, T. Michael; Kim, Charlene B. Y.; Heatley, Gregg A.; Kaufman, Paul L.; Lucarelli, Mark J.; Levin, Leonard A.; Ver Hoeve, James N.

    2010-01-01

    The purpose of this study was to evaluate the relationship between elevations of intraocular pressure (IOP) and the multifocal electroretinogram (mfERG) in non-human primates. Experimental glaucoma was induced in 4 rhesus and 4 cynomolgus monkeys by laser trabecular meshwork destruction (LTD) in one eye. To evaluate the contribution of ganglion cells to mfERG changes, one monkey of each species had previously underwent unilateral optic nerve transection (ONT). After ≥ 44 weeks of elevation, the IOP was reduced by trabeculectomy in 2 non-transected animals. In the intact (non-transected) animals there was an increase in the amplitude of the early mfERG waveforms (N1 and P1) of the first order kernel (K1) throughout the period of IOP elevation in all of the rhesus, but not all of the cynomolgus monkeys. A species difference was also present as a decrease of the second order kernel, first slice (K2.1) in all of the cynomolgus monkeys but only in 1 of the rhesus monkeys (the 1 with the ONT). Similar IOP effects on the mfERG were seen in the ONT animals. Surgical lowering of IOP resulted in a return of the elevated K1 amplitudes to baseline levels. However, the depressed K2.1 RMS in the cynomolgus monkeys did not recover. These results demonstrate species-specific changes in cone-driven retinal function during periods of elevated IOP. These IOP-related effects can occur in the absence of retinal ganglion cells and may be reversible. PMID:20422254

  16. Jaw-Opening Reflex and Corticobulbar Motor Excitability Changes During Quiet Sleep in Non-Human Primates

    PubMed Central

    Yao, Dongyuan; Lavigne, Gilles J.; Lee, Jye-Chang; Adachi, Kazunori; Sessle, Barry J.

    2013-01-01

    Study Objective: To test the hypothesis that the reflex and corticobulbar motor excitability of jaw muscles is reduced during sleep. Design: Polysomnographic recordings in the electrophysiological study. Setting: University sleep research laboratories. Participants and Interventions: The reflex and corticobulbar motor excitability of jaw muscles was determined during the quiet awake state (QW) and quiet sleep (QS) in monkeys (n = 4). Measurements and Results: During QS sleep, compared to QW periods, both tongue stimulation-evoked jaw-opening reflex peak and root mean square amplitudes were significantly decreased with stimulations at 2-3.5 × thresholds (P < 0.001). The jaw-opening reflex latency during sleep was also significantly longer than during QW. Intracortical microstimulation (ICMS) within the cortical masticatory area induced rhythmic jaw movements at a stable threshold (≤ 60 μA) during QW; but during QS, ICMS failed to induce any rhythmic jaw movements at the maximum ICMS intensity used, although sustained jaw-opening movements were evoked at significantly increased threshold (P < 0.001) in one of the monkeys. Similarly, during QW, ICMS within face primary motor cortex induced orofacial twitches at a stable threshold (≤ 35 μA), but the ICMS thresholds were elevated during QS. Soon after the animal awoke, rhythmic jaw movements and orofacial twitches could be evoked at thresholds similar to those before QS. Conclusions: The results suggest that the excitability of reflex and corticobulbar-evoked activity in the jaw motor system is depressed during QS. Citation: Yao D; Lavigne GJ; Lee JC; Adachi K; Sessle BJ. Jaw-opening reflex and corticobulbar motor excitability changes during quiet sleep in non-human primates. SLEEP 2013;36(2):269-280. PMID:23372275

  17. Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry.

    PubMed

    Derakhchan, K; Chui, R W; Stevens, D; Gu, W; Vargas, H M

    2014-01-01

    During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter. Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg⁻¹) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics. Sotalol attained Cmax values 1-3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg⁻¹ sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT. The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks. © 2013 The British Pharmacological Society.

  18. Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry

    PubMed Central

    Derakhchan, K; Chui, RW; Stevens, D; Gu, W; Vargas, HM

    2014-01-01

    Background and Purpose: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter. Experimental Approach: Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg−1) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics. Key Results: Sotalol attained Cmax values 1–3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg−1 sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT. Conclusions and Implications: The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks. PMID:24372552

  19. Physiological responses to chronic heat exposure in an aging non-human primate species, the gray mouse lemur (Microcebus murinus).

    PubMed

    Terrien, J; Blanc, S; Zizzari, P; Epelbaum, J; Aujard, F

    2011-09-01

    Epidemiological evidence related to increased death from hyperthermia suggests higher frailty in the elderly when exposed to high ambient temperatures. Despite the recent awareness of such public health problems, integrative studies investigating the effects of age on the physiological responses to heat wave thermal conditions remain scarce. Daily rhythmicity of core temperature (T(c)) and locomotor activity (LA), as well as parameters representative of energy balance and IGF-1 levels which are involved in the aging process and stress resistance, were monitored in a non-human primate species, the gray mouse lemur (Microcebus murinus). Adult and aged animals, acclimated to long days (LD) or short days (SD), were monitored during 8-day periods of exposure to 25 ° C and 34 ° C. Adult animals displayed efficient coping with heat exposure, regardless of the photoperiod. Hence, efficient responses resulted in decrease of energy intake, energy expenditure, IGF-1 levels and LA levels, promoting hyperthermia avoidance. Positive energy balance was maintained and water turnover did not change significantly after heat exposure. In contrast, while aged animals acclimated to LD responded similarly to adults, aged mouse lemurs acclimated to SD showed great difficulties coping with heat exposure. Indeed, in this group, normothermia impairment was associated with increased T(c) levels, alterations in daily rhythmicity, negative energy balance and increased IGF-1 levels. Impaired responses to heat exposure were seen in aged mouse lemurs acclimated to SD only. The main effects were observed during diurnal resting periods, suggesting decreased capacities with age to dissipate excess body heat. Taken together, these data highlight daily rhythmicity and IGF-1 pathway as main targets in the impaired response to heat exposure in the elderly. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. High dose of plasmid IL-15 inhibits immune responses in an influenza non-human primates immunogenicity model

    SciTech Connect

    Yin Jiangmei; Dai Anlan; Laddy, Dominick J.; Yan Jian; Arango, Tatiana; Khan, Amir S.; Lewis, Mark G.; Andersen, Hanne; Kutzler, Michele A.; Draghia-Akli, Ruxandra; Weiner, David B.; Boyer, Jean D.

    2009-10-10

    Interleukin (IL)-15, is a cytokine that is important for the maintenance of long-lasting, high-avidity T cell response to invading pathogens and has, therefore, been used in vaccine and therapeutic platforms as an adjuvant. In addition to pure protein delivery, plasmids encoding the IL-15 gene have been utilized. However, it is critical to determine the appropriate dose to maximize the adjuvanting effects. We immunized rhesus macaques with different doses of IL-15 expressing plasmid in an influenza non-human primate immunogenicity model. We found that co-immunization of rhesus macaques with a Flu DNA-based vaccine and low doses of plasmid encoding macaque IL-15 enhanced the production of IFN-gamma (0.5 mg) and the proliferation of CD4{sup +} and CD8{sup +} T cells, as well as T{sub CM} levels in proliferating CD8{sup +} T cells (0.25 mg). Whereas, high doses of IL-15 (4 mg) decrease the production of IFN-gamma and the proliferation of CD4{sup +} and CD8{sup +} T cells and T{sub CM} levels in the proliferating CD4{sup +} and CD8{sup +} T cells. In addition, the data of hemagglutination inhibition (HI) antibody titer suggest that although not significantly different, there appears to be a slight increase in antibodies at lower doses of IL-15. Importantly, however, the higher doses of IL-15 decrease the antibody levels significantly. This study demonstrates the importance of optimizing DNA-based cytokine adjuvants.

  1. Bridging non-human primate correlates of protection to reassess the Anthrax Vaccine Adsorbed booster schedule in humans.

    PubMed

    Schiffer, Jarad M; Chen, Ligong; Dalton, Shannon; Niemuth, Nancy A; Sabourin, Carol L; Quinn, Conrad P

    2015-07-17

    Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved for use in humans as a priming series of 3 intramuscular (i.m.) injections (0, 1, 6 months; 3-IM) with boosters at 12 and 18 months, and annually thereafter for those at continued risk of infection. A reduction in AVA booster frequency would lessen the burden of vaccination, reduce the cumulative frequency of vaccine associated adverse events and potentially expand vaccine coverage by requiring fewer doses per schedule. Because human inhalation anthrax studies are neither feasible nor ethical, AVA efficacy estimates are determined using cross-species bridging of immune correlates of protection (COP) identified in animal models. We have previously reported that the AVA 3-IM priming series provided high levels of protection in non-human primates (NHP) against inhalation anthrax for up to 4 years after the first vaccination. Penalized logistic regressions of those NHP immunological data identified that anti-protective antigen (anti-PA) IgG concentration measured just prior to infectious challenge was the most accurate single COP. In the present analysis, cross-species logistic regression models of this COP were used to predict probability of survival during a 43 month study in humans receiving the current 3-dose priming and 4 boosters (12, 18, 30 and 42 months; 7-IM) and reduced schedules with boosters at months 18 and 42 only (5-IM), or at month 42 only (4-IM). All models predicted high survival probabilities for the reduced schedules from 7 to 43 months. The predicted survival probabilities for the reduced schedules were 86.8% (4-IM) and 95.8% (5-IM) at month 42 when antibody levels were lowest. The data indicated that 4-IM and 5-IM are both viable alternatives to the current AVA pre-exposure prophylaxis schedule. Published by Elsevier Ltd.

  2. Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

    PubMed Central

    Justinova, Zuzana; Panlilio, Leigh V; Moreno-Sanz, Guillermo; Redhi, Godfrey H; Auber, Alessia; Secci, Maria E; Mascia, Paola; Bandiera, Tiziano; Armirotti, Andrea; Bertorelli, Rosalia; Chefer, Svetlana I; Barnes, Chanel; Yasar, Sevil; Piomelli, Daniele; Goldberg, Steven R

    2015-01-01

    Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3’-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose–response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell—consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement. PMID:25754762

  3. A Recommended Laparoscopic Procedure for Implantation of Microcapsules in the Peritoneal Cavity of Non-human Primates

    PubMed Central

    Qi, Meirigeng; Lacik, Igor; Kolláriková, Gabriela; Strand, Berit L; Formo, Kjetil; Wang, Yong; Marchese, Enza; Mendoza-Elias, Joshua E.; Kinzer, Katie P.; Gatti, Francesca; Paushter, Daniel; Patel, Sonny; Oberholzer, Jose

    2013-01-01

    Background The anatomical spatial distribution of microencapsulated islets transplanted into the peritoneal cavity of large animals remains a relatively unexplored area of study. In this study, we developed a new implantation approach using laparoscopy in order to avoid microcapsule amalgamation. This approach constitutes a clinically relevant method, which can be used to evaluate the distribution and in vivo biocompatibility of various types of transplanted microcapsules in the future. Materials and Methods Two healthy baboons were implanted intraperitoneally with microencapsulated islets through mini-laparotomy and observed at 76 days after implantation. Nine baboons underwent laparoscopic implantation of approximately 80,000 empty microcapsules. Microcapsule distribution was observed by laparoscopic camera during and after implantation at 1, 2, and 4 weeks. At each time point, microcapsules were retrieved and evaluated with brightfield microscopy and histological analysis. Results Mini-laparotomic implantation resulted in microcapusle aggregation in both baboons. In contrast, laparoscopic implantation resulted in even distribution of microcapsules throughout the peritoneum without sedimentation to the Douglas space in all animals. In 8 out of 9 animals, retrieved microcapsules were evenly distributed in the peritoneal cavity and presented with no pericapsular overgrowth and easily washed out during laparoscopic procedure. The one exception was attributed to microcapsule contamination with blood from the abdominal wall following trocar insertion. Conclusions Laparoscopic implantation of microcapsules in non-human primates can be successfully performed and prevents microcapsule aggregation. Given the current widespread clinical application of laparoscopy, we propose that this presented laparoscopy technique could be applied in future clinical trials of microencapsulated islet transplantation. PMID:21435661

  4. Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration.

    PubMed

    Porrino, Linda J; Beveridge, Thomas J R; Smith, Hilary R; Nader, Michael A

    2016-05-01

    Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2-[(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine-paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self-administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure. © 2015 Society for the Study of Addiction.

  5. Demonstration of a setup for chronic optogenetic stimulation and recording across cortical areas in non-human primates

    NASA Astrophysics Data System (ADS)

    Yazdan-Shahmorad, Azadeh; Diaz-Botia, Camilo; Hanson, Tim; Ledochowitsch, Peter; Maharabiz, Michel M.; Sabes, Philip N.

    2015-03-01

    Although several studies have shown the feasibility of using optogenetics in non-human primates (NHP), reliable largescale chronic interfaces have not yet been reported for such studies in NHP. Here we introduce a chronic setup that permits repeated, daily optogenetic stimulation and large-scale recording from the same sites in NHP cortex. The setup combines optogenetics with a transparent artificial dura (AD) and high-density micro-electrocorticography (μECoG). To obtain expression across large areas of cortex, we infused AAV5-CamKIIa-C1V1-EYFP viral vector using an infusion technique based on convection-enhanced delivery (CED) in primary somatosensory (S1) and motor (M1) cortices. By epifluorescent imaging through AD we were able to confirm high levels of expression covering about 110 mm2 of S1 and M1. We then incorporated a 192-channel μECoG array spanning 192 mm2 into the AD for simultaneous electrophysiological recording during optical stimulation. The array consists of patterned Pt-Au-Pt metal traces embedded in ~10 μm Parylene-C insulator. The parylene is sufficiently transparent to allow minimally attenuated optical access for optogenetic stimulation. The array was chronically implanted over the opsin-expressing areas in M1 and S1 for over two weeks. Optical stimulation was delivered via a fiber optic placed on the surface of the AD. With this setup, we recorded reliable evoked activity following light stimulation at several locations. Similar responses were recorded across tens of days, however a decline in the light-evoked signal amplitude was observed during this period due to the growth of dural tissue over the array. These results show the feasibility of a chronic interface for combined largescale optogenetic stimulation and cortical recordings across days.

  6. Effects of metoprolol on epinephrine-induced takotsubo-like left ventricular dysfunction in non-human primates.

    PubMed

    Izumi, Yasukatsu; Okatani, Hideaki; Shiota, Masayuki; Nakao, Takafumi; Ise, Ryota; Kito, Go; Miura, Katsuyuki; Iwao, Hiroshi

    2009-05-01

    Takotsubo cardiomyopathy, alternatively known as stress cardiomyopathy, is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction. To elucidate the mechanism, we tried to make a new model of takotsubo-like cardiomyopathy in non-human primates. Echocardiography revealed that repeated intravenous infusion of epinephrine overdose in cynomolgus monkeys induced takotsubo-like cardiomyopathy, which is characterized by progressive left ventricle and depressed systolic function with severe hypokinesis in apical regions and hyperkinesis in the basal region. Although this cardiac dysfunction almost normalized after a month even without any treatment, metoprolol, a beta-blocker, improved the decreased ejection fraction earlier than in the control. Luxol fast blue staining, which is useful for estimating myocytolysis, showed that increased myocytolysis was observed in the apical ventricle of the epinephrine-infused heart. Metoprolol diminished epinephrine-induced cardiomyocytolysis. To explain the mechanism of takotsubo myopathy and the effect of metoprolol, gene expressions in apical or basal ventricle were compared. Heart failure-related genes, such as brain natriuretic peptide, connective tissue growth factor and osteopontin; calcium signaling-related genes, such as ryanodine receptor 2, sarcoendoplasmic reticulum Ca(2+)-ATPase 2A2 and adenylate cyclase 7; renin-angiotensin system-related genes, such as angiotensinogen, angiotensin II receptor, type 1 and type 2; and mitochondria-related genes, such as peroxisome proliferator-activated receptor-gamma co-activator-1alpha, cytochrome c and transcription factor A mitochondrial, were significantly changed at the apical ventricle rather than at the basal ventricle. The changes of some genes improved with metoprolol treatment. These results indicate that this model is valuable in understanding the pathogenesis of takotsubo cardiomyopathy and the effectivity of beta-blockers.

  7. Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.

    PubMed

    Justinova, Zuzana; Panlilio, Leigh V; Moreno-Sanz, Guillermo; Redhi, Godfrey H; Auber, Alessia; Secci, Maria E; Mascia, Paola; Bandiera, Tiziano; Armirotti, Andrea; Bertorelli, Rosalia; Chefer, Svetlana I; Barnes, Chanel; Yasar, Sevil; Piomelli, Daniele; Goldberg, Steven R

    2015-08-01

    Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.

  8. Multifocal electroretinogram (MFERG) evaluation of laser-induced secondary damage in the non-human primate (NHP)

    NASA Astrophysics Data System (ADS)

    Zwick, Harry; Stuck, Bruce E.; Akers, A.; Edsall, Peter; DiCarlo, Cheryl D.; Lund, David J.

    2005-04-01

    Laser induced retinal damage may involve primary injury to the central retina and secondary damage, including intraretinal scar formation (IRSF) retinal traction (RT) and retinal nerve fiber layer injury (RNFL). We have evaluated these laser induced retinal pathologies with MFERG in non-human primates (NHPs) with a Veris (4.9) MFERG system 103 Hexagons, centered on the macula with non-scaled arrays and in one NHP with a 2-frame/M-step sequence to assess long term exposure effects within the RNFL. Chemical restraint was achieved using Ketamine stability HCL (10 mg/kg IM) and Propofol (0.5 mg-1.2/Kg/min via syringe pump). Peribulbar eye blocks were performed using 2% lidocain or a mixture of 2% Lidocain/Marcain (monitored ocular motility was less than 40 microns in retinal space). Primary and secondary damage effects were induced with either q-switched single pulse Neodymium (1064 nm, 1.0 mJ) or Argon CW (10 to 1000 msec, 10-150 mW). MFERG demonstrated capability to detect primary and secondary induced retinal damage in both 1st and 2nd order kernels. Primary and secondary damage in the central retina was often suppressed in amplitude and with longer latencies relative to the MFERG norm. Preliminary investigations in one NHP with Primary and secondary RNFL damage at 9 to 14 months showed recovery with non-scaled array one frame / M-step sequence but demonstrated significant abnormalities for a two frame/ M-step sequence. Utilization of advanced Veris recording parameters involving spatial and temporal manipulation of the stimulus parameters can improve detection of functional deficits induced by focal laser retinal injury.

  9. Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator

    NASA Astrophysics Data System (ADS)

    Connolly, Allison T.; Muralidharan, Abirami; Hendrix, Claudia; Johnson, Luke; Gupta, Rahul; Stanslaski, Scott; Denison, Tim; Baker, Kenneth B.; Vitek, Jerrold L.; Johnson, Matthew D.

    2015-12-01

    Objective. Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach. Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results. LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10-30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects’ limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30-60 s, but there was no correlation with beta band power. Significance. This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject’s symptomatology.

  10. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species.

    PubMed

    Johnston, Miles; Zakharov, Andrei; Papaiconomou, Christina; Salmasi, Giselle; Armstrong, Dianna

    2004-12-10

    BACKGROUND: The parenchyma of the brain does not contain lymphatics. Consequently, it has been assumed that arachnoid projections into the cranial venous system are responsible for cerebrospinal fluid (CSF) absorption. However, recent quantitative and qualitative evidence in sheep suggest that nasal lymphatics have the major role in CSF transport. Nonetheless, the applicability of this concept to other species, especially to humans has never been clarified. The purpose of this study was to compare the CSF and nasal lymph associations in human and non-human primates with those observed in other mammalian species. METHODS: Studies were performed in sheep, pigs, rabbits, rats, mice, monkeys and humans. Immediately after sacrifice (or up to 7 hours after death in humans), yellow Microfil was injected into the CSF compartment. The heads were cut in a sagittal plane. RESULTS: In the seven species examined, Microfil was observed primarily in the subarachnoid space around the olfactory bulbs and cribriform plate. The contrast agent followed the olfactory nerves and entered extensive lymphatic networks in the submucosa associated with the olfactory and respiratory epithelium. This is the first direct evidence of the association between the CSF and nasal lymph compartments in humans. CONCLUSIONS: The fact that the pattern of Microfil distribution was similar in all species tested, suggested that CSF absorption into nasal lymphatics is a characteristic feature of all mammals including humans. It is tempting to speculate that some disorders of the CSF system (hydrocephalus and idiopathic intracranial hypertension for example) may relate either directly or indirectly to a lymphatic CSF absorption deficit.

  11. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species

    PubMed Central

    Johnston, Miles; Zakharov, Andrei; Papaiconomou, Christina; Salmasi, Giselle; Armstrong, Dianna

    2004-01-01

    Background The parenchyma of the brain does not contain lymphatics. Consequently, it has been assumed that arachnoid projections into the cranial venous system are responsible for cerebrospinal fluid (CSF) absorption. However, recent quantitative and qualitative evidence in sheep suggest that nasal lymphatics have the major role in CSF transport. Nonetheless, the applicability of this concept to other species, especially to humans has never been clarified. The purpose of this study was to compare the CSF and nasal lymph associations in human and non-human primates with those observed in other mammalian species. Methods Studies were performed in sheep, pigs, rabbits, rats, mice, monkeys and humans. Immediately after sacrifice (or up to 7 hours after death in humans), yellow Microfil was injected into the CSF compartment. The heads were cut in a sagittal plane. Results In the seven species examined, Microfil was observed primarily in the subarachnoid space around the olfactory bulbs and cribriform plate. The contrast agent followed the olfactory nerves and entered extensive lymphatic networks in the submucosa associated with the olfactory and respiratory epithelium. This is the first direct evidence of the association between the CSF and nasal lymph compartments in humans. Conclusions The fact that the pattern of Microfil distribution was similar in all species tested, suggested that CSF absorption into nasal lymphatics is a characteristic feature of all mammals including humans. It is tempting to speculate that some disorders of the CSF system (hydrocephalus and idiopathic intracranial hypertension for example) may relate either directly or indirectly to a lymphatic CSF absorption deficit. PMID:15679948

  12. Uterus transplantation in a non-human primate: long-term follow-up after autologous transplantation.

    PubMed

    Johannesson, L; Enskog, A; Dahm-Kähler, P; Hanafy, A; Chai, D C; Mwenda, J M; Díaz-García, C; Olausson, M; Brännström, M

    2012-06-01

    Uterus transplantation (UTx) may provide the first available treatment for women affected by uterine infertility. The present study aimed to further develop a surgical technique for autologous UTx in a non-human primate species and to assess long-term function. Female baboons (n= 16) underwent autologous transplantation of the uterus with the Fallopian tubes and ovaries, performed with a previously published surgical technique (n= 6, Group 1) or using a modified technique (n= 10; Group 2). The uterine arteries were dissected to the proximal end of the anterior branch (Group 1) or the entire (Group 2) internal iliac artery, and the ovarian veins were dissected to the crossing over the ureter (Group 1) or further cranially to include greater lengths and patches of the cava/renal vein (Group 2). Back-table preparation created common venous and arterial ends with arterial anastomosis either end-to-side to the left external iliac artery (Group 1) or end-to-end to the left internal iliac artery (Group 2). Overall short-time survival of the animals was 88% (66% in Group 1 and 100% in Group 2). Of all the operated animals, 75% (66% in Group 1 and 80% in Group 2) resumed ovarian cyclicity. Regular menstruation after UTx was demonstrated only in Group 2 (60%). Menstruating animals (n= 6) were each exposed to timed mating for ≥5 menstrual cycles, but pregnancy did not occur. Adhesions and tubal blockage were seen in post-mortem analysis. The modified UTx model of Group 2 is a safe procedure and shows resumed long-term uterine function in a majority of the animals, although pregnancy could not be demonstrated.

  13. Mechanical Design and Analysis of a Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates

    PubMed Central

    Salegio, Ernesto A.; Camisa, William; Tam, Horace; Beattie, Michael S.; Bresnahan, Jacqueline C.

    2016-01-01

    Abstract Non-human primate (NHP) models of spinal cord injury better reflect human injury and provide a better foundation to evaluate potential treatments and functional outcomes. We combined finite element (FE) and surrogate models with impact data derived from in vivo experiments to define the impact mechanics needed to generate a moderate severity unilateral cervical contusion injury in NHPs (Macaca mulatta). Three independent variables (impactor displacement, alignment, and pre-load) were examined to determine their effects on tissue level stresses and strains. Mechanical measures of peak force, peak displacement, peak energy, and tissue stiffness were analyzed as potential determinants of injury severity. Data generated from FE simulations predicted a lateral shift of the spinal cord at high levels of compression (>64%) during impact. Submillimeter changes in mediolateral impactor position over the midline increased peak impact forces (>50%). Surrogate cords established a 0.5 N pre-load protocol for positioning the impactor tip onto the dural surface to define a consistent dorsoventral baseline position before impact, which corresponded with cerebrospinal fluid displacement and entrapment of the spinal cord against the vertebral canal. Based on our simulations, impactor alignment and pre-load were strong contributors to the variable mechanical and functional outcomes observed in in vivo experiments. Peak displacement of 4 mm after a 0.5N pre-load aligned 0.5–1.0 mm over the midline should result in a moderate severity injury; however, the observed peak force and calculated peak energy and tissue stiffness are required to properly characterize the severity and variability of in vivo NHP contusion injuries. PMID:26670940

  14. Mechanical Design and Analysis of a Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates.

    PubMed

    Sparrey, Carolyn J; Salegio, Ernesto A; Camisa, William; Tam, Horace; Beattie, Michael S; Bresnahan, Jacqueline C

    2016-06-15

    Non-human primate (NHP) models of spinal cord injury better reflect human injury and provide a better foundation to evaluate potential treatments and functional outcomes. We combined finite element (FE) and surrogate models with impact data derived from in vivo experiments to define the impact mechanics needed to generate a moderate severity unilateral cervical contusion injury in NHPs (Macaca mulatta). Three independent variables (impactor displacement, alignment, and pre-load) were examined to determine their effects on tissue level stresses and strains. Mechanical measures of peak force, peak displacement, peak energy, and tissue stiffness were analyzed as potential determinants of injury severity. Data generated from FE simulations predicted a lateral shift of the spinal cord at high levels of compression (>64%) during impact. Submillimeter changes in mediolateral impactor position over the midline increased peak impact forces (>50%). Surrogate cords established a 0.5 N pre-load protocol for positioning the impactor tip onto the dural surface to define a consistent dorsoventral baseline position before impact, which corresponded with cerebrospinal fluid displacement and entrapment of the spinal cord against the vertebral canal. Based on our simulations, impactor alignment and pre-load were strong contributors to the variable mechanical and functional outcomes observed in in vivo experiments. Peak displacement of 4 mm after a 0.5N pre-load aligned 0.5-1.0 mm over the midline should result in a moderate severity injury; however, the observed peak force and calculated peak energy and tissue stiffness are required to properly characterize the severity and variability of in vivo NHP contusion injuries.

  15. Real-Time, Transcranial Monitoring of Safe Blood-Brain Barrier Opening in Non-Human Primates

    PubMed Central

    Wu, Shih-Ying; Tung, Yao-Sheng; Downs, Matthew; Wang, Shutao; Chen, Cherry; Ferrera, Vincent; Konofagou, Elisa E.

    2014-01-01

    The delivery of drugs to specific neural targets faces two fundamental problems: (1) most drugs do not cross the blood-brain barrier, and (2) those that do, spread to the entire brain. To date, there exists only one non-invasive methodology with the potential to solve these problems: selective blood-brain barrier (BBB) opening using micro-bubble enhanced focused ultrasound. We have recently developed a single-element 500-kHz spherical transducer ultrasound setup for targeted BBB opening in the non-human primate that does not require simultaneous MRI monitoring. So far, however, the targeting accuracy that can be achieved with this system has not been quantified systematically. In this paper, the accuracy of this system was tested by targeting caudate nucleus and putamen of the basal ganglia in two macaque monkeys. The average lateral targeting error of the system was ∼2.5 mm while the axial targeting error, i.e., along the ultrasound path, was ∼1.5 mm. We have also developed a real-time treatment monitoring technique based on cavitation spectral analysis. This technique also allowed for delineation of a safe and reliable acoustic parameter window for BBB opening. In summary, the targeting accuracy of the system was deemed to be suitable to reliably open the BBB in specific sub-structures of the basal ganglia even in the absence of MRI-based verification of opening volume and position. This establishes the method and the system as a potentially highly useful tool for brain drug delivery. PMID:24505248

  16. Alveolar ridge dimensional changes following ridge preservation procedure: part-2 - CBCT 3D analysis in non-human primate model.

    PubMed

    Omran, Mostafa; Min, Seiko; Abdelhamid, Alaa; Liu, Yi; Zadeh, Homayoun H

    2016-07-01

    The aim of this study was to evaluate the efficacy of ridge preservation involving novel devices used for obturation of socket orifice (Socket cap; SocketKAP(™) ) and resorbable cage used for space maintenance in sites with facial wall dehiscence (Socket cage; SocketKAGE(™) ). Eight teeth were extracted in each of six Macaca fascicularis non-human primates. Six intervention groups consisted of the following: Group A: intact socket negative control. Group B: intact socket: socket cap. Group C: intact socket filled with anorganic bovine bone mineral (ABBM) + socket cap. Group D: dehiscence: negative control. Group E: dehiscence: socket cap + socket cage. Group F: dehiscence: filled with ABBM + socket cap + socket cage. CBCT scans were obtained preoperatively and at 6 and 12 weeks following intervention. The pre- and postoperative scans were superimposed, to quantify 3D volumetric alveolar bone changes. Volumetric bone loss occurred in all sockets, not only within the cretal zone (0-3 mm) to the ridge crest, as has been commonly reported by other investigators, but significant bone loss was also detected in the zone which was 3-6 mm apical to the alveolar crest. For intact sockets, socket cap + ABBM led to significantly greater percentages of remaining bone volume when compared to groups A and B. A significant difference favoring socket cap + socket cage + ABBM treatment was observed for sockets with facial dehiscence defects compared to groups D and E. Socket cap in conjunction with ABBM appears effective in limiting post-extraction volumetric bone loss in intact sockets, while socket cap + socket cage + ABBM appears effective in limiting post-extraction bone loss in sockets with dehiscence defects. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. A Coaxial Optrode As Multifunction Write-Read Probe for Optogenetic Studies in Non-Human Primates

    PubMed Central

    Ozden, Ilker; Wang, Jing; Lu, Yao; May, Travis; Lee, Joonhee; Goo, Werapong; O’Shea, Daniel J.; Kalanithi, Paul; Diester, Ilka; Diagne, Mohamed; Deisseroth, Karl; Shenoy, Krishna V.; Nurmikko, Arto V.

    2013-01-01

    Background Advances in optogenetics have led to first reports of expression of light-gated ion-channels in non-human primates (NHPs). However, a major obstacle preventing effective application of optogenetics in NHPs and translation to optogenetic therapeutics is the absence of compatible multifunction optoelectronic probes for (1) precision light delivery, (2) low-interference electrophysiology, (3) protein fluorescence detection, and (4) repeated insertion with minimal brain trauma. New Method Here we describe a novel brain probe device, a “coaxial optrode”, designed to minimize brain tissue damage while microfabricated to perform simultaneous electrophysiology, light delivery and fluorescence measurements in the NHP brain. The device consists of a tapered, gold-coated optical fiber inserted in a polyamide tube. A portion of the gold coating is exposed at the fiber tip to allow electrophysiological recordings in addition to light delivery/collection at the tip. Results Coaxial optrode performance was demonstrated by experiments in rodents and NHPs, and characterized by computational models. The device mapped opsin expression in the brain and achieved precisely targeted optical stimulation and electrophysiology with minimal cortical damage. Comparison with Existing Methods Overall, combined electrical, optical and mechanical features of the coaxial optrode allowed a performance for NHP studies which was not possible with previously existing devices. Conclusions Coaxial optrode is currently being used in two NHP laboratories as a major tool to study brain function by inducing light modulated neural activity and behavior. By virtue of its design, the coaxial optrode can be extended for use as a chronic implant and multisite neural stimulation/recording. PMID:23867081

  18. A coaxial optrode as multifunction write-read probe for optogenetic studies in non-human primates.

    PubMed

    Ozden, Ilker; Wang, Jing; Lu, Yao; May, Travis; Lee, Joonhee; Goo, Werapong; O'Shea, Daniel J; Kalanithi, Paul; Diester, Ilka; Diagne, Mohamed; Deisseroth, Karl; Shenoy, Krishna V; Nurmikko, Arto V

    2013-09-30

    Advances in optogenetics have led to first reports of expression of light-gated ion-channels in non-human primates (NHPs). However, a major obstacle preventing effective application of optogenetics in NHPs and translation to optogenetic therapeutics is the absence of compatible multifunction optoelectronic probes for (1) precision light delivery, (2) low-interference electrophysiology, (3) protein fluorescence detection, and (4) repeated insertion with minimal brain trauma. Here we describe a novel brain probe device, a "coaxial optrode", designed to minimize brain tissue damage while microfabricated to perform simultaneous electrophysiology, light delivery and fluorescence measurements in the NHP brain. The device consists of a tapered, gold-coated optical fiber inserted in a polyamide tube. A portion of the gold coating is exposed at the fiber tip to allow electrophysiological recordings in addition to light delivery/collection at the tip. Coaxial optrode performance was demonstrated by experiments in rodents and NHPs, and characterized by computational models. The device mapped opsin expression in the brain and achieved precisely targeted optical stimulation and electrophysiology with minimal cortical damage. Overall, combined electrical, optical and mechanical features of the coaxial optrode allowed a performance for NHP studies which was not possible with previously existing devices. Coaxial optrode is currently being used in two NHP laboratories as a major tool to study brain function by inducing light modulated neural activity and behavior. By virtue of its design, the coaxial optrode can be extended for use as a chronic implant and multisite neural stimulation/recording. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Refinements in husbandry, care and common procedures for non-human primates: Ninth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement.

    PubMed

    Jennings, M; Prescott, M J; Buchanan-Smith, Hannah M; Gamble, Malcolm R; Gore, Mauvis; Hawkins, Penny; Hubrecht, Robert; Hudson, Shirley; Jennings, Maggy; Keeley, Joanne R; Morris, Keith; Morton, David B; Owen, Steve; Pearce, Peter C; Prescott, Mark J; Robb, David; Rumble, Rob J; Wolfensohn, Sarah; Buist, David

    2009-04-01

    Preface Whenever animals are used in research, minimizing pain and distress and promoting good welfare should be as important an objective as achieving the experimental results. This is important for humanitarian reasons, for good science, for economic reasons and in order to satisfy the broad legal principles in international legislation. It is possible to refine both husbandry and procedures to minimize suffering and improve welfare in a number of ways, and this can be greatly facilitated by ensuring that up-to-date information is readily available. The need to provide such information led the British Veterinary Association Animal Welfare Foundation (BVAAWF), the Fund for the Replacement of Animals in Medical Experiments (FRAME), the Royal Society for the Prevention of Cruelty to Animals (RSPCA) and the Universities Federation for Animal Welfare (UFAW) to establish a Joint Working Group on Refinement (JWGR) in the UK. The chair is Professor David Morton and the secretariat is provided by the RSPCA. This report is the ninth in the JWGR series. The RSPCA is opposed to the use of animals in experiments that cause pain, suffering, distress or lasting harm and together with FRAME has particular concerns about the continued use of non-human primates. The replacement of primate experiments is a primary goal for the RSPCA and FRAME. However, both organizations share with others in the Working Group, the common aim of replacing primate experiments wherever possible, reducing suffering and improving welfare while primate use continues. The reports of the refinement workshops are intended to help achieve these aims. This report produced by the British Veterinary Association Animal Welfare Foundation (BVAAWF)/Fund for the Replacement of Animals in Medical Experiments (FRAME)/Royal Society for the Prevention of Cruelty to Animals (RSPCA)/Universities Federation for Animal Welfare (UFAW) Joint Working Group on Refinement (JWGR) sets out practical guidance on refining the

  20. Nodular Worm Infections in Wild Non-human Primates and Humans Living in the Sebitoli Area (Kibale National Park, Uganda): Do High Spatial Proximity Favor Zoonotic Transmission?

    PubMed

    Cibot, Marie; Guillot, Jacques; Lafosse, Sophie; Bon, Céline; Seguya, Andrew; Krief, Sabrina

    2015-01-01

    Nodular Oesophagostomum genus nematodes are a major public health concern in some African regions because they can be lethal to humans. Their relatively high prevalence in people has been described in Uganda recently. While non-human primates also harbor Oesophagostomum spp., the epidemiology of this oesophagostomosis and the role of these animals as reservoirs of the infection in Eastern Africa are not yet well documented. The present study aimed to investigate Oesophagostomum infection in terms of parasite species diversity, prevalence and load in three non-human primates (Pan troglodytes, Papio anubis, Colobus guereza) and humans living in close proximity in a forested area of Sebitoli, Kibale National Park (KNP), Uganda. The molecular phylogenetic analyses provided the first evidence that humans living in the Sebitoli area harbored O. stephanostomum, a common species in free-ranging chimpanzees. Chimpanzees were also infected by O. bifurcum, a common species described in human populations throughout Africa. The recently described Oesophagostomum sp. found in colobine monkeys and humans and which was absent from baboons in the neighboring site of Kanyawara in KNP (10 km from Sebitoli), was only found in baboons. Microscopic analyses revealed that the infection prevalence and parasite load in chimpanzees were significantly lower in Kanyawara than in Sebitoli, an area more impacted by human activities at its borders. Three different Oesophagostomum species circulate in humans and non-human primates in the Sebitoli area and our results confirm the presence of a new genotype of Oesophagostomum recently described in Uganda. The high spatiotemporal overlap between humans and chimpanzees in the studied area coupled with the high infection prevalence among chimpanzees represent factors that could increase the risk of transmission for O. stephanostomum between the two primate species. Finally, the importance of local-scale research for zoonosis risk management is

  1. Prevalence of gastrointestinal parasites in captive non-human primates of twenty-four zoological gardens in China.

    PubMed

    Li, Mei; Zhao, Bo; Li, Bo; Wang, Qiang; Niu, Lili; Deng, Jiabo; Gu, Xiaobin; Peng, Xuerong; Wang, Tao; Yang, Guangyou

    2015-06-01

    Captive primates are susceptible to gastrointestinal (GIT) parasitic infections, which are often zoonotic and can contribute to morbidity and mortality. Fecal samples were examined by the means of direct smear, fecal flotation, fecal sedimentation, and fecal cultures. Of 26.51% (317/1196) of the captive primates were diagnosed gastrointestinal parasitic infections. Trichuris spp. were the most predominant in the primates, while Entamoeba spp. were the most prevalent in Old World monkeys (P < 0.05). These preliminary data will improve the management of captive primates and the safety of animal keepers and visitors.

  2. Learning at a distance II. Statistical learning of non-adjacent dependencies in a non-human primate.

    PubMed

    Newport, Elissa L; Hauser, Marc D; Spaepen, Geertrui; Aslin, Richard N

    2004-09-01

    among learners in the types of patterned regularities they can acquire. Such studies with tamarins open interesting questions about the perceptual and computational capacities of human learners that may be essential for language acquisition, and how they may differ from those of non-human primates.

  3. Replication of live attenuated cold-adapted H2N2 influenza virus vaccine candidates in non human primates.

    PubMed

    Broadbent, Andrew J; Santos, Celia P; Paskel, Myeisha; Matsuoka, Yumiko; Lu, Janine; Chen, Zhongying; Jin, Hong; Subbarao, Kanta

    2015-01-01

    The development of an H2N2 vaccine is a priority in pandemic preparedness planning. We previously showed that a single dose of a cold-adapted (ca) H2N2 live attenuated influenza vaccine (LAIV) based on the influenza A/Ann Arbor/6/60 (AA ca) virus was immunogenic and efficacious in mice and ferrets. However, in a Phase I clinical trial, viral replication was restricted and immunogenicity was poor. In this study, we compared the replication of four H2N2 LAIV candidate viruses, AA ca, A/Tecumseh/3/67 (TEC67 ca), and two variants of A/Japan/305/57 (JAP57 ca) in three non-human primate (NHP) species: African green monkeys (AGM), cynomolgus macaques (CM) and rhesus macaques (RM). One JAP57 ca virus had glutamine and glycine at HA amino acid positions 226 and 228 (Q-G) that binds to α2-3 linked sialic acids, and one had leucine and serine that binds to α2-3 and α2-6 linked residues (L-S). The replication of all ca viruses was restricted, with low titers detected in the upper respiratory tract of all NHP species, however replication was detected in significantly more CMs than AGMs. The JAP57 ca Q-G and TEC67 ca viruses replicated in a significantly higher percentage of NHPs than the AA ca virus, with the TEC67 ca virus recovered from the greatest percentage of animals. Altering the receptor specificity of the JAP57 ca virus from α2-3 to both α2-3 and α2-6 linked sialic acid residues did not significantly increase the number of animals infected or the titer to which the virus replicated. Taken together, our data show that in NHPs the AA ca virus more closely reflects the human experience than mice or ferret studies. We suggest that CMs and RMs may be the preferred species for evaluating H2N2 LAIV viruses, and the TEC67 ca virus may be the most promising H2N2 LAIV candidate for further evaluation.

  4. Replication of live attenuated cold-adapted H2N2 influenza virus vaccine candidates in non human primates

    PubMed Central

    Broadbent, Andrew J.; Santos, Celia P.; Paskel, Myeisha; Matsuoka, Yumiko; Lu, Janine; Chen, Zhongying; Jin, Hong; Subbarao, Kanta

    2014-01-01

    The development of an H2N2 vaccine is a priority in pandemic preparedness planning. We previously showed that a single dose of a cold-adapted (ca) H2N2 live attenuated influenza vaccine (LAIV) based on the influenza A/Ann Arbor/6/60 (AA ca) virus was immunogenic and efficacious in mice and ferrets. However, in a Phase I clinical trial, viral replication was restricted and immunogenicity was poor. In this study, we compared the replication of four H2N2 LAIV candidate viruses, AA ca, A/Tecumseh/3/67 (TEC67 ca), and two variants of A/Japan/305/57 (JAP57 ca) in three non-human primate (NHP) species: African green monkeys (AGM), cynomolgus macaques (CM) and rhesus macaques (RM). One JAP57 ca virus had glutamine and glycine at HA amino acid positions 226 and 228 (Q-G) that binds to α2-3 linked sialic acids, and one had leucine and serine that binds to α2-3 and α2-6 linked residues (L-S). The replication of all ca viruses was restricted, with low titers detected in the upper respiratory tract of all NHP species, however replication was detected in significantly more CMs than AGMs. The JAP57 ca Q-G and TEC67 ca viruses replicated in a significantly higher percentage of NHPs than the AA ca virus, with the TEC67 ca virus recovered from the greatest percentage of animals. Altering the receptor specificity of the JAP57 ca virus from α2-3 to both α2-3 and α2-6 linked sialic acid residues did not significantly increase the number of animals infected or the titer to which the virus replicated. Taken together, our data show that in NHPs the AA ca virus more closely reflects the human experience than mice or ferret studies. We suggest that CMs and RMs may be the preferred species for evaluating H2N2 LAIV viruses, and the TEC67 ca virus may be the most promising H2N2 LAIV candidate for further evaluation. PMID:25444799

  5. Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model.

    PubMed

    League-Pascual, James C; Lester-McCully, Cynthia M; Shandilya, Shaefali; Ronner, Lukas; Rodgers, Louis; Cruz, Rafael; Peer, Cody J; Figg, William D; Warren, Katherine E

    2017-03-13

    The blood-brain barrier (BBB) limits entry of most chemotherapeutic agents into the CNS, resulting in inadequate exposure within CNS tumor tissue. Intranasal administration is a proposed means of delivery that can bypass the BBB, potentially resulting in more effective chemotherapeutic exposure at the tumor site. The objective of this study was to evaluate the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model. Three chemotherapeutic agents with known differences in CNS penetration were selected for intranasal administration in a NHP model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. Intravenous (IV) temozolomide (TMZ), oral (PO) valproic acid, and PO perifosine were administered to adult male rhesus macaques. The animals received a single dose of each agent systemically and intranasally in separate experiments, with each animal acting as his own control. The dose of the agents administered systemically was the human equivalent of a clinically appropriate dose, while the intranasal dose was the maximum achievable dose based on the volume limitation of 1 mL. Multiple serial paired plasma and CSF samples were collected and quantified using a validated uHPLC/tandem mass spectrometry assay after each drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis. CSF penetration was calculated from the ratio of areas under the concentration-time curves for CSF and plasma (AUCCSF:plasma). Intranasal administration was feasible and tolerable for all agents with no significant toxicities observed. For TMZ, the degrees of CSF drug penetration after intranasal and IV administration were 36 (32-57) and 22 (20-41)%, respectively. Although maximum TMZ drug concentration in the CSF (Cmax) was lower after intranasal

  6. Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates.

    PubMed

    Kotterman, M A; Yin, L; Strazzeri, J M; Flannery, J G; Merigan, W H; Schaffer, D V

    2015-02-01

    Gene delivery vectors based on adeno-associated viruses (AAV) have exhibited promise in both preclinical disease models and human clinical trials for numerous disease targets, including the retinal degenerative disorders Leber's congenital amaurosis and choroideremia. One general challenge for AAV is that preexisting immunity, as well as subsequent development of immunity following vector administration, can severely inhibit systemic AAV vector gene delivery. However, the role of neutralizing antibodies (NABs) in AAV transduction of tissues considered to be immune privileged, such as the eye, is unclear in large animals. Intravitreal AAV administration allows for broad retinal delivery, but is more susceptible to interactions with the immune system than subretinal administration. To assess the effects of systemic anti-AAV antibody levels on intravitreal gene delivery, we quantified the anti-AAV antibodies present in sera from non-human primates before and after intravitreal injections with various AAV capsids. Analysis showed that intravitreal administration resulted in an increase in anti-AAV antibodies regardless of the capsid serotype, transgene or dosage of virus injected. For monkeys injected with wild-type AAV2 and/or an AAV2 mutant, the variable that most significantly affected the production of anti-AAV2 antibodies was the amount of virus delivered. In addition, post-injection antibody titers were highest against the serotype administered, but the antibodies were also cross-reactive against other AAV serotypes. Furthermore, NAB levels in serum correlated with those in vitreal fluid, demonstrating both that this route of administration exposes AAV capsid epitopes to the adaptive immune system and that serum measurements are predictive of vitreous fluid NAB titers. Moreover, the presence of preexisting NAB titers in the serum of monkeys correlated strongly (R=0.76) with weak, decaying or no transgene expression following intravitreal administration of AAV

  7. Induction of endometriosis alters the peripheral and endometrial regulatory T cell population in the non-human primate

    PubMed Central

    Braundmeier, A.; Jackson, K.; Hastings, J.; Koehler, J.; Nowak, R.; Fazleabas, A.

    2012-01-01

    BACKGROUND Endometriosis is a gynecological condition that is characterized by extreme abdominal pain and also decreased fertility. Regulatory T cells (Tregs) have immunosuppressive activity critical for embryonic implantation and likewise the acceptance of tissue engraftment. Utilizing the induced non-human primate (Papio anubis) model of endometriosis, we hypothesize that endometriosis decreases the peripheral and endomet rial Treg profile, whereas ectopic lesions have increased Treg localization. METHODS Peripheral blood and endometrium were obtained throughout the menstrual cycle prior to and after induction of disease. Animals were randomly assigned to control (n = 7) or diseased (n = 16) treatment groups. Endometriosis was induced by i.p. injection of autologous menstrual tissue for 2 consecutive months during menses. Peripheral blood and endometrial tissue were collected at d9-11PO at 1, 3, 6, 9, 12 and 15 months post-induction of disease for fluorescence-activated cell sorting, quantitative RT–PCR and immunohistochemistry. Ectopic lesions were excised at 1 and 6 months post-inoculation and also harvested at necropsy (15 months) and processed for RNA of IHC. Identification of Tregs through analysis of FOXP3 expression was conducted utlilizing several methodologies. Differences were determined by non-parametric statistical analysis between all treatment groups and time points. RESULTS In control animals, the proportion of peripheral natural Tregs (nTregs) was reduced (P < 0.05) during the mid- and late secretory stages of the menstrual cycle compared with menses. The induction of disease decreased peripheral Treg expression at early time points (P < 0.05) and this remained low throughout the time course, compared with the pre-inoculatory level of an individual. FOXP3 gene expression and Treg populations were also decreased in the eutopic endometrium (P < 0.05) compared with control animals, whereas these parameters were increased in ectopic lesions (P < 0

  8. Hypothalamic Expression of KISS1 and Gonadotropin Inhibitory Hormone Genes During the Menstrual Cycle of a Non-Human Primate1

    PubMed Central

    Smith, Jeremy T.; Shahab, Muhammad; Pereira, Alda; Pau, K.-Y. Francis; Clarke, Iain J.

    2010-01-01

    Kisspeptin, the product of the KISS1 gene, stimulates gonadotropin-releasing hormone (GnRH) secretion; gonadotropin inhibitory hormone (GnIH), encoded by the RF-amide-related peptide (RFRP) or NPVF gene, inhibits the reproductive axis. In sheep, kisspeptin neurons are found in the lateral preoptic area (POA) and the arcuate nucleus (ARC) and may be important for initiating the preovulatory GnRH/luteinizing hormone (LH) surge. GnIH cells are located in the ovine dorsomedial hypothalamic nucleus (DMN) and paraventricular nucleus (PVN), with similar distribution in the primate. KISS1 cells are found in the primate POA and ARC, but the function that kisspeptin and GnIH play in primates has not been elucidated. We examined KISS1 and NPVF mRNA throughout the menstrual cycle of a female primate, rhesus macaque (Macaca mulatta), using in situ hybridization. KISS1-expressing cells were found in the POA and ARC, and NPVF-expressing cells were located in the PVN/DMN. KISS1 expression in the caudal ARC and POA was higher in the late follicular phase of the cycle (just before the GnRH/LH surge) than in the luteal phase. NPVF expression was also higher in the late follicular phase. We ascertained whether kisspeptin and/or GnIH cells project to GnRH neurons in the primate. Close appositions of kisspeptin and GnIH fibers were found on GnRH neurons, with no change across the menstrual cycle. These data suggest a role for kisspeptin in the stimulation of GnRH cells before the preovulatory GnRH/LH surge in non-human primates. The role of GnIH is less clear, with paradoxical up-regulation of gene expression in the late follicular phase of the menstrual cycle. PMID:20574054

  9. Humans frequently exposed to a range of non-human primate malaria parasite species through the bites of Anopheles dirus mosquitoes in South-central Vietnam.

    PubMed

    Maeno, Yoshimasa; Quang, Nguyen Tuyen; Culleton, Richard; Kawai, Satoru; Masuda, Gaku; Nakazawa, Shusuke; Marchand, Ron P

    2015-07-16

    Recent studies have described natural human infections of the non-human primate parasites Plasmodium knowlesi and Plasmodium cynomolgi. In Southeast Asia, mosquitoes of the Anopheles leucosphyrus group bite both humans and monkeys in the forest and thus offer a possible route for Plasmodium species to bridge the species barrier. In this study we analysed the species composition of malarial sporozoites infecting the salivary glands of Anopheles dirus in order to determine their potential role as bridge vectors of Plasmodium parasites from monkeys to humans. Mosquitoes were collected in the forest and forest fringe area of Khanh Phu commune by human-baited landing collection. Anopheles species were determined on the basis of morphologic features. Sporozoite-infected salivary glands were applied to filter paper and dried in an ambient atmosphere, before storage in closed vials at 4-6 °C. Detection and identification of Plasmodium species in salivary glands were carried out by nested-PCR of the small subunit ribosomal RNA gene. Six species of Plasmodium parasites were detected by PCR, of which P. vivax was the most common, followed by P. knowlesi, P. inui, P. cynomolgi, P. coatneyi and P. falciparum. Twenty-six of the 79 sporozoite infected mosquitoes showed multiple infections, most of which were a combination of P. vivax with one or more of the non-human primate Plasmodium species. These results suggest that humans overnighting in this forest are frequently inoculated with both human and non-human primate malaria parasites, leading to a situation conducive for the emergence of novel zoonotic malaria.

  10. Detection of antibodies to Oropouche virus in non-human primates in Goiânia City, Goiás.

    PubMed

    Gibrail, Marize Moreira; Fiaccadori, Fabíola Souza; Souza, Menira; Almeida, Tâmera Nunes Vieira; Chiang, Jannifer Oliveira; Martins, Lívia Caricio; Ferreira, Milene Silveira; Cardoso, Divina das Dôres de Paula

    2016-01-01

    Arboviruses are associated with human disease, and non-human primates (NHPs) are important primary hosts. This study shows the detection of antibodies to Oropouche virus (OROV) in NHPs either living in urban parks or acclimatized at the Wild Animal Screening Center, Goiânia city. Fifty blood samples were analyzed by hemagglutination-inhibition and neutralization assays. Two monkeys (Alouatta caraya) had antibodies to OROV by both techniques. This is the first report demonstrating the detection of OROV antibodies in Goiás State and may represent the introduction/circulation of OROV in the region and a potential risk to the human population.

  11. Fecal Microbiomes of Non-Human Primates in Western Uganda Reveal Species-Specific Communities Largely Resistant to Habitat Perturbation

    PubMed Central

    McCORD, ALEIA I.; CHAPMAN, COLIN A.; WENY, GEOFFREY; TUMUKUNDE, ALEX; HYEROBA, DAVID; KLOTZ, KELLY; KOBLINGS, AVERY S.; MBORA, DAVID N.M.; CREGGER, MELISSA; WHITE, BRYAN A.; LEIGH, STEVEN R.; GOLDBERG, TONY L.

    2014-01-01

    Primate gastrointestinal microbial communities are becoming increasingly appreciated for their relevance to comparative medicine and conservation, but the factors that structure primate “microbiomes” remain controversial. This study examined a community of primates in Kibale National Park, Uganda, to assess the relative importance of host species and location in structuring gastrointestinal microbiomes. Fecal samples were collected from primates in intact forest and from primates in highly disturbed forest fragments. People and livestock living nearby were also included, as was a geographically distant population of related red colobus in Kenya. A culture-free microbial community fingerprinting technique was used to analyze fecal microbiomes from 124 individual red colobus (Procolobus rufomitratus), 100 individual black-and-white colobus (Colobus guereza), 111 individual red-tailed guenons (Cercopithecus ascanius), 578 human volunteers, and 364 domestic animals, including cattle (Bos indicus and B. indicus × B. taurus crosses), goats (Caprus hircus), sheep (Ovis aries), and pigs (Sus scrofa). Microbiomes sorted strongly by host species, and forest fragmentation did not alter this pattern. Microbiomes of Kenyan red colobus sorted distinctly from microbiomes of Ugandan red colobus, but microbiomes from these two red colobus populations clustered more closely with each other than with any other species. Microbiomes from red colobus and black-and-white colobus were more differentiated than would be predicted by the phylogenetic relatedness of these two species, perhaps reflecting heretofore underappreciated differences in digestive physiology between the species. Within Kibale, social group membership influenced intra-specific variation among microbiomes. However, intra-specific variation was higher among primates in forest fragments than among primates in intact forest, perhaps reflecting the physical separation of fragments. These results suggest that, in this

  12. Hidden Population Structure and Cross-species Transmission of Whipworms (Trichuris sp.) in Humans and Non-human Primates in Uganda

    PubMed Central

    Ghai, Ria R.; Simons, Noah D.; Chapman, Colin A.; Omeja, Patrick A.; Davies, T. Jonathan; Ting, Nelson; Goldberg, Tony L.

    2014-01-01

    Background Whipworms (Trichuris sp.) are a globally distributed genus of parasitic helminths that infect a diversity of mammalian hosts. Molecular methods have successfully resolved porcine whipworm, Trichuris suis, from primate whipworm, T. trichiura. However, it remains unclear whether T. trichiura is a multi-host parasite capable of infecting a wide taxonomic breadth of primate hosts or a complex of host specific parasites that infect one or two closely related hosts. Methods and Findings We examined the phylogenetic structure of whipworms in a multi-species community of non-human primates and humans in Western Uganda, using both traditional microscopy and molecular methods. A newly developed nested polymerase chain reaction (PCR) method applied to non-invasively collected fecal samples detected Trichuris with 100% sensitivity and 97% specificity relative to microscopy. Infection rates varied significantly among host species, from 13.3% in chimpanzees (Pan troglodytes) to 88.9% in olive baboons (Papio anubis). Phylogenetic analyses based on nucleotide sequences of the Trichuris internal transcribed spacer regions 1 and 2 of ribosomal DNA revealed three co-circulating Trichuris groups. Notably, one group was detected only in humans, while another infected all screened host species, indicating that whipworms from this group are transmitted among wild primates and humans. Conclusions and Significance Our results suggest that the host range of Trichuris varies by taxonomic group, with some groups showing host specificity, and others showing host generality. In particular, one Trichuris taxon should be considered a multi-host pathogen that is capable of infecting wild primates and humans. This challenges past assumptions about the host specificity of this and similar helminth parasites and raises concerns about animal and human health. PMID:25340752

  13. Hidden population structure and cross-species transmission of whipworms (Trichuris sp.) in humans and non-human primates in Uganda.

    PubMed

    Ghai, Ria R; Simons, Noah D; Chapman, Colin A; Omeja, Patrick A; Davies, T Jonathan; Ting, Nelson; Goldberg, Tony L

    2014-10-01

    Whipworms (Trichuris sp.) are a globally distributed genus of parasitic helminths that infect a diversity of mammalian hosts. Molecular methods have successfully resolved porcine whipworm, Trichuris suis, from primate whipworm, T. trichiura. However, it remains unclear whether T. trichiura is a multi-host parasite capable of infecting a wide taxonomic breadth of primate hosts or a complex of host specific parasites that infect one or two closely related hosts. We examined the phylogenetic structure of whipworms in a multi-species community of non-human primates and humans in Western Uganda, using both traditional microscopy and molecular methods. A newly developed nested polymerase chain reaction (PCR) method applied to non-invasively collected fecal samples detected Trichuris with 100% sensitivity and 97% specificity relative to microscopy. Infection rates varied significantly among host species, from 13.3% in chimpanzees (Pan troglodytes) to 88.9% in olive baboons (Papio anubis). Phylogenetic analyses based on nucleotide sequences of the Trichuris internal transcribed spacer regions 1 and 2 of ribosomal DNA revealed three co-circulating Trichuris groups. Notably, one group was detected only in humans, while another infected all screened host species, indicating that whipworms from this group are transmitted among wild primates and humans. Our results suggest that the host range of Trichuris varies by taxonomic group, with some groups showing host specificity, and others showing host generality. In particular, one Trichuris taxon should be considered a multi-host pathogen that is capable of infecting wild primates and humans. This challenges past assumptions about the host specificity of this and similar helminth parasites and raises concerns about animal and human health.

  14. Recombinant human parainfluenza virus type 2 with mutations in V that permit cellular interferon signaling are not attenuated in non-human primates

    PubMed Central

    Schaap-Nutt, Anne; D’Angelo, Christopher; Amaro-Carambot, Emerito; Nolan, Sheila M.; Davis, Stephanie; Wise, Shenelle-Marie; Higgins, Caraline; Bradley, Konrad; Kim, Olivia; Mayor, Reina; Skiadopoulos, Mario H.; Collins, Peter L.; Murphy, Brian R.; Schmidt, Alexander C.

    2010-01-01

    The HPIV2 V protein inhibits type I interferon (IFN) induction and signaling. To manipulate the V protein, whose coding sequence overlaps that of the polymerase-associated phosphoprotein (P), without altering the P protein, we generated an HPIV2 virus in which P and V are expressed from separate genes (rHPIV2-P+V). rHPIV2-P+V replicated like HPIV2-WT in vitro and in non-human primates. HPIV2-P+V was modified by introducing two separate mutations into the V protein to create rHPIV2-L101E/L102E and rHPIV2-Δ122–127. In contrast to HPIV2-WT, both mutant viruses were unable to degrade STAT2, leaving virus-infected cells susceptible to IFN. Neither mutant, nor HPIV2-WT, induced significant amounts of IFN-β in infected cells. Surprisingly, neither rHPIV2-L101E/L102E nor rHPIV2-Δ122–127 was attenuated in two species of non-human primates. This indicates that loss of HPIV2's ability to inhibit IFN signaling is insufficient to attenuate virus replication in vivo as long as IFN induction is still inhibited. PMID:20667570

  15. Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection.

    PubMed

    Byrum, Stephanie D; Burdine, Marie S; Orr, Lisa; Mackintosh, Samuel G; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin; Tackett, Alan J

    2017-01-01

    Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure.

  16. Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection

    PubMed Central

    Burdine, Marie S.; Orr, Lisa; Mackintosh, Samuel G.; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin; Tackett, Alan J.

    2017-01-01

    Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure. PMID:28350824

  17. Immunogenicity in mice and non-human primates of the Group A Streptococcal J8 peptide vaccine candidate conjugated to CRM197.

    PubMed

    Caro-Aguilar, Ivette; Ottinger, Elizabeth; Hepler, Robert W; Nahas, Deborah D; Wu, Chengwei; Good, Michael F; Batzloff, Michael; Joyce, Joseph G; Heinrichs, Jon H; Skinner, Julie M

    2013-03-01

    Vaccine development for Group A streptococcal (GAS) infection has been extensively focused on the N-terminal hypervariable or the C-terminal conserved regions of the M protein, a major virulence factor of GAS. We evaluated the immunogenicity and functional activity of the conserved C-terminal peptide vaccine candidate, J8, conjugated to CRM197, in two mouse strains: C3H (H2(k)) and Balb/c (H2(d)), and in rhesus macaques. Mice were immunized with J8-CRM197 formulated with Amorphous Aluminum Hydroxyphosphate Sulfate Adjuvant (AAHSA), and non-human primates were immunized with J8-CRM197 formulated with AAHSA, ISCOMATRIX (TM) adjuvant, or AAHSA/ISCOMATRIX adjuvant. J8-CRM197 was immunogenic in mice from both H2(k) and H2(d) backgrounds, and the antibodies generated bound to the surface of four different GAS serotypes and had functional bacterial opsonic activity. Mice immunized with J8-CRM197/AAHSA demonstrated varying degrees of protection from lethal challenge. We also demonstrated that J8-CRM197 is immunogenic in non-human primates. Our data confirm the utility of J8 as a potential GAS vaccine candidate and demonstrate that CRM197 is an acceptable protein carrier for this peptide.

  18. Social networks dynamics revealed by temporal analysis: An example in a non-human primate (Macaca sylvanus) in "La Forêt des Singes".

    PubMed

    Sosa, Sebastian; Zhang, Peng; Cabanes, Guénaël

    2017-06-01

    This study applied a temporal social network analysis model to describe three affiliative social networks (allogrooming, sleep in contact, and triadic interaction) in a non-human primate species, Macaca sylvanus. Three main social mechanisms were examined to determine interactional patterns among group members, namely preferential attachment (i.e., highly connected individuals are more likely to form new connections), triadic closure (new connections occur via previous close connections), and homophily (individuals interact preferably with others with similar attributes). Preferential attachment was only observed for triadic interaction network. Triadic closure was significant in allogrooming and triadic interaction networks. Finally, gender homophily was seasonal for allogrooming and sleep in contact networks, and observed in each period for triadic interaction network. These individual-based behaviors are based on individual reactions, and their analysis can shed light on the formation of the affiliative networks determining ultimate coalition networks, and how these networks may evolve over time. A focus on individual behaviors is necessary for a global interactional approach to understanding social behavior rules and strategies. When combined, these social processes could make animal social networks more resilient, thus enabling them to face drastic environmental changes. This is the first study to pinpoint some of the processes underlying the formation of a social structure in a non-human primate species, and identify common mechanisms with humans. The approach used in this study provides an ideal tool for further research seeking to answer long-standing questions about social network dynamics. © 2017 Wiley Periodicals, Inc.

  19. PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector.

    PubMed

    Fontanellas, A; Hervas-Stubbs, S; Sampedro, A; Collantes, M; Azpilicueta, A; Mauleón, I; Pañeda, A; Quincoces, G; Prieto, J; Melero, I; Peñuelas, I

    2009-01-01

    Non-invasive in vivo imaging of transgene expression is currently providing very important means to optimize gene therapy regimes. Results in non-human primates are considered the most predictive models for the outcome in patients. In this study, we have documented that tumour and primary cell lines from human and non-human primates are comparably gene-transduced in vitro by serotype 5 adenovirus expressing HSV1-thymidine kinase. Transgene expression can be quantified in human and monkey cultured cells by positron emission tomography (PET) imaging when transduced cells are incubated with a fluoride-18 labelled penciclovir analogue. In our hands, PET images of cell cultures estimate the number of transduced cells rather than intensity of transgene expression once a threshold of TK per cell is reached. Interestingly, in vivo systemic administration of a clinical grade recombinant adenovirus expressing TK into macaques gives rise to an intense retention of the radiotracer in the liver parenchyma, providing an experimental system to visualize transgene expression that ought to be similar in human and macaques. Such imaging methodology might contribute to improve strategies based on adenoviral vectors.

  20. Pulmonary administration of interferon Beta-1a-fc fusion protein in non-human primates using an immunoglobulin transport pathway.

    PubMed

    Vallee, Sebastien; Rakhe, Swapnil; Reidy, Thomas; Walker, Sandra; Lu, Qi; Sakorafas, Paul; Low, Susan; Bitonti, Alan

    2012-04-01

    Currently, products containing interferon beta (IFNβ) are injected either intramuscularly or subcutaneously. To avoid the necessity of injection, we developed a novel monomeric Fc fusion protein of IFNβ (IFNβFc) that is absorbed via an immunoglobulin transport system present in the upper and central airways upon administration of the drug as an inhaled aerosol. The systemic absorption of IFNβFc through the lung in non-human primates, at deposited doses of 1, 3, and 10 μg/kg, was compared to the absorption of a single 3 μg/kg dose of IFNβ-1a (Avonex®) subcutaneously administered. IFNβFc was well absorbed through the lung, displaying dose proportional increases in serum concentrations, and was biologically active, as shown by increases in plasma neopterin levels. The circulating half-life of IFNβFc was ∼3 times longer (∼30 h) than that of IFNβ-1a, (8-9 h). At approximately equimolar doses of IFNβFc (10 μg/kg) and IFNβ-1a (3 μg/kg), the stimulation of neopterin over background levels was approximately equivalent, demonstrating that the longer half-life of IFNβFc compensated for the lower relative specific antiviral activity of IFNβFc measured in vitro. In conclusion, IFNβFc was efficiently absorbed after pulmonary delivery in non-human primates, retained its biological activity, and may offer a convenient alternative to injectable IFNβ.

  1. Impact of short access nicotine self-administration on expression of α4β2* nicotinic acetylcholine receptors in non-human primates.

    PubMed

    Le Foll, Bernard; Chefer, Svetlana I; Kimes, Alane S; Stein, Elliot A; Goldberg, Steven R; Mukhin, Alexey G

    2016-05-01

    Although nicotine exposure upregulates the α4β2* subtype of nicotinic acetylcholine receptors (nAChRs), the upregulation of nAChRs in non-human primates voluntarily self-administering nicotine has never been demonstrated. The objective of the study is to determine if short access to nicotine in a non-human primate model of nicotine self-administration is sufficient to induce nAChRs upregulation. We combined a nicotine self-administration paradigm with in vivo measure of α4β2* nAChRs using 2-[(18)F]fluoro-A-85380 (2-FA) and positron emission tomography (PET) in six squirrel monkeys. PET measurement was performed before and after intravenous nicotine self-administration (unit dose 10 μg/kg per injection). Monkeys were trained to self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Intermittent access (1 h daily per weekday) to nicotine was allowed for 4 weeks and levels of α4β2* nAChRs were measured 4 days later. This intermittent access was sufficient to induce upregulation of α4β2* receptors in the whole brain (31 % upregulation) and in specific brain areas (+36 % in amygdala and +62 % in putamen). These results indicate that intermittent nicotine exposure is sufficient to produce change in nAChRs expression.

  2. Seasonal H3N2 influenza A virus fails to enhance Staphylococcus aureus co-infection in a non-human primate respiratory tract infection model

    PubMed Central

    Kobayashi, Scott D; Olsen, Randall J; LaCasse, Rachel A; Safronetz, David; Ashraf, Madiha; Porter, Adeline R; Braughton, Kevin R; Feldmann, Friederike; Clifton, Dawn R; Kash, John C; Bailey, John R; Gardner, Donald J; Otto, Michael; Brining, Douglas L; Kreiswirth, Barry N; Taubenberger, Jeffrey K; Parnell, Michael J; Feldmann, Heinz; Musser, James M; DeLeo, Frank R

    2013-01-01

    Staphylococcus aureus community-acquired pneumonia is often associated with influenza or an influenza-like syndrome. Morbidity and mortality due to methicillin-resistant S. aureus (MRSA) or influenza and pneumonia, which includes bacterial co-infection, are among the top causes of death by infectious diseases in the United States. We developed a non-lethal influenza A virus (IAV) (H3N2)/S. aureus co-infection model in cynomolgus macaques (Macaca fascicularis) to test the hypothesis that seasonal IAV infection predisposes non-human primates to severe S. aureus pneumonia. Infection and disease progression were monitored by clinical assessment of animal health; analysis of blood chemistry, nasal swabs, and X-rays; and gross pathology and histopathology of lungs from infected animals. Seasonal IAV infection in healthy cynomolgus macaques caused mild pneumonia, but unexpectedly, did not predispose these animals to subsequent severe infection with the community-associated MRSA clone USA300. We conclude that in our co-infection model, seasonal IAV infection alone is not sufficient to promote severe S. aureus pneumonia in otherwise healthy non-human primates. The implication of these findings is that comorbidity factors in addition to IAV infection are required to predispose individuals to secondary S. aureus pneumonia. PMID:24104465

  3. Nodular Worm Infections in Wild Non-human Primates and Humans Living in the Sebitoli Area (Kibale National Park, Uganda): Do High Spatial Proximity Favor Zoonotic Transmission?

    PubMed Central

    Cibot, Marie; Guillot, Jacques; Lafosse, Sophie; Bon, Céline; Seguya, Andrew; Krief, Sabrina

    2015-01-01

    Background Nodular Oesophagostomum genus nematodes are a major public health concern in some African regions because they can be lethal to humans. Their relatively high prevalence in people has been described in Uganda recently. While non-human primates also harbor Oesophagostomum spp., the epidemiology of this oesophagostomosis and the role of these animals as reservoirs of the infection in Eastern Africa are not yet well documented. Methodology/Principal Findings The present study aimed to investigate Oesophagostomum infection in terms of parasite species diversity, prevalence and load in three non-human primates (Pan troglodytes, Papio anubis, Colobus guereza) and humans living in close proximity in a forested area of Sebitoli, Kibale National Park (KNP), Uganda. The molecular phylogenetic analyses provided the first evidence that humans living in the Sebitoli area harbored O. stephanostomum, a common species in free-ranging chimpanzees. Chimpanzees were also infected by O. bifurcum, a common species described in human populations throughout Africa. The recently described Oesophagostomum sp. found in colobine monkeys and humans and which was absent from baboons in the neighboring site of Kanyawara in KNP (10 km from Sebitoli), was only found in baboons. Microscopic analyses revealed that the infection prevalence and parasite load in chimpanzees were significantly lower in Kanyawara than in Sebitoli, an area more impacted by human activities at its borders. Conclusions/Significance Three different Oesophagostomum species circulate in humans and non-human primates in the Sebitoli area and our results confirm the presence of a new genotype of Oesophagostomum recently described in Uganda. The high spatiotemporal overlap between humans and chimpanzees in the studied area coupled with the high infection prevalence among chimpanzees represent factors that could increase the risk of transmission for O. stephanostomum between the two primate species. Finally, the

  4. DNA sequencing of 13 cytokine gene fragments of Aotus infulatus and Saimiri sciureus, two non-human primate models for malaria.

    PubMed

    Alves, F A; Souza, M T; Gonçalves, E C; Schneider, M P C; Marinho, A M; Muniz, J A P C; Fragoso, S P; Krieger, M A; Goldenberg, S; Daniel-Ribeiro, C T; Carvalho, L J M

    2010-12-01

    Aotus and Saimiri are non-human primate models recommended by the World Health Organization for experimental studies in malaria, especially for vaccine pre-clinical trials. However, research using these primates is hindered by the lack of specific reagents to evaluate immune responses to infection or vaccination. As a step toward developing molecular tools for cytokine expression studies in these species, primer pairs for 18 cytokine gene fragments were designed based on human DNA sequences and used to amplify the corresponding genes in Aotus infulatus and Saimiri sciureus genomic DNA samples. IFNγ, TNFα, LTA, IL2, IL3, IL4, IL5, IL6, IL10, IL12, IL13, CSF2 and TGFβ2 gene fragments were amplified and sequenced. Primer pairs for IL8, IL17, IL18, IL27 and MIF failed to generate amplification products. When compared to the available corresponding human and non-human primate sequences, most--except IL3 and IL4--showed identity degrees above 90%. Small variations in sequence can help to explain the failure to amplify certain genes or the amplification only at lower annealing temperatures as compared to human DNA samples for several primer pairs. The sequences made available provide the basis for designing molecular tools such as primers for real time PCR specific for A. infulatus and/or S. sciureus. The nucleotide sequences reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned accession numbers DQ985386 to DQ985389, DQ989356 to DQ989369, FJ89020 to FJ89024, and FJ89029.

  5. Development of the first marmoset-specific DNA microarray (EUMAMA): a new genetic tool for large-scale expression profiling in a non-human primate

    PubMed Central

    Datson, Nicole A; Morsink, Maarten C; Atanasova, Srebrena; Armstrong, Victor W; Zischler, Hans; Schlumbohm, Christina; Dutilh, Bas E; Huynen, Martijn A; Waegele, Brigitte; Ruepp, Andreas; de Kloet, E Ronald; Fuchs, Eberhard

    2007-01-01

    Background The common marmoset monkey (Callithrix jacchus), a small non-endangered New World primate native to eastern Brazil, is becoming increasingly used as a non-human primate model in biomedical research, drug development and safety assessment. In contrast to the growing interest for the marmoset as an animal model, the molecular tools for genetic analysis are extremely limited. Results Here we report the development of the first marmoset-specific oligonucleotide microarray (EUMAMA) containing probe sets targeting 1541 different marmoset transcripts expressed in hippocampus. These 1541 transcripts represent a wide variety of different functional gene classes. Hybridisation of the marmoset microarray with labelled RNA from hippocampus, cortex and a panel of 7 different peripheral tissues resulted in high detection rates of 85% in the neuronal tissues and on average 70% in the non-neuronal tissues. The expression profiles of the 2 neuronal tissues, hippocampus and cortex, were highly similar, as indicated by a correlation coefficient of 0.96. Several transcripts with a tissue-specific pattern of expression were identified. Besides the marmoset microarray we have generated 3215 ESTs derived from marmoset hippocampus, which have been annotated and submitted to GenBank [GenBank: EF214838 – EF215447, EH380242 – EH382846]. Conclusion We have generated the first marmoset-specific DNA microarray and demonstrated its use to characterise large-scale gene expression profiles of hippocampus but also of other neuronal and non-neuronal tissues. In addition, we have generated a large collection of ESTs of marmoset origin, which are now available in the public domain. These new tools will facilitate molecular genetic research into this non-human primate animal model. PMID:17592630

  6. The Physiological Effect of Human Grooming on the Heart Rate and the Heart Rate Variability of Laboratory Non-Human Primates: A Pilot Study in Male Rhesus Monkeys

    PubMed Central

    Grandi, Laura Clara; Ishida, Hiroaki

    2015-01-01

    Grooming is a widespread, essential, and complex behavior with social and affiliative valence in the non-human primate world. Its impact at the autonomous nervous system level has been studied during allogrooming among monkeys living in a semi-naturalistic environment. For the first time, we investigated the effect of human grooming to monkey in a typical experimental situation inside laboratory. We analyzed the autonomic response of male monkeys groomed by a familiar human (experimenter), in terms of the heart rate (HR) and heart rate variability (HRV) at different body parts. We considered the HRV in both the time (SDNN, RMSSD, and RMSSD/SDNN) and the frequency domain (HF, LF, and LF/HF). For this purpose, we recorded the electrocardiogram of two male rhesus monkeys seated in a primate chair while the experimenter groomed their mouth, chest, or arm. We demonstrated that (1) the grooming carried out by a familiar human determined a decrement of the HR and an increment of the HRV; (2) there was a difference in relation to the groomed body part. In particular, during grooming the mouth the HRV was higher than during grooming the arm and the chest. Taken together, the results represent the first evidence that grooming carried out by a familiar human on experimental monkeys has the comparable positive physiological effect of allogrooming between conspecifics. Moreover, since the results underlined the positive modulation of both HR and HRV, the present study could be a starting point to improve the well-being of non-human primates in experimental condition by means of grooming by a familiar person. PMID:26664977

  7. First case of peritoneal cysticercosis in a non-human primate host (Macaca tonkeana) due to Taenia martis.

    PubMed

    Brunet, Julie; Pesson, Bernard; Chermette, René; Regnard, Pierrick; Grimm, Felix; Deplazes, Peter; Ferreira, Xavier; Sabou, Marcela; Pfaff, Alexander W; Abou-Bacar, Ahmed; Candolfi, Ermanno

    2014-09-04

    Infections with larval stages (metacestodes) of a variety of taeniid species have been described in primates, including humans, with partial to severe clinical consequences. Taenia martis is a tapeworm of mustelids, and martens are mainly their definitive hosts in Central Europe. In the rodent intermediate host cysticerci develop in the pleural and peritoneal cavities. The present report describes a case of T. martis peritoneal cysticercosis in a Tonkean macaque. An abdominal mass was detected in a 3-year-old male Tonkean macaque (Macaca tonkeana) born and raised in a primate colony in France. Examination of the mass after laparotomy showed numerous vesicles identified as cysticerci of T. martis, based on the morphology of scolex and hooks, with confirmation by PCR amplification and sequence analysis of the mitochondrial cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1) genes. Exeresis of the lesion was not possible and praziquantel (5.7 mg/kg) was given twice at an interval of 3 days. The abdominal mass was greatly diminished upon examination 2 months later and no signs of recurrence were noticed during the following 4 years. This is the first report of T. martis cysticercosis in a monkey. This record and the recent first description of an ocular T. martis cysticercosis in a human show the susceptibility of primates to T. martis and its zoonotic potential. This taeniid species must be considered in the differential diagnosis of cysticercosis in primates.

  8. Establishing 'quality of life' parameters using behavioural guidelines for humane euthanasia of captive non-human primates.

    PubMed

    Lambeth, Sp; Schapiro, Sj; Bernacky, Bj; Wilkerson, Gk

    2013-09-01

    Chronic pain and distress are universally accepted conditions that may adversely affect an animal's quality of life (QOL) and lead to the humane euthanasia of an animal. At most research institutions and zoological parks in the USA, a veterinarian, who has physically examined the animal and reviewed the clinical records, ultimately decides when an animal has reached a humane endpoint. To aid in the difficult process of interpreting pain and distress, we have developed specific behavioural guidelines, in addition to standard clinical information, to help define unique characteristics and traits of primates to assess and promote discussion of an individual primate's QOL, and thereby, to assist in the decision-making process regarding euthanasia. These guidelines advocate the creation of a QOL team when the animal is diagnosed with a life-threatening or debilitating chronic condition, or at the time the animal is entered into a terminal study. The team compiles a list of characteristics unique to that individual animal by utilising a questionnaire and a behavioural ethogram. This list enables the team to quantitatively assess any deviations from the established normal behavioural repertoire of that individual. Concurrently, the QOL team determines the number of behavioural deviations that are needed to trigger an immediate discussion of the necessity for humane euthanasia of the animal. The team remains intact once created, and revisits the animal's condition as frequently as deemed necessary. This process improves animal welfare by continuing the quest to optimally define QOL for captive primates, and potentially for all captive animals.

  9. Examination of the Safety of Pediatric Vaccine Schedules in a Non-Human Primate Model: Assessments of Neurodevelopment, Learning, and Social Behavior

    PubMed Central

    Curtis, Britni; Liberato, Noelle; Rulien, Megan; Morrisroe, Kelly; Kenney, Caroline; Yutuc, Vernon; Ferrier, Clayton; Marti, C. Nathan; Mandell, Dorothy; Burbacher, Thomas M.; Sackett, Gene P.

    2015-01-01

    Background In the 1990s, the mercury-based preservative thimerosal was used in most pediatric vaccines. Although there are currently only two thimerosal-containing vaccines (TCVs) recommended for pediatric use, parental perceptions that vaccines pose safety concerns are affecting vaccination rates, particularly in light of the much expanded and more complex schedule in place today. Objectives The objective of this study was to examine the safety of pediatric vaccine schedules in a non-human primate model. Methods We administered vaccines to six groups of infant male rhesus macaques (n = 12–16/group) using a standardized thimerosal dose where appropriate. Study groups included the recommended 1990s Pediatric vaccine schedule, an accelerated 1990s Primate schedule with or without the measles–mumps–rubella (MMR) vaccine, the MMR vaccine only, and the expanded 2008 schedule. We administered saline injections to age-matched control animals (n = 16). Infant development was assessed from birth to 12 months of age by examining the acquisition of neonatal reflexes, the development of object concept permanence (OCP), computerized tests of discrimination learning, and infant social behavior. Data were analyzed using analysis of variance, multilevel modeling, and survival analyses, where appropriate. Results We observed no group differences in the acquisition of OCP. During discrimination learning, animals receiving TCVs had improved performance on reversal testing, although some of these same animals showed poorer performance in subsequent learning-set testing. Analysis of social and nonsocial behaviors identified few instances of negative behaviors across the entire infancy period. Although some group differences in specific behaviors were reported at 2 months of age, by 12 months all infants, irrespective of vaccination status, had developed the typical repertoire of macaque behaviors. Conclusions This comprehensive 5-year case–control study, which closely examined

  10. HIV Treatments Reduce Malaria Liver Stage Burden in a Non-Human Primate Model of Malaria Infection at Clinically Relevant Concentrations In Vivo

    PubMed Central

    Hobbs, Charlotte V.; Neal, Jillian; Conteh, Solomon; Donnelly, Liam; Chen, Jingyang; Marsh, Kennan; Lambert, Lynn; Orr-Gonzalez, Sachy; Hinderer, Jessica; Healy, Sara; Borkowsky, William; Penzak, Scott R.; Chakravarty, Sumana; Hoffman, Stephen L.; Duffy, Patrick E.

    2014-01-01

    We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination), but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts. PMID:24988386

  11. Assessment of bleeding propensity in non-human primates by combination of selective tissue factor/VIIa inhibition and aspirin compared to warfarin and aspirin treatment.

    PubMed

    Salyers, Anita K; Szalony, James A; Suleymanov, Osman D; Parlow, John J; Wood, Rhonda S; South, Michael S; Nicholson, Nancy S

    2004-02-01

    This study in non-human primates was designed to evaluate the bleeding propensity of a selective, small molecule inhibitor of tissue factor (TF)/VIIa in combination with acetylsalicylic acid (ASA) in comparison to the combination of ASA and warfarin. Bleeding time was increased by ASA but was not prolonged further by the addition of the TF/VIIa inhibitor, PHA-927, at doses that elevated the prothrombin time to 8-fold. In contrast, bleeding time was prolonged by warfarin alone and further exacerbated by the presence of ASA. Acute blood loss at the bleeding site, while not significantly increased by either warfarin or PHA-927, was increased substantially in several individuals treated with a combination of warfarin and ASA but not by the combination of TF/VIIa inhibitor and ASA. These data predict that TF/VIIa inhibition, in the presence of chronic aspirin therapy in patients with cardiovascular risk factors, will be a safe therapy for thrombotic disorders.

  12. Increases in Endogenous or Exogenous Progestins Promote Virus-Target Cell Interactions within the Non-human Primate Female Reproductive Tract

    PubMed Central

    Carias, Ann M.; Fought, Angela J.; Kotnik Halavaty, Katarina; Anderson, Meegan R.; Jimenez, Maria L.; McRaven, Michael D.; Gioia, Casey J.; Henning, Tara R.; Smith, James M.; Pereira, Lara E.; Butler, Katherine; McNicholl, S. Janet M.; Hendry, R. Michael; Hope, Thomas J.

    2016-01-01

    Currently, there are mounting data suggesting that HIV-1 acquisition in women can be affected by the use of certain hormonal contraceptives. However, in non-human primate models, endogenous or exogenous progestin-dominant states are shown to increase acquisition. To gain mechanistic insights into this increased acquisition, we studied how mucosal barrier function and CD4+ T-cell and CD68+ macrophage density and localization changed in the presence of natural progestins or after injection with high-dose DMPA. The presence of natural or injected progestins increased virus penetration of the columnar epithelium and the infiltration of susceptible cells into a thinned squamous epithelium of the vaginal vault, increasing the likelihood of potential virus interactions with target cells. These data suggest that increasing either endogenous or exogenous progestin can alter female reproductive tract barrier properties and provide plausible mechanisms for increased HIV-1 acquisition risk in the presence of increased progestin levels. PMID:27658293

  13. Trypanosoma cruzi in non-human primates with a history of stillbirths: a retrospective study (Papio hamadryas spp.) and case report (Macaca fascicularis)

    PubMed Central

    Grieves, Jessica L.; Hubbard, Gene B.; Williams, Jeff T.; VandeBerg, John L.; Dick, Edward J.; López-Alvarenga, Juan C.; Schlabritz-Loutsevitch, Natalia E.

    2011-01-01

    Background Congenital transmission of Trypanosoma cruzi has been described in humans and experimental work has been conducted with mice, but not with non-human primates (NHPs). Methods We conducted a retrospective study of female baboons (Papio hamadryas spp.) naturally seropositive or seronegative for T. cruzi with history of fetal loss, and we report a stillbirth in a cynomolgus macaque (Macaca fascicularis) with placental T. cruzi amastigotes. Results There were no differences in menstrual cycle parameters and the number of fetal losses between seropositive and seronegative baboons with history of fetal loss. The amount of parasite DNA detected using quantitative polymerase chain reaction (Q-PCR) in M. fascicularis placenta was within the range detected in infected baboon tissues. Conclusions There is no evidence that chronic maternal T. cruzi infection causes fetal loss in baboons. Q-PCR is a useful diagnostic tool to study archived NHP placentas. PMID:18671769

  14. Dynamic Regulation of Hypothalamic DMXL2, KISS1, and RFRP Expression During Postnatal Development in Non-Human Primates.

    PubMed

    Wahab, Fazal; Drummer, Charis; Schlatt, Stefan; Behr, Rüdiger

    2016-12-12

    The neurobiological mechanism of puberty onset in primates is currently only partly understood. A recent study reported an important role of Dmx-like 2 (DMXL2), a gene encoding rabconnectin-3α vesicular protein, in human subjects with mental retardation and neuroendocrine impairment of reproduction. To further characterize the potential role of DMXL2 in the regulation of reproduction, we analyzed the expression of DMXL2 in hypothalami of newborn, infantile, juvenile, pubertal, and postpubertal female and male common marmoset monkeys. Additionally, as the relative hypothalamic levels of gonadotropin-inhibitory hormone (GnIH) transcript during postnatal development are unknown in primates, we also quantified messenger RNA (mRNA) levels of RFRP, a gene encoding GnIH. Moreover, the transcript levels of kisspeptin, a well-known regulator of the hypothalamic neurohormonal axis controlling reproduction, were also checked. Transcript and protein levels of DMXL2 and Kiss1 transcript levels increase from the newborn to the infantile and from the juvenile (prepubertal) to the pubertal and the postpubertal period. We also noted a clear upsurge in RFRP transcript levels in the prepubertal period. In conclusion, the hypothalamic expressions of Kiss1 and DMXL2 mRNA increase during infantile, pubertal, and adult stages compared to newborn and juvenile stages in common marmoset monkeys. In contrast, the expression of RFRP mRNA upsurges in juvenile monkeys. Further mechanistic studies are needed to characterize the potential inhibitory role of the GnIH-GPR147 signaling in the prepubertal period and the role of DMXL2 in the molecular cascade regulating the neuroendocrine reproductive axis in primates.

  15. Knowledge-guided robust MRI brain extraction for diverse large-scale neuroimaging studies on humans and non-human primates.

    PubMed

    Wang, Yaping; Nie, Jingxin; Yap, Pew-Thian; Li, Gang; Shi, Feng; Geng, Xiujuan; Guo, Lei; Shen, Dinggang

    2014-01-01

    Accurate and robust brain extraction is a critical step in most neuroimaging analysis pipelines. In particular, for the large-scale multi-site neuroimaging studies involving a significant number of subjects with diverse age and diagnostic groups, accurate and robust extraction of the brain automatically and consistently is highly desirable. In this paper, we introduce population-specific probability maps to guide the brain extraction of diverse subject groups, including both healthy and diseased adult human populations, both developing and aging human populations, as well as non-human primates. Specifically, the proposed method combines an atlas-based approach, for coarse skull-stripping, with a deformable-surface-based approach that is guided by local intensity information and population-specific prior information learned from a set of real brain images for more localized refinement. Comprehensive quantitative evaluations were performed on the diverse large-scale populations of ADNI dataset with over 800 subjects (55 ∼ 90 years of age, multi-site, various diagnosis groups), OASIS dataset with over 400 subjects (18 ∼ 96 years of age, wide age range, various diagnosis groups), and NIH pediatrics dataset with 150 subjects (5 ∼ 18 years of age, multi-site, wide age range as a complementary age group to the adult dataset). The results demonstrate that our method consistently yields the best overall results across almost the entire human life span, with only a single set of parameters. To demonstrate its capability to work on non-human primates, the proposed method is further evaluated using a rhesus macaque dataset with 20 subjects. Quantitative comparisons with popularly used state-of-the-art methods, including BET, Two-pass BET, BET-B, BSE, HWA, ROBEX and AFNI, demonstrate that the proposed method performs favorably with superior performance on all testing datasets, indicating its robustness and effectiveness.

  16. A high density of human communication-associated genes in chromosome 7q31-q36: differential expression in human and non-human primate cortices.

    PubMed

    Schneider, E; Jensen, L R; Farcas, R; Kondova, I; Bontrop, R E; Navarro, B; Fuchs, E; Kuss, A W; Haaf, T

    2012-01-01

    The human brain is distinguished by its remarkable size, high energy consumption, and cognitive abilities compared to all other mammals and non-human primates. However, little is known about what has accelerated brain evolution in the human lineage. One possible explanation is that the appearance of advanced communication skills and language has been a driving force of human brain development. The phenotypic adaptations in brain structure and function which occurred on the way to modern humans may be associated with specific molecular signatures in today's human genome and/or transcriptome. Genes that have been linked to language, reading, and/or autism spectrum disorders are prime candidates when searching for genes for human-specific communication abilities. The database and genome-wide expression analyses we present here revealed a clustering of such communication-associated genes (COAG) on human chromosomes X and 7, in particular chromosome 7q31-q36. Compared to the rest of the genome, we found a high number of COAG to be differentially expressed in the cortices of humans and non-human primates (chimpanzee, baboon, and/or marmoset). The role of X-linked genes for the development of human-specific cognitive abilities is well known. We now propose that chromosome 7q31-q36 also represents a hot spot for the evolution of human-specific communication abilities. Selective pressure on the T cell receptor beta locus on chromosome 7q34, which plays a pivotal role in the immune system, could have led to rapid dissemination of positive gene variants in hitchhiking COAG. Copyright © 2012 S. Karger AG, Basel.

  17. Knowledge-Guided Robust MRI Brain Extraction for Diverse Large-Scale Neuroimaging Studies on Humans and Non-Human Primates

    PubMed Central

    Wang, Yaping; Nie, Jingxin; Yap, Pew-Thian; Li, Gang; Shi, Feng; Geng, Xiujuan; Guo, Lei; Shen, Dinggang

    2014-01-01

    Accurate and robust brain extraction is a critical step in most neuroimaging analysis pipelines. In particular, for the large-scale multi-site neuroimaging studies involving a significant number of subjects with diverse age and diagnostic groups, accurate and robust extraction of the brain automatically and consistently is highly desirable. In this paper, we introduce population-specific probability maps to guide the brain extraction of diverse subject groups, including both healthy and diseased adult human populations, both developing and aging human populations, as well as non-human primates. Specifically, the proposed method combines an atlas-based approach, for coarse skull-stripping, with a deformable-surface-based approach that is guided by local intensity information and population-specific prior information learned from a set of real brain images for more localized refinement. Comprehensive quantitative evaluations were performed on the diverse large-scale populations of ADNI dataset with over 800 subjects (55∼90 years of age, multi-site, various diagnosis groups), OASIS dataset with over 400 subjects (18∼96 years of age, wide age range, various diagnosis groups), and NIH pediatrics dataset with 150 subjects (5∼18 years of age, multi-site, wide age range as a complementary age group to the adult dataset). The results demonstrate that our method consistently yields the best overall results across almost the entire human life span, with only a single set of parameters. To demonstrate its capability to work on non-human primates, the proposed method is further evaluated using a rhesus macaque dataset with 20 subjects. Quantitative comparisons with popularly used state-of-the-art methods, including BET, Two-pass BET, BET-B, BSE, HWA, ROBEX and AFNI, demonstrate that the proposed method performs favorably with superior performance on all testing datasets, indicating its robustness and effectiveness. PMID:24489639

  18. Activation of TrkB with TAM-163 results in opposite effects on body weight in rodents and non-human primates.

    PubMed

    Perreault, Mylène; Feng, Guo; Will, Sarah; Gareski, Tiffany; Kubasiak, David; Marquette, Kimberly; Vugmeyster, Yulia; Unger, Thaddeus J; Jones, Juli; Qadri, Ariful; Hahm, Seung; Sun, Ying; Rohde, Cynthia M; Zwijnenberg, Raphael; Paulsen, Janet; Gimeno, Ruth E

    2013-01-01

    Strong genetic data link the Tyrosine kinase receptor B (TrkB) and its major endogenous ligand brain-derived neurotrophic factor (BDNF) to the regulation of energy homeostasis, with loss-of-function mutations in either gene causing severe obesity in both mice and humans. It has previously been reported that peripheral administration of the endogenous TrkB agonist ligand neurotrophin-4 (NT-4) profoundly decreases food intake and body weight in rodents, while paradoxically increasing these same parameters in monkeys. We generated a humanized TrkB agonist antibody, TAM-163, and characterized its therapeutic potential in several models of type 2 diabetes and obesity. In vitro, TAM-163 bound to human and rodent TrkB with high affinity, activated all aspects of the TrkB signaling cascade and induced TrkB internalization and degradation in a manner similar to BDNF. In vivo, peripheral administration of TAM-163 decreased food intake and/or body weight in mice, rats, hamsters, and dogs, but increased food intake and body weight in monkeys. The magnitude of weight change was similar in rodents and non-human primates, occurred at doses where there was no appreciable penetration into deep structures of the brain, and could not be explained by differences in exposures between species. Rather, peripherally administered TAM-163 localized to areas in the hypothalamus and the brain stem located outside the blood-brain barrier in a similar manner between rodents and non-human primates, suggesting differences in neuroanatomy across species. Our data demonstrate that a TrkB agonist antibody, administered peripherally, causes species-dependent effects on body weight similar to the endogenous TrkB ligand NT-4. The possible clinical utility of TrkB agonism in treating weight regulatory disorder, such as obesity or cachexia, will require evaluation in man.

  19. Activation of TrkB with TAM-163 Results in Opposite Effects on Body Weight in Rodents and Non-Human Primates

    PubMed Central

    Perreault, Mylène; Feng, Guo; Will, Sarah; Gareski, Tiffany; Kubasiak, David; Marquette, Kimberly; Vugmeyster, Yulia; Unger, Thaddeus J.; Jones, Juli; Qadri, Ariful; Hahm, Seung; Sun, Ying; Rohde, Cynthia M.; Zwijnenberg, Raphael; Paulsen, Janet; Gimeno, Ruth E.

    2013-01-01

    Strong genetic data link the Tyrosine kinase receptor B (TrkB) and its major endogenous ligand brain-derived neurotrophic factor (BDNF) to the regulation of energy homeostasis, with loss-of-function mutations in either gene causing severe obesity in both mice and humans. It has previously been reported that peripheral administration of the endogenous TrkB agonist ligand neurotrophin-4 (NT-4) profoundly decreases food intake and body weight in rodents, while paradoxically increasing these same parameters in monkeys. We generated a humanized TrkB agonist antibody, TAM-163, and characterized its therapeutic potential in several models of type 2 diabetes and obesity. In vitro, TAM-163 bound to human and rodent TrkB with high affinity, activated all aspects of the TrkB signaling cascade and induced TrkB internalization and degradation in a manner similar to BDNF. In vivo, peripheral administration of TAM-163 decreased food intake and/or body weight in mice, rats, hamsters, and dogs, but increased food intake and body weight in monkeys. The magnitude of weight change was similar in rodents and non-human primates, occurred at doses where there was no appreciable penetration into deep structures of the brain, and could not be explained by differences in exposures between species. Rather, peripherally administered TAM-163 localized to areas in the hypothalamus and the brain stem located outside the blood-brain barrier in a similar manner between rodents and non-human primates, suggesting differences in neuroanatomy across species. Our data demonstrate that a TrkB agonist antibody, administered peripherally, causes species-dependent effects on body weight similar to the endogenous TrkB ligand NT-4. The possible clinical utility of TrkB agonism in treating weight regulatory disorder, such as obesity or cachexia, will require evaluation in man. PMID:23700410

  20. Comparing adjuvanted H28 and modified vaccinia virus ankara expressingH28 in a mouse and a non-human primate tuberculosis model.

    PubMed

    Billeskov, Rolf; Christensen, Jan P; Aagaard, Claus; Andersen, Peter; Dietrich, Jes

    2013-01-01

    Here we report for the first time on the immunogenicity and protective efficacy of a vaccine strategy involving the adjuvanted fusion protein "H28" (consisting of Ag85B-TB10.4-Rv2660c) and Modified Vaccinia Virus Ankara expressing H28. We show that a heterologous prime-boost regimen involving priming with H28 in a Th1 adjuvant followed by boosting with H28 expressed by MVA (H28/MVA28) induced the highest percentage of IFN-γ expressing T cells, the highest production of IFN-γ per single cell and the highest induction of CD8 T cells compared to either of the vaccines given alone. In contrast, in mice vaccinated with adjuvanted recombinant H28 alone (H28/H28) we observed the highest production of IL-2 per single cell and the highest frequency of antigen specific TNF-α/IL-2 expressing CD4 T cells pre and post infection. Interestingly, TNF-α/IL-2 expressing central memory-like CD4 T cells showed a significant positive correlation with protection at week 6 post infection, whereas the opposite was observed for post infection CD4 T cells producing only IFN-γ. Moreover, as a BCG booster vaccine in a clinically relevant non-human primate TB model, the H28/H28 vaccine strategy induced a slightly more prominent reduction of clinical disease and pathology for up to one year post infection compared to H28/MVA28. Taken together, our data showed that the adjuvanted subunit and MVA strategies led to different T cell subset combinations pre and post infection and that TNF-α/IL-2 double producing but not IFN-γ single producing CD4 T cell subsets correlated with protection in the mouse TB model. Moreover, our data demonstrated that the H28 vaccine antigen was able to induce strong protection in both a mouse and a non-human primate TB model.

  1. Saccades during visual exploration align hippocampal 3–8 Hz rhythms in human and non-human primates

    PubMed Central

    Hoffman, Kari L.; Dragan, Michelle C.; Leonard, Timothy K.; Micheli, Cristiano; Montefusco-Siegmund, Rodrigo; Valiante, Taufik A.

    2013-01-01

    Visual exploration in primates depends on saccadic eye movements (SEMs) that cause alternations of neural suppression and enhancement. This modulation extends beyond retinotopic areas, and is thought to facilitate perception; yet saccades may also influence brain regions critical for forming memories of these exploratory episodes. The hippocampus, for example, shows oscillatory activity that is generally associated with encoding of information. Whether or how hippocampal oscillations are influenced by eye movements is unknown. We recorded the neural activity in the human and macaque hippocampus during visual scene search. Across species, SEMs were associated with a time-limited alignment of a low-frequency (3–8 Hz) rhythm. The phase alignment depended on the task and not only on eye movements per se, and the frequency band was not a direct consequence of saccade rate. Hippocampal theta-frequency oscillations are produced by other mammals during repetitive exploratory behaviors, including whisking, sniffing, echolocation, and locomotion. The present results may reflect a similar yet distinct primate homologue supporting active perception during exploration. PMID:24009562

  2. Antipsychotic-like effect of the muscarinic acetylcholine receptor agonist BuTAC in non-human primates.

    PubMed

    Andersen, Maibritt B; Croy, Carrie Hughes; Dencker, Ditte; Werge, Thomas; Bymaster, Frank P; Felder, Christian C; Fink-Jensen, Anders

    2015-01-01

    Cholinergic, muscarinic receptor agonists exhibit functional dopamine antagonism and muscarinic receptors have been suggested as possible future targets for the treatment of schizophrenia and drug abuse. The muscarinic ligand (5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane (BuTAC) exhibits high affinity for muscarinic receptors with no or substantially less affinity for a large number of other receptors and binding sites, including the dopamine receptors and the dopamine transporter. In the present study, we wanted to examine the possible antipsychotic-like effects of BuTAC in primates. To this end, we investigated the effects of BuTAC on d-amphetamine-induced behaviour in antipsychotic-naive Cebus paella monkeys. Possible adverse events of BuTAC, were evaluated in the same monkeys as well as in monkeys sensitized to antipsychotic-induced extrapyramidal side effects. The present data suggests that, the muscarinic receptor ligand BuTAC exhibits antipsychotic-like behaviour in primates. The behavioural data of BuTAC as well as the new biochemical data further substantiate the rationale for the use of muscarinic M1/M2/M4-preferring receptor agonists as novel pharmacological tools in the treatment of schizophrenia.

  3. Non-human primate models of alcohol-related phenotypes: the influence of genetic and environmental factors.

    PubMed

    Barr, Christina S

    2013-01-01

    Because of their complex social structures, behaviors, and genetic similarities to humans, nonhuman primates are useful for studying how genetic factors influence alcohol consumption. The neurobiological systems that influence addiction vulnerability may do so by acting on alcohol response, reward pathways, behavioral dyscontrol, and vulnerability to stress and anxiety. Rhesus macaques show individual differences in alcohol response and temperament, and such differences are influenced by genetic variants that are similar functionally to those present in humans. Genes at which variation moderates these phenotypes include those encoding monoamine oxidase A (MAOA-LPR), the serotonin transporter (HTTLPR), corticotropin releasing hormone (CRH-248C/T and -2232 C/G), Neuropeptide Y (NPY-1002 T/G), and the μ-opioid receptor (OPRM1 C77G). These provide opportunities for modeling how genetic and environmental factors (i.e., stress, individual's sex, or alcohol exposure) interact to influence alcohol consumption. Studies in primates may also reveal selective factors have driven maintenance or fixation of alleles that increase risk for alcohol use disorders in modern humans.

  4. Optimal Region of the Putamen for Image-Guided Convection-Enhanced Delivery of Therapeutics in Human and Non-human Primates

    PubMed Central

    Yin, Dali; Valles, Francisco E.; Fiandaca, Massimo S.; Bringas, John; Gimenez, Francisco; Berger, Mitchel S.; Forsayeth, John; Bankiewicz, Krystof S.

    2009-01-01

    Optimal results in the direct brain delivery of brain therapeutics such as growth factors or viral vector into primate brain depends on reproducible distribution throughout the target region. In the present study, we retrospectively analyzed MRI of 25 convection-enhanced delivery (CED) infusions with MRI contrast into the putamen of non-human primates (NHP). Infused volume (Vi) was compared to total volume of distribution (Vd), vs. Vd within the target putamen. Excellent distribution of contrast agent within the putamen was obtained in 8 cases that were used to define an optimal target volume, or “green” zone. Partial or poor distribution with leakage into adjacent anatomical structures was noted in 17 cases, defining “blue” and “red” zones respectively. Quantitative containment (99 ± 1%) of infused Gadoteridol within the putamen was obtained when the cannula was placed in the green zone, 87 ± 3% in the blue zone and 49 ± 0.05% in the red zone. These results were used to determine a set of 3D stereotactic coordinates that define an optimal site for putaminal infusions in NHP and human putamen. We conclude that cannula placement and definition of optimal (green zone) stereotactic coordinates have important implications in ensuring effective delivery of therapeutics into the putamen utilizing routine stereotactic MRI localization procedures, and should be considered when local therapies such as gene transfer or protein administration are being translated into clinical therapy. PMID:19761848

  5. Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

    PubMed Central

    Ma, Kuo-Hsing; Liu, Tsung-Ta; Weng, Shao-Ju; Chen, Chien-Fu F.; Huang, Yuahn-Sieh; Chueh, Sheau-Huei; Liao, Mei-Hsiu; Chang, Kang-Wei; Sung, Chi-Chang; Hsu, Te-Hung; Huang, Wen-Sheng; Cheng, Cheng-Yi

    2016-01-01

    3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate. PMID:27941910

  6. Examination of the safety of pediatric vaccine schedules in a non-human primate model: assessments of neurodevelopment, learning, and social behavior.

    PubMed

    Curtis, Britni; Liberato, Noelle; Rulien, Megan; Morrisroe, Kelly; Kenney, Caroline; Yutuc, Vernon; Ferrier, Clayton; Marti, C Nathan; Mandell, Dorothy; Burbacher, Thomas M; Sackett, Gene P; Hewitson, Laura

    2015-06-01

    In the 1990s, the mercury-based preservative thimerosal was used in most pediatric vaccines. Although there are currently only two thimerosal-containing vaccines (TCVs) recommended for pediatric use, parental perceptions that vaccines pose safety concerns are affecting vaccination rates, particularly in light of the much expanded and more complex schedule in place today. The objective of this study was to examine the safety of pediatric vaccine schedules in a non-human primate model. We administered vaccines to six groups of infant male rhesus macaques (n = 12-16/group) using a standardized thimerosal dose where appropriate. Study groups included the recommended 1990s Pediatric vaccine schedule, an accelerated 1990s Primate schedule with or without the measles-mumps-rubella (MMR) vaccine, the MMR vaccine only, and the expanded 2008 schedule. We administered saline injections to age-matched control animals (n = 16). Infant development was assessed from birth to 12 months of age by examining the acquisition of neonatal reflexes, the development of object concept permanence (OCP), computerized tests of discrimination learning, and infant social behavior. Data were analyzed using analysis of variance, multilevel modeling, and survival analyses, where appropriate. We observed no group differences in the acquisition of OCP. During discrimination learning, animals receiving TCVs had improved performance on reversal testing, although some of these same animals showed poorer performance in subsequent learning-set testing. Analysis of social and nonsocial behaviors identified few instances of negative behaviors across the entire infancy period. Although some group differences in specific behaviors were reported at 2 months of age, by 12 months all infants, irrespective of vaccination status, had developed the typical repertoire of macaque behaviors. This comprehensive 5-year case-control study, which closely examined the effects of pediatric vaccines on early primate

  7. Of mice and monkeys: using non-human primate models to bridge mouse- and human-based investigations of autism spectrum disorders.

    PubMed

    Watson, Karli K; Platt, Michael L

    2012-07-30

    The autism spectrum disorders (ASDs) arise from a diverse array of genetic and environmental origins that disrupt the typical developmental trajectory of neural connectivity and synaptogenesis. ASDs are marked by dysfunctional social behavior and cognition, among other deficits. Greater understanding of the biological substrates of typical social behavior in animal models will further our understanding of the etiology of ASDs. Despite the precision and tractability of molecular genetics models of ASDs in rodents, these organisms lack the complexity of human social behavior, thus limiting their impact on understanding ASDs to basic mechanisms. Non-human primates (NHPs) provide an attractive, complementary model for ASDs, due in part to the complexity and dynamics of social structures, reliance on vision for social signaling, and deep homology in brain circuitry mediating social behavior and reward. This knowledge is based on a rich literature, compiled over 50 years of observing primate behavior in the wild, which, in the case of rhesus macaques, is complemented by a large body of research characterizing neuronal activity during cognitive behavior. Several recent developments in this field are directly relevant to ASDs, including how the brain represents the perceptual features of social stimuli, how social information influences attention processes in the brain, and how the value of social interaction is computed. Because the symptoms of ASDs may represent extreme manifestations of traits that vary in intensity within the general population, we will additionally discuss ways in which nonhuman primates also show variation in social behavior and reward sensitivity. In cases where variation in species-typical behavior is analogous to similar variations in human behavior, we believe that study of the neural circuitry underlying this variation will provide important insights into the systems-level mechanisms contributing to ASD pathology.

  8. Anatomical Organization of Urocortin 3-Synthesizing Neurons and Immunoreactive Terminals in the Central Nervous System of Non-Human Primates [Sapajus spp.

    PubMed Central

    Battagello, Daniella S.; Diniz, Giovanne B.; Candido, Paulo L.; da Silva, Joelcimar M.; de Oliveira, Amanda R.; Torres da Silva, Kelly R.; Lotfi, Claudimara F. P.; de Oliveira, José A.; Sita, Luciane V.; Casatti, Cláudio A.; Lovejoy, David A.; Bittencourt, Jackson C.

    2017-01-01

    Urocortin 3 (UCN3) is a neuropeptide member of the corticotropin-releasing factor (CRF) peptide family that acts as a selective endogenous ligand for the CRF, subtype 2 (CRF2) receptor. Immunohistochemistry and in situ hybridization data from rodents revealed UCN3-containing neurons in discrete regions of the central nervous system (CNS), such as the medial preoptic nucleus, the rostral perifornical area (PFA), the medial nucleus of the amygdala and the superior paraolivary nucleus. UCN3-immunoreactive (UCN3-ir) terminals are distributed throughout regions that mostly overlap with regions of CRF2 messenger RNA (mRNA) expression. Currently, no similar mapping exists for non-human primates. To better understand the role of this neuropeptide, we aimed to study the UCN3 distribution in the brains of New World monkeys of the Sapajus genus. To this end, we analyzed the gene and peptide sequences in these animals and performed immunohistochemistry and in situ hybridization to identify UCN3 synthesis sites and to determine the distribution of UCN3-ir terminals. The sequencing of the Sapajus spp. UCN3-coding gene revealed 88% and 65% identity to the human and rat counterparts, respectively. Additionally, using a probe generated from monkey cDNA and an antiserum raised against human UCN3, we found that labeled cells are mainly located in the hypothalamic and limbic regions. UCN3-ir axons and terminals are primarily distributed in the ventromedial hypothalamic nucleus (VMH) and the lateral septal nucleus (LS). Our results demonstrate that UCN3-producing neurons in the CNS of monkeys are phylogenetically conserved compared to those of the rodent brain, that the distribution of fibers agrees with the distribution of CRF2 in other primates and that there is anatomical evidence for the participation of UCN3 in neuroendocrine control in primates. PMID:28790894

  9. No effect of inter-group conflict on within-group harmony in non-human primates

    PubMed Central

    Grueter, Cyril C

    2013-01-01

    It has been a longstanding assumption that the threat of extra-group conflict can promote the expression of socio-positive behavior and cohesion within animal groups. I conducted a comparative analysis on the effect of inter-group conflict (indexed by home range overlap) on within-group affiliation levels (indexed by time engaged in allogrooming) in a sample of 48 primate species. There was no association between the 2 variables in a phylogenetic generalized least squares regression. I conclude that inter-group conflict may at best elicit short-term immediate changes in affiliation levels, but permanently elevated cohesion appears unique to humans with their large-scale social integration and scaled up inter-group conflict. PMID:24563713

  10. Transplantation of Human Embryonic Stem Cell-Derived Retinal Cells into the Subretinal Space of a Non-Human Primate

    PubMed Central

    Chao, Jennifer R.; Lamba, Deepak A.; Klesert, Todd R.; Torre, Anna La; Hoshino, Akina; Taylor, Russell J.; Jayabalu, Anu; Engel, Abbi L.; Khuu, Thomas H.; Wang, Ruikang K.; Neitz, Maureen; Neitz, Jay; Reh, Thomas A.

    2017-01-01

    Purpose Previous studies have demonstrated the ability of retinal cells derived from human embryonic stem cells (hESCs) to survive, integrate into the host retina, and mediate light responses in murine mouse models. Our aim is to determine whether these cells can also survive and integrate into the retina of a nonhuman primate, Saimiri sciureus, following transplantation into the subretinal space. Methods hESCs were differentiated toward retinal neuronal fates using our previously published technique and cultured for 60 to 70 days. Differentiated cells were further treated with 20 μM N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) for a period of 5 days immediately prior to subretinal transplantation. Differentiated cells were labeled with a lentivirus expressing GFP. One million cells (10,000 cells/μL) were injected into the submacular space into a squirrel monkey eye, using an ab externo technique. Results RetCam imaging demonstrated the presence and survival of human donor cells 3 months after transplantation in the S. sciureus eye. Injected cells consolidated in the temporal macula. GFP+ axonal projections were observed to emanate from the central consolidation of cells at 1 month, with some projecting into the optic nerve by 3 months after transplantation. Conclusions Human ES cell-derived retinal neurons injected into the submacular space of a squirrel monkey survive at least 3 months postinjection without immunosuppression. Some donor cells appeared to integrate into the host inner retina, and numerous donor axonal projections were noted throughout, with some projecting into the optic nerve. Translational Relevance These data illustrate the feasibility of hESC-derived retinal cell replacement in the nonhuman primate eye. PMID:28516002

  11. Establishing ‘quality of life’ parameters using behavioural guidelines for humane euthanasia of captive non-human primates

    PubMed Central

    Lambeth, SP; Schapiro, SJ; Bernacky, BJ; Wilkerson, GK

    2014-01-01

    Chronic pain and distress are universally accepted conditions that may adversely affect an animal’s quality of life (QOL) and lead to the humane euthanasia of an animal. At most research institutions and zoological parks in the USA, a veterinarian, who has physically examined the animal and reviewed the clinical records, ultimately decides when an animal has reached a humane endpoint. To aid in the difficult process of interpreting pain and distress, we have developed specific behavioural guidelines, in addition to standard clinical information, to help define unique characteristics and traits of primates to assess and promote discussion of an individual primate’s QOL, and thereby, to assist in the decision-making process regarding euthanasia. These guidelines advocate the creation of a QOL team when the animal is diagnosed with a life-threatening or debilitating chronic condition, or at the time the animal is entered into a terminal study. The team compiles a list of characteristics unique to that individual animal by utilising a questionnaire and a behavioural ethogram. This list enables the team to quantitatively assess any deviations from the established normal behavioural repertoire of that individual. Concurrently, the QOL team determines the number of behavioural deviations that are needed to trigger an immediate discussion of the necessity for humane euthanasia of the animal. The team remains intact once created, and revisits the animal’s condition as frequently as deemed necessary. This process improves animal welfare by continuing the quest to optimally define QOL for captive primates, and potentially for all captive animals. PMID:25505822

  12. Defensive Vocalizations and Motor Asymmetry Triggered by Disinhibition of the Periaqueductal Gray in Non-human Primates

    PubMed Central

    Forcelli, Patrick A.; Waguespack, Hannah F.; Malkova, Ludise

    2017-01-01

    Rapid and reflexive responses to threats are present across phylogeny. The neural circuitry mediating reflexive defense reactions has been well-characterized in a variety of species, for example, in rodents and cats, the detection of and species-typical response to threats is mediated by a network of structures including the midbrain tectum (deep and intermediate layers of the superior colliculus [DLSC]), periaqueductal gray (PAG), and forebrain structures such as the amygdala and hypothalamus. However, relatively little is known about the functional architecture of defense circuitry in primates. We have previously reported that pharmacological activation of the DLSC evokes locomotor asymmetry, defense-associated vocalizations, cowering behavior, escape responses, and attack of inanimate objects (Holmes et al., 2012; DesJardin et al., 2013; Forcelli et al., 2016). Here, we sought to determine if pharmacological activation of the PAG would induce a similar profile of responses. We activated the PAG in three awake, behaving macaques by microinfusion of GABA-A receptor antagonist, bicuculline methiodide. Activation of PAG evoked defense-associated vocalizations and postural/locomotor asymmetry, but not motor defense responses (e.g., cowering, escape behavior). These data suggest a partial dissociation between the role of the PAG and the DLSC in the defense network of macaques, but a general conservation of the role of PAG in defense responses across species. PMID:28424576

  13. Transcranial sonography: a technique for the study of the temporal lobes of the human and non-human primate brain.

    PubMed

    Ruggiero, Marco; Magherini, Stefano; Fiore, Maria Giulia; Chiarelli, Brunetto; Morucci, Gabriele; Branca, Jacopo Junio Valerio; Gulisano, Massimo; Pacini, Stefania

    2013-01-01

    We developed a modified transcranial sonography technique to study the morphology of the temporal lobe, a brain region involved in language, memory and social functions in humans that can be visualized in correspondence of the acoustic window of the temporal squama. Previous studies raise the possibility that a unique derived feature of Homo sapiens is a relatively larger temporal lobe compared to those of other hominins and apes. Such a brain reorganization might have contributed to the evolution of various "higher" cognitive functions of Homo sapiens, including language. Hence, the importance of further comparative analyses of the temporal region. With the technique that we developed we were able to study the meninges, the subarachnoidal space and the cortex of the human temporal lobe. The spatial resolution and the ability to visualize structures of 200-300 microm size led us to hypothesize that the linear structures parallel to the subarachnoidal space might be referred to the neuronal layers of the cortex. The low cost, simplicity and safety of the procedure suggest that this technique may have a significant potential in the comparative study of the primate temporal lobe. Furthermore, the procedure described here can also be used for the study of vascularization of the meninges, in order to better understand the evolutionary relationships between the neurocranial shape and the middle meningeal vessels in living and fossil human species.

  14. A pilot study in non-human primates shows no adverse response to intravenous injection of quantum dots

    NASA Astrophysics Data System (ADS)

    Ye, Ling; Yong, Ken-Tye; Liu, Liwei; Roy, Indrajit; Hu, Rui; Zhu, Jing; Cai, Hongxing; Law, Wing-Cheung; Liu, Jianwei; Wang, Kai; Liu, Jing; Liu, Yaqian; Hu, Yazhuo; Zhang, Xihe; Swihart, Mark T.; Prasad, Paras N.

    2012-07-01

    Quantum dots have been used in biomedical research for imaging, diagnostics and sensing purposes. However, concerns over the cytotoxicity of their heavy metal constituents and conflicting results from in vitro and small animal toxicity studies have limited their translation towards clinical applications. Here, we show in a pilot study that rhesus macaques injected with phospholipid micelle-encapsulated CdSe/CdS/ZnS quantum dots do not exhibit evidence of toxicity. Blood and biochemical markers remained within normal ranges following treatment, and histology of major organs after 90 days showed no abnormalities. Our results show that acute toxicity of these quantum dots in vivo can be minimal. However, chemical analysis revealed that most of the initial dose of cadmium remained in the liver, spleen and kidneys after 90 days. This means that the breakdown and clearance of quantum dots is quite slow, suggesting that longer-term studies will be required to determine the ultimate fate of these heavy metals and the impact of their persistence in primates.

  15. Assessment of functional impairment following permanent middle cerebral artery occlusion in a non-human primate species.

    PubMed

    Marshall, J W; Ridley, R M

    1996-09-01

    The purpose of the present study was to examine and quantify the functional consequence of a focal cerebral ischaemic lesion in a primate species, the marmoset. Following craniotomy and retraction of the frontal and temporal lobes, the middle cerebral artery was permanently occluded by means of electrocoagulation. Three and eight weeks after surgery, various behavioural tests were used to give a quantifiable measure to the neurological deficits produced. These tests required the monkeys to reach into tubes for foodbits, retrieve rewards from the steps of two designs of 'staircases', respond to one of two simultaneously presented rewarded tubes, remove adhesive labels attached to their feet, and respond to sensory stimuli. Unilateral motor impairment of the contralateral forelimb and neglect of contralateral tactile stimuli were seen in all subjects, and spatial neglect was also present in some monkeys. Subsequent histological analysis revealed unilateral cortical damage in all subjects with varying amounts of injury to the caudate and the putamen in some animals. These results demonstrate the potential for the use of this species in future investigations to examine the effect of neuroprotective treatment on functional outcome after a focal ischaemic insult.

  16. Patterns of microRNA Expression in Non-Human Primate Cells Correlate with Neoplastic Development In Vitro

    PubMed Central

    Teferedegne, Belete; Murata, Haruhiko; Quiñones, Mariam; Peden, Keith; Lewis, Andrew M.

    2010-01-01

    MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression post-transcriptionally. They play a critical role in developmental and physiological processes and have been implicated in the pathogenesis of several diseases including cancer. To identify miRNA signatures associated with different stages of neoplastic development, we examined the expression profile of 776 primate miRNAs in VERO cells (a neoplastically transformed cell line being used for the manufacture of viral vaccines), progenitor primary African green monkey kidney (pAGMK) cells, and VERO cell derivatives: spontaneously immortalized, non-tumorigenic, low-passage VERO cells (10-87 LP); tumorigenic, high-passage VERO cells (10-87 HP); and a cell line (10-87 T) derived from a 10-87 HP cell tumor xenograft in athymic nude mice. When compared with pAGMK cells, the majority of miRNAs were expressed at lower levels in 10-87 LP, 10-87 HP, and 10-87 T cells. We identified 10 up-regulated miRNAs whose level of expression correlated with VERO cell evolution from a non-tumorigenic phenotype to a tumorigenic phenotype. The overexpression of miR-376a and the polycistronic cluster of miR-376a, miR-376b and miR-376c conferred phenotypic changes to the non-tumorigenic 10-87 LP cells that mimic the tumorigenic 10-87 HP cells. Thirty percent of miRNAs that were components of the identified miRNAs in our spontaneously transformed AGMK cell model are also dysregulated in a variety of human tumors. These results may prove to be relevant to the biology of neoplastic development. In addition, one or more of these miRNAs could be biomarkers for the expression of a tumorigenic phenotype. PMID:21203544

  17. Patterns of microRNA expression in non-human primate cells correlate with neoplastic development in vitro.

    PubMed

    Teferedegne, Belete; Murata, Haruhiko; Quiñones, Mariam; Peden, Keith; Lewis, Andrew M

    2010-12-22

    MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression post-transcriptionally. They play a critical role in developmental and physiological processes and have been implicated in the pathogenesis of several diseases including cancer. To identify miRNA signatures associated with different stages of neoplastic development, we examined the expression profile of 776 primate miRNAs in VERO cells (a neoplastically transformed cell line being used for the manufacture of viral vaccines), progenitor primary African green monkey kidney (pAGMK) cells, and VERO cell derivatives: spontaneously immortalized, non-tumorigenic, low-passage VERO cells (10-87 LP); tumorigenic, high-passage VERO cells (10-87 HP); and a cell line (10-87 T) derived from a 10-87 HP cell tumor xenograft in athymic nude mice. When compared with pAGMK cells, the majority of miRNAs were expressed at lower levels in 10-87 LP, 10-87 HP, and 10-87 T cells. We identified 10 up-regulated miRNAs whose level of expression correlated with VERO cell evolution from a non-tumorigenic phenotype to a tumorigenic phenotype. The overexpression of miR-376a and the polycistronic cluster of miR-376a, miR-376b and miR-376c conferred phenotypic changes to the non-tumorigenic 10-87 LP cells that mimic the tumorigenic 10-87 HP cells. Thirty percent of miRNAs that were components of the identified miRNAs in our spontaneously transformed AGMK cell model are also dysregulated in a variety of human tumors. These results may prove to be relevant to the biology of neoplastic development. In addition, one or more of these miRNAs could be biomarkers for the expression of a tumorigenic phenotype.

  18. Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates.

    PubMed

    Matet, Alexandre; Kostic, Corinne; Bemelmans, Alexis-Pierre; Moulin, Alexandre; Rosolen, Serge G; Martin, Samia; Mavilio, Fulvio; Amirjanians, Vazrik; Stieger, Knut; Lorenz, Birgit; Behar-Cohen, Francine; Arsenijevic, Yvan

    2017-10-01

    Several approaches have been developed for gene therapy in RPE65-related Leber congenital amaurosis. To date, strategies that have reached the clinical stages rely on adeno-associated viral vectors and two of them documented limited long-term effect. We have developed a lentiviral-based strategy of RPE65 gene transfer that efficiently restored protein expression and cone function in RPE65-deficient mice. In this study, we evaluated the ocular and systemic tolerances of this lentiviral-based therapy (LV-RPE65) on healthy nonhuman primates (NHPs), without adjuvant systemic anti-inflammatory prophylaxis. For the first time, we describe the early kinetics of retinal detachment at 2, 4, and 7 days after subretinal injection using multimodal imaging in 5 NHPs. We revealed prolonged reattachment times in LV-RPE65-injected eyes compared to vehicle-injected eyes. Low- (n = 2) and high-dose (n = 2) LV-RPE65-injected eyes presented a reduction of the outer nuclear and photoreceptor outer segment layer thickness in the macula, that was more pronounced than in vehicle-injected eyes (n = 4). All LV-RPE65-injected eyes showed an initial perivascular reaction that resolved spontaneously within 14 days. Despite foveal structural changes, full-field electroretinography indicated that the overall retinal function was preserved over time and immunohistochemistry identified no difference in glial, microglial, or leucocyte ocular activation between low-dose, high-dose, and vehicle-injected eyes. Moreover, LV-RPE65-injected animals did not show signs of vector shedding or extraocular targeting, confirming the safe ocular restriction of the vector. Our results evidence a limited ocular tolerance to LV-RPE65 after subretinal injection without adjuvant anti-inflammatory prophylaxis, with complications linked to this route of administration necessitating to block this transient inflammatory event. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Genomic and evolutionary characterization of TT virus (TTV) in tupaias and comparison with species-specific TTVs in humans and non-human primates.

    PubMed

    Okamoto, H; Nishizawa, T; Takahashi, M; Tawara, A; Peng, Y; Kishimoto, J; Wang, Y

    2001-09-01

    TT virus (TTV) was recovered from the sera of tupaias (Tupaia belangeri chinensis) by PCR using primers derived from the noncoding region of the human TTV genome, and its entire genomic sequence was determined. One tupaia TTV isolate (Tbc-TTV14) consisted of only 2199 nucleotides (nt) and had three open reading frames (ORFs), spanning 1506 nt (ORF1), 177 nt (ORF2) and 642 nt (ORF3), which were in the same orientation as the ORFs of the human prototype TTV (TA278). ORF3 was presumed to arise from a splicing of TTV mRNA, similar to reported human TTVs whose spliced mRNAs have been identified, and encoded a joint protein of 214 amino acids with a Ser-, Lys- and Arg-rich sequence at the C terminus. Tbc-TTV14 was less than 50% similar to previously reported TTVs of 3.4-3.9 kb and TTV-like mini viruses (TLMVs) of 2.8-3.0 kb isolated from humans and non-human primates, and known animal circoviruses. Although Tbc-TTV14 has a genomic length similar to animal circoviruses (1.8-2.3 kb), Tbc-TTV14 resembled TTVs and TLMVs with regard to putative genomic organization and transcription profile. Conserved motifs were commonly observed in the coding and noncoding regions of the Tbc-TTV14 genome and in all TTV and TLMV genomes. Phylogenetic analysis revealed that Tbc-TTV14 is the closest to TLMVs, and is closer to TTVs isolated from tamarin and douroucouli than to TTVs isolated from humans and chimpanzees. These results indicate that tupaias are naturally infected with a new TTV species that has not been identified among primates.

  20. Giardia duodenalis assemblages and Entamoeba species infecting non-human primates in an Italian zoological garden: zoonotic potential and management traits

    PubMed Central

    2011-01-01

    Background Giardia duodenalis and Entamoeba spp. are among the most common intestinal human protozoan parasites worldwide and they are frequently reported in captive non-human primates (NHP). From a public health point of view, infected animals in zoos constitute a risk for animal caretakers and visitors. In this study we carried out the molecular identification of G. duodenalis and Entamoeba spp. from nine species of primates housed in the zoological garden of Rome, to better ascertain their occurrence and zoonotic potential. Results G. duodenalis was found only in Lemur catta (47.0%). Entamoeba spp. were detected in all species studied, with the exception of Eulemur macaco and Varecia rubra. The number of positive pools ranged from 5.9% in L. catta to 81.2% in Mandrillus sphinx; in Pan troglodytes the observed prevalence was 53.6%. A mixed Entamoeba-Giardia infection was recorded only in one sample of L. catta. All G. duodenalis isolates belonged to the zoonotic assemblage B, sub assemblage BIV. Three Entamoeba species were identified: E. hartmanni, E. coli and E. dispar. Conclusions Our results highlight the importance of regularly testing animals kept in zoos for the diagnosis of zoonotic parasites, in order to evaluate their pathogenic role in the housed animals and the zoonotic risk linked to their presence. A quick detection of the arrival of pathogens into the enclosures could also be a prerequisite to limit their spread into the structure via the introduction of specific control strategies. The need for molecular identification of some parasite species/genotype in order to better define the zoonotic risk is also highlighted. PMID:21988762

  1. Resveratrol Metabolism in a Non-Human Primate, the Grey Mouse Lemur (Microcebus murinus), Using Ultra-High-Performance Liquid Chromatography–Quadrupole Time of Flight

    PubMed Central

    Menet, Marie-Claude; Marchal, Julia; Dal-Pan, Alexandre; Taghi, Méryam; Nivet-Antoine, Valérie; Dargère, Delphine; Laprévote, Olivier; Beaudeux, Jean-Louis; Aujard, Fabienne; Epelbaum, Jacques; Cottart, Charles-Henry

    2014-01-01

    The grey mouse lemur (Microcebus murinus) is a non-human primate used to study the ageing process. Resveratrol is a polyphenol that may increase lifespan by delaying age-associated pathologies. However, no information about resveratrol absorption and metabolism is available for this primate. Resveratrol and its metabolites were qualitatively and quantitatively analyzed in male mouse-lemur plasma (after 200 mg.kg−1 of oral resveratrol) by ultra-high performance liquid chromatography (UHPLC), coupled to a quadrupole-time-of-flight (Q-TOF) mass spectrometer used in full-scan mode. Data analyses showed, in MSE mode, an ion common to resveratrol and all its metabolites: m/z 227.072, and an ion common to dihydro-resveratrol metabolites: m/z 229.08. A semi-targeted study enabled us to identify six hydrophilic resveratrol metabolites (one diglucurono-conjugated, two monoglucurono-conjugated, one monosulfo-conjugated and two both sulfo- and glucurono-conjugated derivatives) and three hydrophilic metabolites of dihydro-resveratrol (one monoglucurono-conjugated, one monosulfo-conjugated, and one both sulfo- and glucurono-conjugated derivatives). The presence of such metabolites has been already detected in the mouse, rat, pig, and humans. Free resveratrol was measurable for several hours in mouse-lemur plasma, and its two main metabolites were trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Free dihydro-resveratrol was not measurable whatever the time of plasma collection, while its hydrophilic metabolites were present at 24 h after intake. These data will help us interpret the effect of resveratrol in mouse lemurs and provide further information on the inter-species characteristics of resveratrol metabolism. PMID:24663435

  2. Effect of palm olein oil in a moderate-fat diet on plasma lipoprotein profile and aortic atherosclerosis in non-human primates.

    PubMed

    van Jaarsveld, Paul J; Smuts, Cornelius M; Benadé, A Spinnler

    2002-01-01

    Several studies have reported on the effect of palm olein oil (PO; palmitic acid content approximately 38%) incorporation into the diet on blood cholesterol concentration. Information on the effect of PO on atherosclerosis is, however, lacking. In vervet monkeys (Cercopithecus aethiops), low-density lipoprotein cholesterol (LDL-C) concen-trations can be modulated by the type and amount of fat in the diet. The vervet is a proven model for both the type and composition of human atherosclerotic lesions. The aim of this study was to determine the effect of PO in a moderate-fat moderate-cholesterol diet (MFD) on plasma lipoproteins and the progression of atherosclerosis in a non-human primate model after 25.5 months of dietary exposure. Thirty adult male vervets, never exposed to a Western-type atherogenic diet, were stabilised on a MFD (28%E fat; 26 mg cholesterol/1000 kJ) with a polyunsaturated to saturated fatty acid (P/S) ratio of 0.4 for six weeks. Baseline LDL-C, high-density lipoprotein (HDL)-C and bodyweight were used to stratify the vervets into three comparable groups of 10 each. One group continued with the MFD in which 11.0%E was derived from lard (AF). In the other two groups, the AF was substituted isocalorically with either sunflower oil (SO) or PO. Plasma lipids were measured at 6-monthly intervals and atherosclerosis was assessed in the aorta and in five peripheral arteries after 25.5 months of dietary exposure. The frequency of atherosclerosis in peripheral arteries and aortas was low. PO, relative to SO and AF, significantly reduced the risk for developing early lesions in peripheral arteries (P = 0.0277 and P = 0.0038, respectively) and, relative to AF, in aortas (P = 0.0335). The cholesterolaemic effect of MFD-PO was not significantly different from MFD-SO and MFD-AF. However, at 24 months the plasma total cholesterol concentration with MFD-AF was significantly higher than with MFD-SO (P = 0.0256). It is confirmed that a MFD with PO is no different

  3. Erythrocytes from GGTA1/CMAH knockout pigs: implications for xenotransfusion and testing in non-human primates

    PubMed Central

    Wang, Zheng-Yu; Burlak, Christopher; Estrada, Jose L.; Li, Ping; Tector, Matthew F.; Tector, A. Joseph

    2015-01-01

    compared to GGTA1 KO erythrocytes, but markedly increased 3-fold by baboon serum IgG. Human IgM binding was decreased 227-fold on GGTA1/CMAH KO erythrocytes compared to GGTA1 KO erythrocytes, but enhanced 5-fold by baboon serum IgM. Conclusions Removal of aGal and Neu5Gc antigens from pig erythrocytes significantly reduced human preformed antibody-mediated cytotoxicity but may have complicated future in vivo analysis by enhancing reactivity from baboons. The creation of the GGTA1/CMAH KO pig has provided the xenotransplantion researcher with organs and cells that attract fewer human antibodies than baboon and our closest primate relative, chimpanzee. These finding suggest that while GGTA1/CMAH KO erythrocytes may be useful for human transfusions, in vivo testing in the baboon may not provide a direct transplation to the clinic. PMID:24986655

  4. Erythrocytes from GGTA1/CMAH knockout pigs: implications for xenotransfusion and testing in non-human primates.

    PubMed

    Wang, Zheng-Yu; Burlak, Christopher; Estrada, Jose L; Li, Ping; Tector, Matthew F; Tector, A Joseph

    2014-01-01

    KO erythrocytes, but markedly increased 3-fold by baboon serum IgG. Human IgM binding was decreased 227-fold on GGTA1/CMAH KO erythrocytes compared with GGTA1 KO erythrocytes, but enhanced 5-fold by baboon serum IgM. Removal of aGal and Neu5Gc antigens from pig erythrocytes significantly reduced human preformed antibody-mediated cytotoxicity but may have complicated future in vivo analysis by enhancing reactivity from baboons. The creation of the GGTA1/CMAH KO pig has provided the xenotransplantation researcher with organs and cells that attract fewer human antibodies than baboon and our closest primate relative, chimpanzee. These finding suggest that while GGTA1/CMAH KO erythrocytes may be useful for human transfusions, in vivo testing in the baboon may not provide a direct transplantation to the clinic. © 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.

  5. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    NASA Technical Reports Server (NTRS)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, media] gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  6. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    NASA Technical Reports Server (NTRS)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. Purpose: The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, medial gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  7. Path to the clinic: Assessment of iPSC-based cell therapies in vivo in a non-human primate model

    PubMed Central

    Wu, Chuanfeng; Guo, Vicky; Pittaluga, Stefania; Nicolae, Alina; Donahue, Robert E.; Metzger, Mark E.; Price, Sandra D.; Uchida, Naoya; Kuznetsov, Sergei A.; Kilts, Tina; Li, Li; Robey, Pamela G.; Dunbar, Cynthia E.

    2014-01-01

    Summary Induced pluripotent stem cell (iPSC)-based cell therapies have a great potential for regenerative medicine, but are also potentially associated with tumorigenic risks. Current rodent models are not the optimal predictors of efficiency and safety for clinical application. Therefore, we developed a clinically relevant non-human primate model to assess the tumorigenic potential and in vivo efficacy of both undifferentiated and differentiated iPSCs in the autologous settings without immunosuppression. Undifferentiated autologous iPSCs indeed formed mature teratomas in a dose-dependent manner. However, tumor formation was accompanied by an inflammatory reaction. On the other hand, iPSC-derived mesodermal stromal-like cells formed new bone in vivo without any evidence of teratoma formation. We therefore show for the first time in a large animal model that closely resembles human physiology that undifferentiated autologous iPSCs form teratomas, and that iPSC-derived progenitor cells can give rise to a functional tissue in vivo. PMID:24835994

  8. Real-Time Ophthalmoscopic Findings of Super-Selective Intra-Ophthalmic Artery Chemotherapy in a Non-Human Primate Model

    PubMed Central

    Wilson, Matthew W.; Jackson, John S.; Phillips, Blanca X.; Buchanan, Jacquelyn; Frase, Sharon; Wang, Fan; Steinle, Jena J.; Stewart, Clinton F.; Mandrell, Timothy D.; Haik, Barrett G.; Williams, J. Scott

    2012-01-01

    Objectives To report real-time ophthalmoscopic findings during super-selective intra-ophthalmic artery chemotherapy (SSIOAC) in a non-human primate (NHP) model. Methods Six adult male Rhesus macaques (Macacca mulatta) were randomly assigned into one of two treatment cohorts; MEL treated with 5 mg/30 mL melphalan, and CBP treated with 30 mg/30 mL carboplatin. Each animal underwent three separate SSIOAC procedures at three-week intervals. Digital retinal images were obtained during each infusion. Intravenous fluorescein angiography was performed immediately after each procedure. Results All SSIOAC procedures were successfully completed. Toxicities were equally distributed between drug cohorts. Systemic toxicities included mild bone marrow suppression in all animals and anorexia in one. One animal had greater than 50% narrowing of the treated ophthalmic artery after its second infusion. All 18 procedures (100%) resulted in pulsatile optic nerve and choroid blanching, retinal artery narrowing, and retinal edema. Retinal artery sheathing was found during 17 (of 18, 94%) procedures, and retinal artery precipitates were seen in 10 (of 18, 56%). Choroidal hypoperfusion (18 of 18, 100%) was seen by fluorescein angiogram. Conclusions Real-time ophthalmic investigations are useful and, in our NHP model, indicate prevalent, acute ocular vascular toxicities during SSIOAC. Clinical Relevance Real-time retinal imaging is feasible in an NHP model of SSIOAC. Application to SSIOAC in children may shed insight into reported vascular toxicities. PMID:22084215

  9. Surveillance for yellow Fever virus in non-human primates in southern Brazil, 2001-2011: a tool for prioritizing human populations for vaccination.

    PubMed

    Almeida, Marco A B; Cardoso, Jader da C; Dos Santos, Edmilson; da Fonseca, Daltro F; Cruz, Laura L; Faraco, Fernando J C; Bercini, Marilina A; Vettorello, Kátia C; Porto, Mariana A; Mohrdieck, Renate; Ranieri, Tani M S; Schermann, Maria T; Sperb, Alethéa F; Paz, Francisco Z; Nunes, Zenaida M A; Romano, Alessandro P M; Costa, Zouraide G; Gomes, Silvana L; Flannery, Brendan

    2014-03-01

    In Brazil, epizootics among New World monkey species may indicate circulation of yellow fever (YF) virus and provide early warning of risk to humans. Between 1999 and 2001, the southern Brazilian state of Rio Grande do Sul initiated surveillance for epizootics of YF in non-human primates to inform vaccination of human populations. Following a YF outbreak, we analyzed epizootic surveillance data and assessed YF vaccine coverage, timeliness of implementation of vaccination in unvaccinated human populations. From October 2008 through June 2009, circulation of YF virus was confirmed in 67 municipalities in Rio Grande do Sul State; vaccination was recommended in 23 (34%) prior to the outbreak and in 16 (24%) within two weeks of first epizootic report. In 28 (42%) municipalities, vaccination began more than two weeks after first epizootic report. Eleven (52%) of 21 laboratory-confirmed human YF cases occurred in two municipalities with delayed vaccination. By 2010, municipalities with confirmed YF epizootics reported higher vaccine coverage than other municipalities that began vaccination. In unvaccinated human populations timely response to epizootic events is critical to prevent human yellow fever cases.

  10. Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates

    NASA Astrophysics Data System (ADS)

    Doloff, Joshua C.; Veiseh, Omid; Vegas, Arturo J.; Tam, Hok Hei; Farah, Shady; Ma, Minglin; Li, Jie; Bader, Andrew; Chiu, Alan; Sadraei, Atieh; Aresta-Dasilva, Stephanie; Griffin, Marissa; Jhunjhunwala, Siddharth; Webber, Matthew; Siebert, Sean; Tang, Katherine; Chen, Michael; Langan, Erin; Dholokia, Nimit; Thakrar, Raj; Qi, Meirigeng; Oberholzer, Jose; Greiner, Dale L.; Langer, Robert; Anderson, Daniel G.

    2017-06-01

    Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

  11. Changes in Cerebral Blood Flow during an Alteration in Glycemic State in a Large Non-human Primate (Papio hamadryas sp.)

    PubMed Central

    Kochunov, Peter; Wey, Hsiao-Ying; Fox, Peter T.; Lancaster, Jack L.; Davis, Michael D.; Wang, Danny J. J.; Lin, Ai-Ling; Bastarrachea, Raul A.; Andrade, Marcia C. R.; Mattern, Vicki; Frost, Patrice; Higgins, Paul B.; Comuzzie, Anthony G.; Voruganti, Venkata S.

    2017-01-01

    Changes in cerebral blood flow (CBF) during a hyperglycemic challenge were mapped, using perfusion-weighted MRI, in a group of non-human primates. Seven female baboons were fasted for 16 h prior to 1-h imaging experiment, performed under general anesthesia, that consisted of a 20-min baseline, followed by a bolus infusion of glucose (500 mg/kg). CBF maps were collected every 7 s and blood glucose and insulin levels were sampled at regular intervals. Blood glucose levels rose from 51.3 ± 10.9 to 203.9 ± 38.9 mg/dL and declined to 133.4 ± 22.0 mg/dL, at the end of the experiment. Regional CBF changes consisted of four clusters: cerebral cortex, thalamus, hypothalamus, and mesencephalon. Increases in the hypothalamic blood flow occurred concurrently with the regulatory response to systemic glucose change, whereas CBF declined for other clusters. The return to baseline of hypothalamic blood flow was observed while CBF was still increasing in other brain regions. The spatial pattern of extra-hypothalamic CBF changes was correlated with the patterns of several cerebral networks including the default mode network. These findings suggest that hypothalamic blood flow response to systemic glucose levels can potentially be explained by regulatory activity. The response of extra-hypothalamic clusters followed a different time course and its spatial pattern resembled that of the default-mode network. PMID:28261040

  12. Ebola virus genome plasticity as a marker of its passaging history: a comparison of in vitro passaging to non-human primate infection.

    PubMed

    Kugelman, Jeffrey R; Lee, Michael S; Rossi, Cynthia A; McCarthy, Sarah E; Radoshitzky, Sheli R; Dye, John M; Hensley, Lisa E; Honko, Anna; Kuhn, Jens H; Jahrling, Peter B; Warren, Travis K; Whitehouse, Chris A; Bavari, Sina; Palacios, Gustavo

    2012-01-01

    To identify polymorphic sites that could be used as biomarkers of Ebola virus passage history, we repeatedly amplified Ebola virus (Kikwit variant) in vitro and in vivo and performed deep sequencing analysis of the complete genomes of the viral subpopulations. We then determined the sites undergoing selection during passage in Vero E6 cells. Four locations within the Ebola virus Kikwit genome were identified that together segregate cell culture-passaged virus and virus obtained from infected non-human primates. Three of the identified sites are located within the glycoprotein gene (GP) sequence: the poly-U (RNA editing) site at position 6925, as well as positions 6677, and 6179. One site was found in the VP24 gene at position 10833. In all cases, in vitro and in vivo, both populations (majority and minority variants) were maintained in the viral swarm, with rapid selections occurring after a few passages or infections. This analysis approach will be useful to differentiate whether filovirus stocks with unknown history have been passaged in cell culture and may support filovirus stock standardization for medical countermeasure development.

  13. Targeting accuracy and closing timeline of the microbubble-enhanced focused ultrasound blood-brain barrier opening in non-human primates

    NASA Astrophysics Data System (ADS)

    Marquet, Fabrice; Tung, Yao-Sheng; Teichert, Tobias; Wu, Shih-Ying; Wang, Shutao; Downs, Matthew; Ferrera, Vincent P.; Konofagou, Elisa E.

    2012-11-01

    The delivery of drugs to specific neural targets faces two fundamental problems: Most drugs do not cross the blood-brain barrier and those that do spread to all parts of the brain. To date there exists only one non-invasive methodology with the potential to solve these problems: selective blood-brain barrier disruption using micro-bubble enhanced focused ultrasound. We have recently developed a single-element 500 kHz spherical transducer ultrasound setup for use in the non-human primate. Using this system for selective blood-brain barrier disruption is technically no more challenging than positioning a TMS coil, and does not rely on MRI-guided targeting or expensive phased array ultrasound systems. So far, however, the targeting accuracy that can be achieved with this system has not been quantified systematically. Here we tested the accuracy of the system by targeting the caudate nucleus of the basal ganglia in two macaque monkeys. Our results show that average in-plane error of the system is on the order of 2 mm and targeting error in depth, i.e., along the ultrasound path, is even smaller and averaged 1.2 mm. In summary, targeting accuracy of our system is good enough to enable the selective delivery of drugs to specific sub-structures of the basal ganglia.

  14. Cross-species and tissue variations in cyanide detoxification rates in rodents and non-human primates on protein-restricted diet.

    PubMed

    Kimani, S; Moterroso, V; Morales, P; Wagner, J; Kipruto, S; Bukachi, F; Maitai, C; Tshala-Katumbay, D

    2014-04-01

    We sought to elucidate the impact of diet, cyanide or cyanate exposure on mammalian cyanide detoxification capabilities (CDC). Male rats (~8 weeks old) (N=52) on 75% sulfur amino acid (SAA)-deficient diet were treated with NaCN (2.5mg/kg bw) or NaOCN (50mg/kg bw) for 6 weeks. Macaca fascicularis monkeys (~12 years old) (N=12) were exclusively fed cassava for 5 weeks. CDC was assessed in plasma, or spinal cord, or brain. In rats, NaCN induced seizures under SAA-restricted diet whereas NaOCN induced motor deficits. No deficits were observed in non-human primates. Under normal diet, the CDC were up to ~80× faster in the nervous system (14 ms to produce one μmol of thiocyanate from the detoxification of cyanide) relative to plasma. Spinal cord CDC was impaired by NaCN, NaOCN, or SAA deficiency. In M. fascicularis, plasma CDC changed proportionally to total proteins (r=0.43; p<0.001). The plasma CDC was ~2× relative to that of rodents. The nervous system susceptibility to cyanide may result from a "multiple hit" by the toxicity of cyanide or its cyanate metabolite, the influences of dietary deficiencies, and the tissue variations in CDC. Chronic dietary reliance on cassava may cause metabolic derangement including poor CDC.

  15. Structural architecture of the social network of a non-human primate (Macaca sylvanus): a study of its topology in La Forêt des Singes, Rocamadour.

    PubMed

    Sosa, Sebastian

    2014-01-01

    For a decade, technological or natural networks have appeared to have a common mathematical architecture. This type of architecture has a node connectivity which follows a power law distribution. This architecture confers to these networks a resistance property to the loss of nodes. Such properties are advantageous for evolutional networks through time. Thus, this architecture can be expected in animal social networks. Another characteristic commonly met concerns the structuration of the network into communities by the mechanism of assortative mixing by vertex degree (i.e. by the number of ties individuals have). Such a structure is a reflection of evolutional mechanisms: the preferential attachment and the triadic closure processes. Using recent analytical techniques on an affiliative social network in a non-human primate species (Macaca sylvanus), we analysed the mathematical architecture and its properties. We demonstrate that in spite of the use of a recent protocol supposed to permit this type of analysis, the type of distribution cannot be clearly determined, encouraging us to carefully interpret the results obtained until then. Nevertheless, we observed interesting properties of the network at an ecological and evolutional level with network resilience that allows a cohesive society to be maintained even when faced with a catastrophe (high predation, epidemic).

  16. Cross-species and tissue variations in cyanide detoxification rates in rodents and non-human primates on protein-restricted diet

    PubMed Central

    Kimani, S.; Moterroso, V.; Morales, P.; Wagner, J.; Kipruto, S.; Bukachi, F.; Maitai, C.; Tshala-Katumbay, D.

    2014-01-01

    We sought to elucidate the impact of diet, cyanide or cyanate exposure on mammalian cyanide detoxification capabilities (CDC). Male rats (~8 weeks old) (N=52) on 75% sulfur amino acid (SAA)-deficient diet were treated with NaCN (2.5 mg/kg bw) or NaOCN (50 mg/kg bw) for 6 weeks. Macaca fascicularis monkeys (~12 years old) (N=12) were exclusively fed cassava for 5 weeks. CDC was assessed in plasma, or spinal cord, or brain. In rats, NaCN induced seizures under SAA-restricted diet whereas NaOCN induced motor deficits. No deficits were observed in non-human primates. Under normal diet, the CDC were up to ~ 80X faster in the nervous system (14 milliseconds to produce one μmol of thiocyanate from the detoxification of cyanide) relative to plasma. Spinal cord CDC was impaired by NaCN, NaOCN, or SAA deficiency. In macaca fascicularis, plasma CDC changed proportionally to total proteins (r=0.43; p<0.001). The plasma CDC was ~ 2X relative to that of rodents. The nervous system susceptibility to cyanide may result from a “multiple hit” by the toxicity of cyanide or its cyanate metabolite, the influences of dietary deficiencies, and the tissue variations in CDC. Chronic dietary reliance on cassava may cause metabolic derangement including poor CDC. PMID:24500607

  17. Changes in Cerebral Blood Flow during an Alteration in Glycemic State in a Large Non-human Primate (Papio hamadryas sp.).

    PubMed

    Kochunov, Peter; Wey, Hsiao-Ying; Fox, Peter T; Lancaster, Jack L; Davis, Michael D; Wang, Danny J J; Lin, Ai-Ling; Bastarrachea, Raul A; Andrade, Marcia C R; Mattern, Vicki; Frost, Patrice; Higgins, Paul B; Comuzzie, Anthony G; Voruganti, Venkata S

    2017-01-01

    Changes in cerebral blood flow (CBF) during a hyperglycemic challenge were mapped, using perfusion-weighted MRI, in a group of non-human primates. Seven female baboons were fasted for 16 h prior to 1-h imaging experiment, performed under general anesthesia, that consisted of a 20-min baseline, followed by a bolus infusion of glucose (500 mg/kg). CBF maps were collected every 7 s and blood glucose and insulin levels were sampled at regular intervals. Blood glucose levels rose from 51.3 ± 10.9 to 203.9 ± 38.9 mg/dL and declined to 133.4 ± 22.0 mg/dL, at the end of the experiment. Regional CBF changes consisted of four clusters: cerebral cortex, thalamus, hypothalamus, and mesencephalon. Increases in the hypothalamic blood flow occurred concurrently with the regulatory response to systemic glucose change, whereas CBF declined for other clusters. The return to baseline of hypothalamic blood flow was observed while CBF was still increasing in other brain regions. The spatial pattern of extra-hypothalamic CBF changes was correlated with the patterns of several cerebral networks including the default mode network. These findings suggest that hypothalamic blood flow response to systemic glucose levels can potentially be explained by regulatory activity. The response of extra-hypothalamic clusters followed a different time course and its spatial pattern resembled that of the default-mode network.

  18. Global CNS Gene Delivery and Evasion of Anti-AAV Neutralizing Antibodies by Intrathecal AAV Administration in Non-Human Primates

    PubMed Central

    Gray, Steven J.; Kalburgi, Sahana Nagabhushan; McCown, Thomas J.; Samulski, R. Jude

    2012-01-01

    Injection of AAV into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4, AAV5) in rodents, we report that a naturally-occurring capsid (AAV9) and rationally-engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of ~2×1012 vg per 3-6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the CNS. AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared to intravascular delivery, and the presence of circulating anti-AAV neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases. PMID:23303281

  19. Evaluation of the immunocontraceptive potential of Escherichia coli expressed recombinant non-human primate zona pellucida glycoproteins in homologous animal model.

    PubMed

    Govind, Chhabi K; Srivastava, Neelu; Gupta, Satish K

    2002-11-22

    In order to evaluate the immunocontraceptive potential of zona pellucida (ZP) glycoproteins, recombinant bonnet monkey (Macaca radiata) zona pellucida glycoprotein-1 (r-bmZP1) and -2 (r-bmZP2) were expressed as polyhistidine fusion proteins in Escherichia coli. Female bonnet monkeys were immunized with the purified r-bmZP1 (n=5) and r-bmZP2 (n=4) conjugated to diphtheria toxoid (DT). Immunization led to generation of antibodies against r-bmZP1, r-bmZP2 and DT as determined by enzyme linked immunosorbent assay. The immunized animals exhibited normal menstrual cyclicity and progesterone profile, except during the summer amenorrhoea. Immunized animals, when mated with males of proven fertility, showed protection from conceiving for cumulative 45 ovulatory cycles in r-bmZP1-DT immunized group and 32 ovulatory cycles in r-bmZP2-DT immunized group. Ovarian histopathology of both the immunized groups revealed the presence of atretic follicles with degenerated oocytes, which may have been the principle cause for the failure of immunized animals to conceive in spite of the decline in either anti-r-bmZP1 or anti-r-bmZP2 antibody titres to background levels. These studies demonstrate, for the first time, that the block of fertility subsequent to immunization with r-bmZP1 and r-bmZP2, in a homologous non-human primate model, may be mediated due to ovarian dysfunction.

  20. Surveillance for Yellow Fever Virus in Non-Human Primates in Southern Brazil, 2001–2011: A Tool for Prioritizing Human Populations for Vaccination

    PubMed Central

    Almeida, Marco A. B.; Cardoso, Jader da C.; dos Santos, Edmilson; da Fonseca, Daltro F.; Cruz, Laura L.; Faraco, Fernando J. C.; Bercini, Marilina A.; Vettorello, Kátia C.; Porto, Mariana A.; Mohrdieck, Renate; Ranieri, Tani M. S.; Schermann, Maria T.; Sperb, Alethéa F.; Paz, Francisco Z.; Nunes, Zenaida M. A.; Romano, Alessandro P. M.; Costa, Zouraide G.; Gomes, Silvana L.; Flannery, Brendan

    2014-01-01

    In Brazil, epizootics among New World monkey species may indicate circulation of yellow fever (YF) virus and provide early warning of risk to humans. Between 1999 and 2001, the southern Brazilian state of Rio Grande do Sul initiated surveillance for epizootics of YF in non-human primates to inform vaccination of human populations. Following a YF outbreak, we analyzed epizootic surveillance data and assessed YF vaccine coverage, timeliness of implementation of vaccination in unvaccinated human populations. From October 2008 through June 2009, circulation of YF virus was confirmed in 67 municipalities in Rio Grande do Sul State; vaccination was recommended in 23 (34%) prior to the outbreak and in 16 (24%) within two weeks of first epizootic report. In 28 (42%) municipalities, vaccination began more than two weeks after first epizootic report. Eleven (52%) of 21 laboratory-confirmed human YF cases occurred in two municipalities with delayed vaccination. By 2010, municipalities with confirmed YF epizootics reported higher vaccine coverage than other municipalities that began vaccination. In unvaccinated human populations timely response to epizootic events is critical to prevent human yellow fever cases. PMID:24625681

  1. PET neuroimaging studies of [18F]CABS13 in a double transgenic mouse model of Alzheimer’s disease and non-human primates

    PubMed Central

    Liang, Steven H.; Holland, Jason P.; Stephenson, Nickeisha A.; Kassenbrock, Alina; Rotstein, Benjamin H.; Daignault, Cory P.; Lewis, Rebecca; Collier, Lee; Hooker, Jacob M.; Vasdev, Neil

    2016-01-01

    Fluorine-18 labeled 2-fluoro-8-hydroxyquinoline ([18F]CABS13) is a promising positron emission tomography (PET) radiopharmaceutical based on a metal chelator developed to probe the “metal hypothesis of Alzheimer’s disease”. Herein, a practical radiosynthesis of [18F]CABS13 was achieved by radiofluorination followed by deprotection of an O-benzyloxymethyl group. Automated production and formulation of [18F]CABS13 resulted in 19 ± 5% uncorrected radiochemical yield, relative to starting [18F]fluoride, with ≥95% chemical and radiochemical purities, and high specific activity (>2.5 Ci/μmol) within 80 minutes. Temporal PET neuroimaging studies were carried out in female transgenic B6C3- Tg(APPswe,PSEN1dE9)85Dbo/J (APP/PS1) and age-matched wild-type (WT) B6C3F1/J control mice at 3, 7 and 10 months of age. [18F]CABS13 showed an overall higher uptake and retention of radioactivity in the central nervous system of APP/PS1 mice versus WT mice with increasing age. However, PET/magnetic resonance imaging in normal non-human primates revealed that the tracer had low uptake in the brain and rapid formation of a hydrophilic radiometabolite. Identification of more metabolically stable 18F-hydroxyquinolines that can be readily accessed by the radiochemical strategy presented herein is underway. PMID:25776827

  2. Testing the H56 Vaccine Delivered in 4 Different Adjuvants as a BCG-Booster in a Non-Human Primate Model of Tuberculosis

    PubMed Central

    Billeskov, Rolf; Tan, Esterlina V.; Cang, Marjorie; Abalos, Rodolfo M.; Burgos, Jasmin; Pedersen, Bo Vestergaard; Christensen, Dennis; Agger, Else Marie; Andersen, Peter

    2016-01-01

    The search for new and improved tuberculosis (TB) vaccines has focused on IFN-γ both for selecting antigens and for evaluating vaccine delivery strategies. The essential role of IFN-γ in endogenous host protection is well established, but it is still uncertain whether this also holds true for vaccine protection. Here we evaluate the H56 fusion protein vaccine as a BCG booster in a non-human primate (NHP) model of TB that closely recapitulates human TB pathogenesis. To date, only a handful of novel adjuvants have been tested in the NHP model of TB, and therefore we administered H56 in 3 novel cationic liposome adjuvants of increasing immunogenicity (CAF01, CAF04, CAF05) and compared them to H56 in the IC31® adjuvant previously reported to promote protection in this model. The individual clinical parameters monitored during infection (weight, ESR, X-ray) all correlated with survival, and boosting BCG with H56 in all adjuvants resulted in better survival rates compared to BCG alone. The adjuvants promoted IFN-γ-responses of increasing intensity as measured by ELISPOT in the peripheral blood, but the level of vaccine-specific IFN-γ production did not correlate with or predict disease outcome. This study’s main outcome underscores the importance of the choice of adjuvant for TB subunit vaccines, and secondly it highlights the need for better correlates of protection in preclinical models of TB. PMID:27525651

  3. A retrospective evaluation of species-specific sensitivity for neurological signs in toxicological studies: Is the dog more sensitive than the non-human primate?

    PubMed

    Backes, Kathrin; Lorenz, Helga; Laplanche, Loic; Hudzik, Thomas J; Potschka, Heidrun; Hempel, Katja

    2016-01-22

    Selection of the appropriate non-rodent species in preclinical programs is crucial for good translatability and human safety. There is no data available in the literature which provides exact comparison of dog and non-human primate (NHP) sensitivity regarding neurological signs in toxicological studies. We performed a retrospective analysis of 174 toxicity studies with 15 neuroscience substances. Neurological signs in dogs and NHPs were evaluated in correlation to exposure data. Overall incidence of substance induced convulsions was similar in both species and no gender differences were observed. The reported liability of beagles to spontaneous convulsions was not confirmed in our studies. The symptom tremor showed the best inter-species translatability. The current toxicological study design does not include exposure assessment at the time-point of neurological signs, therefore, we propose to include additional toxicokinetic samples. Our analysis revealed factors including housing, handling, and behavior, which prevents direct species comparison. In addition only one non-rodent species is routinely tested in development programs, therefore data for both species is rare. We however, had sufficient data which enabled comparison for one compound. In the spirit of 3Rs further examples should be evaluated.

  4. Generation and characterization of large-particle aerosols using a center flow tangential aerosol generator with a non-human-primate, head-only aerosol chamber.

    PubMed

    Bohannon, J Kyle; Lackemeyer, Matthew G; Kuhn, Jens H; Wada, Jiro; Bollinger, Laura; Jahrling, Peter B; Johnson, Reed F

    2015-01-01

    Aerosol droplets or particles produced from infected respiratory secretions have the potential to infect another host through inhalation. These respiratory particles can be polydisperse and range from 0.05 to 500 µm in diameter. Animal models of infection are generally established to facilitate the potential licensure of candidate prophylactics and/or therapeutics. Consequently, aerosol-based animal infection models are needed to properly study and counter airborne infections. Ideally, experimental aerosol exposure should reliably result in animal disease that faithfully reproduces the modeled human disease. Few studies have been performed to explore the relationship between exposure particle size and induced disease course for infectious aerosol particles. The center flow tangential aerosol generator (CenTAG™) produces large-particle aerosols capable of safely delivering a variety of infectious aerosols to non-human primates (NHPs) within a Class III Biological Safety Cabinet (BSC) for establishment or refinement of NHP infectious disease models. Here, we report the adaptation of this technology to the Animal Biosafety Level 4 (ABSL-4) environment for the future study of high-consequence viral pathogens and the characterization of CenTAG™-created sham (no animal, no virus) aerosols using a variety of viral growth media and media supplements.

  5. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease

    PubMed Central

    Hallett, Penelope J; Deleidi, Michela; Astradsson, Arnar; Smith, Gaynor A.; Cooper, Oliver; Osborn, Teresia; Sundberg, Maria; Moore, Michele A.; Perez-Torres, Eduardo; Brownell, Anna-Liisa; Schumacher, James; Spealman, Roger D.; Isacson, Ole

    2015-01-01

    Summary Autologous transplantation of patient-specific iPSC-derived neurons is a potential clinical approach for treatment of neurological disease. Preclinical demonstration of long-term efficacy, feasibility and safety of iPSC-derived dopamine neurons in non human primate models will be an important step in clinical development of cell therapy. Here, we analyzed cynomolgus monkey (CM) iPSC-derived midbrain dopamine neurons for up to 2 years following autologous transplantation in a Parkinson's disease (PD) model. In one animal, with the most successful protocol, we found that unilateral engraftment of CM-iPSCs could provide a gradual onset of functional motor improvement contralateral to the side of dopamine neuron transplantation, and increased motor activity, without a need for immunosuppression. Post-mortem analyses demonstrated robust survival of midbrain-like dopaminergic neurons and extensive outgrowth into the transplanted putamen. Our proof of concept findings support further development of autologous iPSC-derived cell transplantation for treatment of PD. PMID:25732245

  6. First case report of non-human primates (Alouatta clamitans) with the hypervirulent Klebsiella pneumoniae serotype K1 strain ST 23: A possible emerging wildlife pathogen.

    PubMed

    Anzai, Eleine Kuroki; Souza Júnior, Júlio César de; Peruchi, Amanda Rezende; Fonseca, Juliana Mello; Gumpl, Elke Kreuscher; Pignatari, Antônio Carlos Campos; Hirano, Zelinda Maria Braga; Silveira, Alessandro Conrado de Oliveira

    2017-08-15

    Hypervirulent strain of Klebsiella pneumoniae genotype K1 isolates have recently emerged, causing severe pyogenic liver abscess complicated by devastating metastatic infections in humans. We describe a short outbreak of the non-human primate (NHP) research center, associated with a hypervirulent K. pneumoniae. The genetic similarity of the strains was evaluated by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) techniques, and virulence encoding genes were detected by polymerase chain reaction (PCR). The isolates were phenotypically like strains causing community-acquired invasive liver abscess syndrome in humans. All strains exhibited identical PFGE patterns and were found to belong to ST23 and presented a hypermucovisity phenotype and possessed magA and rmpA gene. This is the first case report of NHPs caused by K. pneumoniae displaying a hypermucoviscosity phenotype and belonging to capsular serotypes K1 and ST23. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Increased expression of connective tissue growth factor (CTGF) in multiple organs after exposure of non-human primates (NHP) to lethal doses of radiation

    PubMed Central

    Zhang, Pei; Cui, Wanchang; Hankey, Kim G.; Gibbs, Allison M.; Smith, Cassandra P.; Taylor-Howell, Cheryl; Kearney, Sean R.; MacVittie, Thomas J.

    2015-01-01

    Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP, and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition respectively, suggesting possible crosstalk between spleen and other organs. Our data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs. PMID:26425899

  8. Versatile, modular 3D microelectrode arrays for neuronal ensemble recordings: from design to fabrication, assembly, and functional validation in non-human primates

    NASA Astrophysics Data System (ADS)

    Barz, F.; Livi, A.; Lanzilotto, M.; Maranesi, M.; Bonini, L.; Paul, O.; Ruther, P.

    2017-06-01

    Objective. Application-specific designs of electrode arrays offer an improved effectiveness for providing access to targeted brain regions in neuroscientific research and brain machine interfaces. The simultaneous and stable recording of neuronal ensembles is the main goal in the design of advanced neural interfaces. Here, we describe the development and assembly of highly customizable 3D microelectrode arrays and demonstrate their recording performance in chronic applications in non-human primates. Approach. System assembly relies on a microfabricated stacking component that is combined with Michigan-style silicon-based electrode arrays interfacing highly flexible polyimide cables. Based on the novel stacking component, the lead time for implementing prototypes with altered electrode pitches is minimal. Once the fabrication and assembly accuracy of the stacked probes have been characterized, their recording performance is assessed during in vivo chronic experiments in awake rhesus macaques (Macaca mulatta) trained to execute reaching-grasping motor tasks. Main results. Using a single set of fabrication tools, we implemented three variants of the stacking component for electrode distances of 250, 300 and 350 µm in the stacking direction. We assembled neural probes with up to 96 channels and an electrode density of 98 electrodes mm-2. Furthermore, we demonstrate that the shank alignment is accurate to a few µm at an angular alignment better than 1°. Three 64-channel probes were chronically implanted in two monkeys providing single-unit activity on more than 60% of all channels and excellent recording stability. Histological tissue sections, obtained 52 d after implantation from one of the monkeys, showed minimal tissue damage, in accordance with the high quality and stability of the recorded neural activity. Significance. The versatility of our fabrication and assembly approach should significantly support the development of ideal interface geometries for a broad

  9. Advances in Thin Tissue Golgi-Cox Impregnation: Fast, Reliable Methods for Multi-Assay Analyses in Rodent and Non-human Primate Brain

    PubMed Central

    Levine, Nathan D.; Rademacher, David J.; Collier, Timothy J.; O’Malley, Jennifer A.; Kells, Adrian P.; Sebastian, Waldy San; Bankiewicz, Krystof S.; Steece-Collier, Kathy

    2013-01-01

    In 1873 Camillo Golgi discovered a staining technique that allowed for the visualization of whole neurons within the brain, initially termed ‘the black reaction’ and is now known as Golgi impregnation. Despite the capricious nature of this method, Golgi impregnation remains a widely used method for whole neuron visualization and analysis of dendritic arborization and spine quantification. We describe a series of reliable, modified ‘Golgi-Cox’ impregnation methods that complement some existing methods and have several advantages over traditional whole brain ‘Golgi’ impregnation. First, these methods utilize 60–100μm thick brain sections, which allows for fast, reliable impregnation of neurons in rats (7–14 days) and non-human primates (NHP) (30 days) while avoiding the pitfalls of other ‘rapid Golgi’ techniques traditionally employed with thin sections. Second, these methods employ several common tissue fixatives, resulting in high quality neuron impregnation in brain sections from acrolein, glutaraldehyde, and paraformaldehyde perfused rats, and in glutaraldehyde perfused NHP brain tissue. Third, because thin sections are obtained on a vibratome prior to processing, alternate sections of brain tissue can be used for additional analyses such as immunohistochemistry or electron microscopy. This later advantage allows for comparison of, for example, dendrite morphology in sections adjacent to pertinent histochemical markers or ultrastructural components. Finally, we describe a method for simultaneous light microscopic visualization of both tyrosine hydroxylase immunohistochemistry and Golgi impregnation in the same tissue section. Thus, the methods described here allow for fast, high quality Golgi impregnation and conserve experimental subjects by allowing multiple analyses within an individual animal. PMID:23313849

  10. Motion compensation for brain PET imaging using wireless MR active markers in simultaneous PET-MR: phantom and non-human primate studies.

    PubMed

    Huang, Chuan; Ackerman, Jerome L; Petibon, Yoann; Normandin, Marc D; Brady, Thomas J; El Fakhri, Georges; Ouyang, Jinsong

    2014-05-01

    Brain PET scanning plays an important role in the diagnosis, prognostication and monitoring of many brain diseases. Motion artifacts from head motion are one of the major hurdles in brain PET. In this work, we propose to use wireless MR active markers to track head motion in real time during a simultaneous PET-MR brain scan and incorporate the motion measured by the markers in the listmode PET reconstruction. Several wireless MR active markers and a dedicated fast MR tracking pulse sequence module were built. Data were acquired on an ACR Flangeless PET phantom with multiple spheres and a non-human primate with and without motion. Motions of the phantom and monkey's head were measured with the wireless markers using a dedicated MR tracking sequence module. The motion PET data were reconstructed using list-mode reconstruction with and without motion correction. Static reference was used as gold standard for quantitative analysis. The motion artifacts, which were prominent on the images without motion correction, were eliminated by the wireless marker based motion correction in both the phantom and monkey experiments. Quantitative analysis was performed on the phantom motion data from 24 independent noise realizations. The reduction of bias of sphere-to-background PET contrast by active marker based motion correction ranges from 26% to 64% and 17% to 25% for hot (i.e., radioactive) and cold (i.e., non-radioactive) spheres, respectively. The motion correction improved the channelized Hotelling observer signal-to-noise ratio of the spheres by 1.2 to 6.9 depending on their locations and sizes. The proposed wireless MR active marker based motion correction technique removes the motion artifacts in the reconstructed PET images and yields accurate quantitative values. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Anti-nicotine vaccines: Comparison of adjuvanted CRM197 and Qb-VLP conjugate formulations for immunogenicity and function in non-human primates.

    PubMed

    McCluskie, Michael J; Thorn, Jennifer; Gervais, David P; Stead, David R; Zhang, Ningli; Benoit, Michelle; Cartier, Janna; Kim, In-Jeong; Bhattacharya, Keshab; Finneman, Jari I; Merson, James R; Davis, Heather L

    2015-12-01

    Anti-nicotine vaccines comprise nicotine-like haptens conjugated to a carrier protein plus adjuvant(s). Unfortunately, those tested clinically have failed to improve overall long term quit rates. We had shown in mice that carrier, hapten, linker, hapten load (number of haptens per carrier molecule), aggregation and adducts, as well as adjuvants influence the function of antibodies (Ab) induced. Herein, we tested an optimized antigen, NIC7-CRM, comprised of 5-aminoethoxy-nicotine (NIC7) conjugated to genetically detoxified diphtheria toxin (CRM197), with hapten load of ~16, no aggregation (~100% monomer) and minimal adducts. NIC7-CRM was tested in non-human primates (NHP) and compared to NIC-VLP, which has the same hapten and carrier as the clinical-stage CYT002-NicQb but a slightly different linker and lower hapten load. With alum as sole adjuvant, NIC7-CRM was superior to NIC-VLP for Ab titer, avidity and ex vivo function (83% and 27% nicotine binding at 40ng/mL respectively), but equivalent for in vivo function after intravenous [IV] nicotine challenge (brain levels reduced ~10%). CpG adjuvant added to NIC7-CRM/alum further enhanced the Ab responses and both ex vivo function (100% bound) and in vivo function (~80% reduction in brain). Thus, both optimal antigen design and CpG adjuvant were required to achieve a highly functional vaccine. The compelling NHP data with NIC7-CRM with alum/CpG supported human testing, currently underway. Copyright © 2015. Published by Elsevier B.V.

  12. Development of translational preclinical models in substance abuse: Effects of cocaine administration on cocaine choice in humans and non-human primates.

    PubMed

    Foltin, Richard W; Haney, Margaret; Rubin, Eric; Reed, Stephanie C; Vadhan, Nehal; Balter, Rebecca; Evans, Suzette M

    2015-07-01

    Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how 'free' doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose-response function for cocaine self-administration (10 choices of 0.0125-0.1mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large 'free' self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates. Copyright © 2015. Published by Elsevier Inc.

  13. Effects of dietary resveratrol on the sleep-wake cycle in the non-human primate gray mouse lemur (Microcebus murinus).

    PubMed

    Pifferi, F; Rahman, A; Languille, S; Auffret, A; Babiloni, C; Blin, O; Lamberty, Y; Richardson, J C; Aujard, F

    2012-04-01

    Converging evidence shows that the non-human primate gray mouse lemur (Microcebus murinus) is ideal for the study of the aging process and for testing the effects of new therapies and dietary interventions on age-associated pathologies. One such dietary supplement is resveratrol (RSV), a dietary polyphenolic compound with several positive effects on metabolic functions and longevity. However, little is known about the effect of RSV on the lemur sleep-wake cycle, which reflects mammalian brain function and health. In the present study, the authors investigated this effect by comparing sleep-wake cycles in adult lemurs based on electroencephalographic (EEG) rhythms. The effect of short-term RSV supplementation on the sleep-wake cycle of mouse lemurs was evaluated in entrained conditions (long-day photoperiods, light:dark 14:10). After 3 wks of RSV supplementation, the animals exhibited a significantly increased proportion of active-wake time, occurring mainly during the resting phase of the sleep-wake cycle (+163%). The increase in active-wake time with RSV supplementation was accompanied by a significant reduction of both paradoxical sleep (-95%) and slow-wave sleep (-38%). These changes mainly occurred during the resting phase of the sleep-wake cycle (RSV supplementation induced negligible changes in active-wake time during the active phase of the sleep-wake cycle). The present data suggest that RSV may be a potent regulator of sleep-wake rhythms and could be of major interest in the study of sleep perturbations associated with aging and neuropathology.

  14. Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe-affected non-human primates by intracerebral lentiviral gene therapy.

    PubMed

    Meneghini, Vasco; Lattanzi, Annalisa; Tiradani, Luigi; Bravo, Gabriele; Morena, Francesco; Sanvito, Francesca; Calabria, Andrea; Bringas, John; Fisher-Perkins, Jeanne M; Dufour, Jason P; Baker, Kate C; Doglioni, Claudio; Montini, Eugenio; Bunnell, Bruce A; Bankiewicz, Krystof; Martino, Sabata; Naldini, Luigi; Gritti, Angela

    2016-05-01

    Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD or Krabbe disease) are severe neurodegenerative lysosomal storage diseases (LSD) caused by arylsulfatase A (ARSA) and galactosylceramidase (GALC) deficiency, respectively. Our previous studies established lentiviral gene therapy (GT) as a rapid and effective intervention to provide pervasive supply of therapeutic lysosomal enzymes in CNS tissues of MLD and GLD mice. Here, we investigated whether this strategy is similarly effective in juvenile non-human primates (NHP). To provide proof of principle for tolerability and biological efficacy of the strategy, we established a comprehensive study in normal NHP delivering a clinically relevant lentiviral vector encoding for the human ARSA transgene. Then, we injected a lentiviral vector coding for the human GALC transgene in Krabbe-affected rhesus macaques, evaluating for the first time the therapeutic potential of lentiviral GT in this unique LSD model. We showed favorable safety profile and consistent pattern of LV transduction and enzyme biodistribution in the two models, supporting the robustness of the proposed GT platform. We documented moderate inflammation at the injection sites, mild immune response to vector particles in few treated animals, no indication of immune response against transgenic products, and no molecular evidence of insertional genotoxicity. Efficient gene transfer in neurons, astrocytes, and oligodendrocytes close to the injection sites resulted in robust production and extensive spreading of transgenic enzymes in the whole CNS and in CSF, leading to supraphysiological ARSA activity in normal NHP and close to physiological GALC activity in the Krabbe NHP, in which biological efficacy was associated with preliminary indication of therapeutic benefit. These results support the rationale for the clinical translation of intracerebral lentiviral GT to address CNS pathology in MLD, GLD, and other neurodegenerative LSD. © 2016

  15. Poxvirus antigen staining of immune cells as a biomarker to predict disease outcome in monkeypox and cowpox virus infection in non-human primates.

    PubMed

    Song, Haifeng; Janosko, Krisztina; Johnson, Reed F; Qin, Jing; Josleyn, Nicole; Jett, Catherine; Byrum, Russell; St Claire, Marisa; Dyall, Julie; Blaney, Joseph E; Jennings, Gerald; Jahrling, Peter B

    2013-01-01

    Infection of non-human primates (NHPs) such as rhesus and cynomolgus macaques with monkeypox virus (MPXV) or cowpox virus (CPXV) serve as models to study poxvirus pathogenesis and to evaluate vaccines and anti-orthopox therapeutics. Intravenous inoculation of macaques with high dose of MPXV (>1-2×10(7) PFU) or CPXV (>10(2) PFU) results in 80% to 100% mortality and 66 to 100% mortality respectively. Here we report that NHPs with positive detection of poxvirus antigens in immune cells by flow cytometric staining, especially in monocytes and granulocytes succumbed to virus infection and that early positive pox staining is a strong predictor for lethality. Samples from four independent studies were analyzed. Eighteen NHPs from three different experiments were inoculated with two different MPXV strains at lethal doses. Ten NHPs displayed positive pox-staining and all 10 NHPs reached moribund endpoint. In contrast, none of the three NHPs that survived anticipated lethal virus dose showed apparent virus staining in the monocytes and granulocytes. In addition, three NHPs that were challenged with a lethal dose of MPXV and received cidofovir treatment were pox-antigen negative and all three NHPs survived. Furthermore, data from a CPXV study also demonstrated that 6/9 NHPs were pox-antigen staining positive and all 6 NHPs reached euthanasia endpoint, while the three survivors were pox-antigen staining negative. Thus, we conclude that monitoring pox-antigen staining in immune cells can be used as a biomarker to predict the prognosis of virus infection. Future studies should focus on the mechanisms and implications of the pox-infection of immune cells and the correlation between pox-antigen detection in immune cells and disease progression in human poxviral infection.

  16. A non-glycosylated, plant-produced human monoclonal antibody against anthrax protective antigen protects mice and non-human primates from B. anthracis spore challenge.

    PubMed

    Mett, Vadim; Chichester, Jessica A; Stewart, Michelle L; Musiychuk, Konstantin; Bi, Hong; Reifsnyder, Carolyn J; Hull, Anna K; Albrecht, Mark T; Goldman, Stanley; Baillie, Les W J; Yusibov, Vidadi

    2011-01-01

    The health and economic burden of infectious diseases in general and bioterrorism in particular necessitate the development of medical countermeasures. One proven approach to reduce the disease burden and spread of pathogen is treatment with monoclonal antibodies (mAb). mAbs can prevent or reduce severity of the disease by variety of mechanisms, including neutralizing pathogen growth, limiting its spread from infected to adjacent cells, or by inhibiting biological activity of toxins, such as anthrax lethal toxin. Here, we report the production of glycosylated (pp-mAb (PA) ) and non-glycosylated (pp-mAb (PANG) ) versions of a plant-derived mAb directed against protective antigen (PA) of Bacillus anthracis in Nicotiana benthamiana plants using agroinfiltration. Both forms of the antibody were able to neutralize anthrax lethal toxin activity in vitro and protect mice against an intraperitoneal challenge with spores of B. anthracis Sterne strain. A single 180 µg intraperitoneal dose of pp-mAb (PA) or pp-mAb (PANG) provided 90% and 100% survival, respectively. When tested in non-human primates, pp-mAb (PANG) was demonstrated to be superior to pp-mAb (PA) in that it had a significantly longer terminal half-life and conferred 100% protection against a lethal dose of aerosolized anthrax spore challenge after a single 5 mg/kg intravenous dose compared to a 40% survival rate conferred by pp-mAb (PA) . This study demonstrates the potential of a plant-produced non-glycosylated antibody as a useful tool for the treatment of inhalation anthrax.

  17. Effects of the cannabinoid antagonist SR141716 (rimonabant) and d-amphetamine on palatable food and food pellet intake in non-human primates

    PubMed Central

    Foltin, Richard W.; Haney, Margaret

    2007-01-01

    The purpose of this study was to determine if a cannabinoid CB1 receptor antagonist would selectively decrease consumption of highly palatable food in non-human primates. The CB1 receptor antagonist SR141716 (rimonabant; 0.12 - 1.0 mg/kg, i.m.) and the stimulant anorectic drug d-amphetamine (0.12 - 1.0 mg/kg, i.m.) were administered to non-food deprived baboons for the purpose of measuring the effect of each drug on consumption of the normal diet, and a large single meal of a high-carbohydrate candy. Four male and four female baboons had access to food 24 hr each day, but they had to complete a two phase operant procedure in order to eat. Responding on one lever during a 30-min appetitive phase was required before animals could start a consumption phase, where responding on another lever led to food delivery, i.e., a meal. Three days a week baboons received a jelly sugar-coated candy (Skittles®) during the first meal and then pellets were available in subsequent meals. All baboons ate as many individual candies in one meal as they did pellets throughout the entire day. Acute d-amphetamine and, to a lesser extent, SR141716 decreased both candy intake in a single meal and pellet intake in a single meal and over 24 hr. d-Amphetamine, but not SR141716 increased latency to the candy meal and the first pellet meal indicating that the two drugs differentially altered feeding topography. Although males ate more food pellets than females, few other sex differences were observed. Thus, although effective in decreasing food intake, there was no evidence of a specific effect of CB1 receptor antagonism on consumption of a large meal or a palatable food. PMID:17445873

  18. Effects of the cannabinoid antagonist SR141716 (rimonabant) and d-amphetamine on palatable food and food pellet intake in non-human primates.

    PubMed

    Foltin, Richard W; Haney, Margaret

    2007-04-01

    The purpose of this study was to determine if a cannabinoid CB(1) receptor antagonist would selectively decrease consumption of highly palatable food in non-human primates. The CB(1) receptor antagonist SR141716 (rimonabant; 0.12-1.0 mg/kg, i.m.) and the stimulant anorectic drug d-amphetamine (0.12-1.0 mg/kg, i.m.) were administered to non-food deprived baboons for the purpose of measuring the effect of each drug on consumption of the normal diet, and a large single meal of a high-carbohydrate candy. Four male and four female baboons had access to food 24 h each day, but they had to complete a two phase operant procedure in order to eat. Responding on one lever during a 30-min appetitive phase was required before animals could start a consumption phase, where responding on another lever led to food delivery, i.e., a meal. Three days a week baboons received a jelly sugar-coated candy (Skittles) during the first meal and then pellets were available in subsequent meals. All baboons ate as many individual candies in one meal as they did pellets throughout the entire day. Acute d-amphetamine and, to a lesser extent, SR141716 decreased both candy intake in a single meal and pellet intake in a single meal and over 24 h. d-Amphetamine, but not SR141716, increased latency to the candy meal and the first pellet meal indicating that the two drugs differentially altered feeding topography. Although males ate more food pellets than females, few other sex differences were observed. Thus, although effective in decreasing food intake, there was no evidence of a specific effect of CB(1) receptor antagonism on consumption of a large meal or a palatable food.

  19. Alzheimer’s Disease Aβ Vaccine Reduces Central Nervous System Aβ Levels in a Non-Human Primate, the Caribbean Vervet

    PubMed Central

    Lemere, Cynthia A.; Beierschmitt, Amy; Iglesias, Melitza; Spooner, Edward T.; Bloom, Jeanne K.; Leverone, Jodi F.; Zheng, Jessica B.; Seabrook, Timothy J.; Louard, Dora; Li, Diana; Selkoe, Dennis J.; Palmour, Roberta M.; Ervin, Frank R.

    2004-01-01

    Amyloid β (Aβ) protein immunotherapy lowers cerebral Aβ and improves cognition in mouse models of Alzheimer’s disease (AD). Here we show that Caribbean vervet monkeys (Chlorocebus aethiops, SK) develop cerebral Aβ plaques with aging and that these deposits are associated with gliosis and neuritic dystrophy. Five aged vervets were immunized with Aβ peptide over 10 months. Plasma and cerebral spinal fluid (CSF) samples were collected periodically from the immunized vervets and five aged controls; one monkey per group expired during the study. By Day 42, immunized animals generated plasma Aβ antibodies that labeled Aβ plaques in human, AD transgenic mouse and vervet brains; bound Aβ1–7; and recognized monomeric and oligomeric Aβ but not full-length amyloid precursor protein nor its C-terminal fragments. Low anti-Aβ titers were detected in CSF. Aβx-40 levels were elevated ∼2- to 5-fold in plasma and decreased up to 64% in CSF in immunized vervets. Insoluble Aβx-42 was decreased by 66% in brain homogenates of the four immunized animals compared to archival tissues from 13 age-matched control vervets. Aβ42-immunoreactive plaques were detected in frontal cortex in 11 of the 13 control animals, but not in six brain regions examined in each of the four immunized vervets. No T cell response or inflammation was observed. Our study is the first to demonstrate age-related Aβ deposition in the vervet monkey as well as the lowering of cerebral Aβ by Aβ vaccination in a non-human primate. The findings further support Aβ immunotherapy as a potential prevention and treatment of AD. PMID:15215183

  20. Impaired control of body cooling during heterothermia represents the major energetic constraint in an aging non-human primate exposed to cold.

    PubMed

    Terrien, Jeremy; Zahariev, Alexandre; Blanc, Stephane; Aujard, Fabienne

    2009-10-23

    Daily heterothermia is used by small mammals for energy and water savings, and seems to be preferentially exhibited during winter rather than during summer. This feature induces a trade-off between the energy saved during daily heterothermia and the energy cost of arousal, which can impact energy balance and survival under harsh environmental conditions. Especially, aging may significantly affect such trade off during cold-induced energy stress, but direct evidences are still lacking. We hypothesized that aging could alter the energetics of daily heterothermia, and that the effects could differ according to season. In the gray mouse lemur (Microcebus murinus), a non-human primate species which exhibits daily heterothermia, we investigated the effects of exposures to 25 and 12 degrees C on body composition, energy balance, patterns of heterothermia and water turnover in adult (N = 8) and aged animals (N = 7) acclimated to winter-like or summer-like photoperiods. Acclimation to summer prevented animals from deep heterothermia, even during aging. During winter, adult animals at 12 degrees C and aged animals at 25 degrees C exhibited low levels of energy expenditure with minor modulations of heterothermia. The major effects of cold were observed during winter, and were particularly pronounced in aged mouse lemurs which exhibited deep heterothermia phases. Body composition was not significantly affected by age and could not explain the age-related differences in heterothermia patterns. However, aging was associated with increased levels of energy expenditure during cold exposure, in concomitance with impaired energy balance. Interestingly, increased energy expenditure and depth of heterothermia phases were strongly correlated. In conclusion, it appeared that the exhibition of shallow heterothermia allowed energy savings during winter in adult animals only. Aged animals exhibited deep heterothermia and increased levels of energy expenditure, impairing energy balance

  1. Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task

    PubMed Central

    Downs, Matthew E.; Buch, Amanda; Sierra, Carlos; Karakatsani, Maria Eleni; Chen, Shangshang; Konofagou, Elisa E.; Ferrera, Vincent P.

    2015-01-01

    Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200–400 kPa, 4–5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4–20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of’ visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4–5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used. PMID:25945493

  2. Characterization of Enteroviruses from Non-Human Primates in Cameroon Revealed Virus Types Widespread in Humans along with Candidate New Types and Species

    PubMed Central

    Sadeuh-Mba, Serge Alain; Bessaud, Maël; Joffret, Marie-Line; Endegue Zanga, Marie-Claire; Balanant, Jean; Mpoudi Ngole, Eitel; Njouom, Richard; Reynes, Jean-Marc; Delpeyroux, Francis; Rousset, Dominique

    2014-01-01

    Enteroviruses (EVs) infecting African Non-Human Primates (NHP) are still poorly documented. This study was designed to characterize the genetic diversity of EVs among captive and wild NHP in Cameroon and to compare this diversity with that found in humans. Stool specimens were collected in April 2008 in NHP housed in sanctuaries in Yaounde and neighborhoods. Moreover, stool specimens collected from wild NHP from June 2006 to October 2008 in the southern rain forest of Cameroon were considered. RNAs purified directly from stool samples were screened for EVs using a sensitive RT-nested PCR targeting the VP1 capsid coding gene whose nucleotide sequence was used for molecular typing. Captive chimpanzees (Pan troglodytes) and gorillas (Gorilla gorilla) were primarily infected by EV types already reported in humans in Cameroon and elsewhere: Coxsackievirus A13 and A24, Echovirus 15 and 29, and EV-B82. Moreover EV-A119, a novel virus type recently described in humans in central and west Africa, was also found in a captive Chimpanzee. EV-A76, which is a widespread virus in humans, was identified in wild chimpanzees, thus suggesting its adaptation and parallel circulation in human and NHP populations in Cameroon. Interestingly, some EVs harbored by wild NHP were genetically distinct from all existing types and were thus assigned as new types. One chimpanzee-derived virus was tentatively assigned as EV-J121 in the EV-J species. In addition, two EVs from wild monkeys provisionally registered as EV-122 and EV-123 were found to belong to a candidate new species. Overall, this study indicates that the genetic diversity of EVs among NHP is more important than previously known and could be the source of future new emerging human viral diseases. PMID:25079078

  3. Characterization of Enteroviruses from non-human primates in cameroon revealed virus types widespread in humans along with candidate new types and species.

    PubMed

    Sadeuh-Mba, Serge Alain; Bessaud, Maël; Joffret, Marie-Line; Endegue Zanga, Marie-Claire; Balanant, Jean; Mpoudi Ngole, Eitel; Njouom, Richard; Reynes, Jean-Marc; Delpeyroux, Francis; Rousset, Dominique

    2014-01-01

    Enteroviruses (EVs) infecting African Non-Human Primates (NHP) are still poorly documented. This study was designed to characterize the genetic diversity of EVs among captive and wild NHP in Cameroon and to compare this diversity with that found in humans. Stool specimens were collected in April 2008 in NHP housed in sanctuaries in Yaounde and neighborhoods. Moreover, stool specimens collected from wild NHP from June 2006 to October 2008 in the southern rain forest of Cameroon were considered. RNAs purified directly from stool samples were screened for EVs using a sensitive RT-nested PCR targeting the VP1 capsid coding gene whose nucleotide sequence was used for molecular typing. Captive chimpanzees (Pan troglodytes) and gorillas (Gorilla gorilla) were primarily infected by EV types already reported in humans in Cameroon and elsewhere: Coxsackievirus A13 and A24, Echovirus 15 and 29, and EV-B82. Moreover EV-A119, a novel virus type recently described in humans in central and west Africa, was also found in a captive Chimpanzee. EV-A76, which is a widespread virus in humans, was identified in wild chimpanzees, thus suggesting its adaptation and parallel circulation in human and NHP populations in Cameroon. Interestingly, some EVs harbored by wild NHP were genetically distinct from all existing types and were thus assigned as new types. One chimpanzee-derived virus was tentatively assigned as EV-J121 in the EV-J species. In addition, two EVs from wild monkeys provisionally registered as EV-122 and EV-123 were found to belong to a candidate new species. Overall, this study indicates that the genetic diversity of EVs among NHP is more important than previously known and could be the source of future new emerging human viral diseases.

  4. Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine.

    PubMed

    Gupta, Gaurav; Giannino, Viviana; Rishi, Narayan; Glueck, Reinhard

    2016-09-07

    Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. HPVs are oncogenic small double-stranded DNA viruses that are the primary causal agent of cervical cancer and other types of cancers, including in the anus, oropharynx, vagina, vulva, and penis. Prophylactic vaccination against HPV is an attractive strategy for preventing cervical cancer and some other types of cancers. However, there are few safe and effective vaccines against HPV infections. Current first-generation commercial HPV vaccines are expensive to produce and deliver. The goal of this study was to develop an alternate potent HPV recombinant L1-based vaccines by producing HPV virus-like particles into a vaccine that is currently used worldwide. Live attenuated measles virus (MV) vaccines have a well-established safety and efficacy record, and recombinant MV (rMV) produced by reverse genetics may be useful for generating candidate HPV vaccines to meet the needs of the developing world. We studied in non-human primate rMV-vectored HPV vaccine in parallel with a classical alum adjuvant recombinant HPV16L1 and 18L1 protein vaccine produced in Pichia pastoris. A combined prime-boost approach using both vaccines was evaluated, as well as immune interference due to pre-existing immunity against the MV. The humoral immune response induced by the MV, Pichia-expressed vaccine, and their combination as priming and boosting approaches was found to elicit HPV16L1 and 18L1 specific total IgG and neutralizing antibody titres. Pre-existing antibodies against measles did not prevent the immune response against HPV16L1 and 18L1. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Sequential monitoring and stability of ex vivo-expanded autologous and non-autologous regulatory T cells following infusion in non-human primates

    PubMed Central

    Zhang, H.; Guo, H.; Lu, L.; Zahorchak, A. F.; Wiseman, R. W.; Raimondi, G.; Cooper, D. K. C.; Ezzelarab, M. B.; Thomson, A. W.

    2016-01-01

    Ex vivo-expanded cynomolgus monkey CD4+CD25+CD127− regulatory T cells (Treg) maintained Foxp3 demethylation status at the Treg-Specific Demethylation Region (TSDR), and potently suppressed T cell proliferation through 3 rounds of expansion. When CFSE- or VPD450-labeled autologous (auto) and non-autologous (non-auto) expanded Treg were infused into monkeys, the number of labeled auto-Treg in peripheral blood declined rapidly during the first week, but persisted at low levels in both normal and anti-thymocyte globulin plus rapamycin-treated (immunosuppressed; IS) animals for at least 3 weeks. By contrast, MHC-mismatched non-auto-Treg could not be detected in normal monkey blood or in blood of two out of the three IS monkeys by day 6 post-infusion. They were also more difficult to detect than auto-Treg in peripheral lymphoid tissue. Both auto- and non-auto-Treg maintained Ki67 expression early after infusion. Sequential monitoring revealed that adoptively-transferred auto-Treg maintained similarly high levels of Foxp3 and CD25 and low CD127 compared with endogenous Treg, although Foxp3 staining diminished over time in these non-transplanted recipients. Thus, infused ex vivo-expanded auto-Treg persist longer than MHC-mismatched non-auto-Treg in blood of non-human primates and can be detected in secondary lymphoid tissue. Host lymphodepletion and rapamycin administration did not consistently prolong the persistence of non-auto-Treg in these sites. PMID:25783759

  6. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation.

    PubMed

    Zhang, Pei; Cui, Wanchang; Hankey, Kim G; Gibbs, Allison M; Smith, Cassandra P; Taylor-Howell, Cheryl; Kearney, Sean R; MacVittie, Thomas J

    2015-11-01

    Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs.

  7. AdHu5Ag85A Respiratory Mucosal Boost Immunization Enhances Protection against Pulmonary Tuberculosis in BCG-Primed Non-Human Primates

    PubMed Central

    Yu, Xuefeng; Harkness, Robin; Jiang, Rong; Li, Junqiang; Xing, Zhou; Zhu, Tao

    2015-01-01

    Persisting high global tuberculosis (TB) morbidity and mortality and poor efficacy of BCG vaccine emphasizes an urgent need for developing effective novel boost vaccination strategies following parenteral BCG priming in humans. Most of the current lead TB vaccine candidates in the global pipeline were developed for parenteral route of immunization. Compelling evidence indicates respiratory mucosal delivery of vaccine to be the most effective way to induce robust local mucosal protective immunity against pulmonary TB. However, despite ample supporting evidence from various animal models, there has been a lack of evidence supporting the safety and protective efficacy of respiratory mucosal TB vaccination in non-human primates (NHP) and humans. By using a rhesus macaque TB model we have evaluated the safety and protective efficacy of a recombinant human serotype 5 adenovirus-based TB vaccine (AdHu5Ag85A) delivered via the respiratory mucosal route. We show that mucosal AdHu5Ag85A boost immunization was safe and well tolerated in parenteral BCG-primed rhesus macaques. A single AdHu5Ag85A mucosal boost immunization in BCG-primed rhesus macaques enhanced the antigen–specific T cell responses. Boost immunization significantly improved the survival and bacterial control following M.tb challenge. Furthermore, TB-related lung pathology and clinical outcomes were lessened in BCG-primed, mucosally boosted animals compared to control animals. Thus, for the first time we show that a single respiratory mucosal boost immunization with a novel TB vaccine enhances protection against pulmonary TB in parenteral BCG-primed NHP. Our study provides the evidence for the protective potential of AdHu5Ag85A as a respiratory mucosal boost TB vaccine for human application. PMID:26252520

  8. Systematic evaluation of monoclonal antibodies and immunoassays for the detection of Interferon-γ and Interleukin-2 in old and new world non-human primates.

    PubMed

    Höglind, Ankie; Areström, Irene; Ehrnfelt, Cecilia; Masjedi, Khosro; Zuber, Bartek; Giavedoni, Luis; Ahlborg, Niklas

    2017-02-01

    Non-human primates (NHP) provide important animal models for studies on immune responses to infections and vaccines. When assessing cellular immunity in NHP, cytokines are almost exclusively analyzed utilizing cross-reactive anti-human antibodies. The functionality of antibodies has to be empirically established for each assay/application as well as NHP species. A rational approach was employed to identify monoclonal antibodies (mAb) cross-reactive with many NHP species. Panels of new and established mAbs against human Interferon (IFN)-γ and Interleukin (IL)-2 were assessed for reactivity with eukaryotically expressed recombinant IFN-γ and IL-2, respectively, from Old (rhesus, cynomolgus and pigtail macaques, African green monkey, sooty mangabey and baboon) and New World NHP (Ma's night monkey, squirrel monkey and common marmoset). Pan-reactive mAbs, recognizing cytokines from all NHP species, were further analyzed in capture assays and flow cytometry with NHP peripheral blood mononuclear cells (PBMC). Pan-reactive mAb pairs for IFN-γ well as IL-2 were identified and used in ELISA to measure IFN-γ and IL-2, respectively, in Old and New World NHP PBMC supernatants. The same mAb pairs displayed high functionality in ELISpot and FluoroSpot for the measurement of antigen-specific IFN-γ and IL-2 responses using cynomolgus PBMC. Functionality of pan-reactive mAbs in flow cytometry was also verified with cynomolgus PBMC. The development of well-defined immunoassays functional with a panel of NHP species facilitates improved analyses of cellular immunity and enables inclusion in multiplex cytokine assays intended for a variety of NHP.

  9. Poxvirus Antigen Staining of Immune Cells as a Biomarker to Predict Disease Outcome in Monkeypox and Cowpox Virus Infection in Non-Human Primates

    PubMed Central

    Song, Haifeng; Janosko, Krisztina; Johnson, Reed F.; Qin, Jing; Josleyn, Nicole; Jett, Catherine; Byrum, Russell; Claire, Marisa St.; Dyall, Julie; Blaney, Joseph E.; Jennings, Gerald; Jahrling, Peter B.

    2013-01-01

    Infection of non-human primates (NHPs) such as rhesus and cynomolgus macaques with monkeypox virus (MPXV) or cowpox virus (CPXV) serve as models to study poxvirus pathogenesis and to evaluate vaccines and anti-orthopox therapeutics. Intravenous inoculation of macaques with high dose of MPXV (>1–2×107 PFU) or CPXV (>102 PFU) results in 80% to 100% mortality and 66 to 100% mortality respectively. Here we report that NHPs with positive detection of poxvirus antigens in immune cells by flow cytometric staining, especially in monocytes and granulocytes succumbed to virus infection and that early positive pox staining is a strong predictor for lethality. Samples from four independent studies were analyzed. Eighteen NHPs from three different experiments were inoculated with two different MPXV strains at lethal doses. Ten NHPs displayed positive pox-staining and all 10 NHPs reached moribund endpoint. In contrast, none of the three NHPs that survived anticipated lethal virus dose showed apparent virus staining in the monocytes and granulocytes. In addition, three NHPs that were challenged with a lethal dose of MPXV and received cidofovir treatment were pox-antigen negative and all three NHPs survived. Furthermore, data from a CPXV study also demonstrated that 6/9 NHPs were pox-antigen staining positive and all 6 NHPs reached euthanasia endpoint, while the three survivors were pox-antigen staining negative. Thus, we conclude that monitoring pox-antigen staining in immune cells can be used as a biomarker to predict the prognosis of virus infection. Future studies should focus on the mechanisms and implications of the pox-infection of immune cells and the correlation between pox-antigen detection in immune cells and disease progression in human poxviral infection. PMID:23577120

  10. Lower dose of rhBMP-2 achieves spine fusion when combined with an osteoconductive bulking agent in non-human primates.

    PubMed

    Barnes, Bryan; Boden, Scott D; Louis-Ugbo, John; Tomak, Patrick R; Park, Jin-Soo; Park, Moon-Soo; Minamide, Akihito

    2005-05-15

    A non-human primate lumbar intertransverse process arthrodesis model was used to evaluate the effectiveness of different formulations of recombinant human bone morphogenetic protein-2 (rhBMP-2) to induce consistent bone formation. To determine if the combination of rhBMP-2/absorbable collagen sponge (ACS) wrapped around a bulking agent, consisting of a biphasic calcium phosphate/collagen composite, could achieve posterolateral spine fusion with a dose of rhBMP-2 (3.0 mg/side) that previously failed to induce posterolateral fusion in rhesus monkeys with other carriers. Successful bone induction in both human and non-human primates has required higher concentrations of BMP than were required in lower order models. The Food and Drug Administration approved concentration of rhBMP-2 for interbody fusion (1.5 mg/mL) when delivered on the ACS alone without a bulking agent (doses 3-9 mg/side) has failed to induce clinically relevant amounts of bone formation in a posterolateral spine fusion model in rhesus monkeys. Previously, a higher concentration of 2.0 mg/mL of rhBMP-2 delivered on stacked sheets of a biphasic calcium phosphate ceramic/collagen compression resistant matrix (CRM) was required to achieve fusion in the rhesus monkey and was the basis for this study (doses of 6-12 mg/side). Nine skeletally mature, rhesus macaque monkeys underwent single level posterolateral arthrodesis at L4-L5. Two different rhBMP-2 doses were evaluated in 3 delivery configurations. The first 3 monkeys received 10 mg/side (2.5 mL at 4.0 mg/mL) of rhBMP-2 loadeddirectly onto a CRM carrier (15% hydroxyapatite/85%beta-tricalcium phosphate ceramic/collagen matrix), resulting in a final concentration of 2.0 mg/mL. The second 3 monkeys received 3 mg/side (2.0 mL at 1.5 mg/mL) of rhBMP-2 loaded directly on the CRM carrier, resulting in a 0.6 mg/mL final concentration. Three additional monkeys also received the 3 mg/side (2.0 mL at 1.5 mg/mL) of rhBMP-2 delivered on an ACS, which was then wrapped

  11. Molecular and cellular characteristics of human and non-human primate multipotent stromal cells from the amnion and bone marrow during long term culture.

    PubMed

    Pogozhykh, Olena; Pogozhykh, Denys; Neehus, Anna-Lena; Hoffmann, Andrea; Blasczyk, Rainer; Müller, Thomas

    2015-08-22

    Multipotent stromal cells (MSCs) are among the key candidates in regenerative medicine. However variety of MSC sources and general heterogeneity lead to controversial data in functional characterization. Furthermore, despite intensive usage as preclinical animal model, little is known about MSCs of the common marmoset monkey. MSCs derived from placental amnion and bone marrow samples from human and common marmoset were characterized in parallel over 12 passages to monitor similarities and significant differences (p ≤ 0.05, Student's t-test) in MSC markers and major histocompatibility complex (MHC) class I expression by immunohistochemistry, flow cytometry, real-time PCR, metabolic activity test, with special focus on pluripotency associated genes. Human and non-human primate MSCs were characterized for expression of MSC markers and capability of differentiation into mesenchymal lineages. MSCs could be cultured more than 100 days (26 passages), but metabolic activity was significantly enhanced in amnion vs. bone marrow MSCs. Interestingly, MHC class I expression is significantly reduced in amnion MSCs until passage 6 in human and marmoset, but not in bone marrow cells. For MSC markers, CD73 and CD105 levels remain unchanged in amnion MSCs and slightly decline in bone marrow at late passages; CD166 is significantly higher expressed in human MSCs, CD106 significantly lower vs. marmoset. All cultured MSCs showed pluripotency marker expression like Oct-4A at passage 3 significantly decreasing over time (passages 6-12) while Nanog expression was highest in human bone marrow MSCs. Furthermore, human MSCs demonstrated the highest Sox2 levels vs. marmoset, whereas the marmoset exhibited significantly higher Lin28A values. Bisulfite sequencing of the Oct-4 promoter region displayed fewer methylations of CpG islands in the marmoset vs. human. Little is known about MSC characteristics from the preclinical animal model common marmoset vs. human during long term culture

  12. Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events

    PubMed Central

    Menon, Naresh; Rogers, Claude J.; Lukaszewicz, Agnes I.; Axtelle, James; Yadav, Marshleen; Song, Feifei; Chakravarti, Arnab; Jacob, Naduparambil K.

    2016-01-01

    Development of biomarkers capable of estimating absorbed dose is critical for effective triage of affected individuals after radiological events. Levels of cell-free circulating miRNAs in plasma were compared for dose-response analysis in non-human primates (NHP) exposed to lethal (6.5 Gy) and sub-lethal (1 and 3 Gy) doses over a 7 day period. The doses and test time points were selected to mimic triage needs in the event of a mass casualty radiological event. Changes in miRNA abundance in irradiated animals were compared to a non-irradiated cohort and a cohort experiencing acute inflammation response from exposure to lipopolysaccharide (LPS). An amplification-free, hybridization-based direct digital counting method was used for evaluation of changes in microRNAs in plasma from all animals. Consistent with previous murine studies, circulating levels of miR-150-5p exhibited a dose- and time-dependent decrease in plasma. Furthermore, plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics. Additionally, plasma levels of several other evolutionarily and functionally conserved miRNAs were found altered as a function of dose and time. Interestingly, miR-574-5p exhibited a distinct, dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure before returning to the baseline level by day 3. This particular miRNA response was not detected in previous murine studies but was observed in animals exposed to LPS, indicating distinct molecular and inflammatory responses. Furthermore, an increase in low-abundant miR-126, miR-144, and miR-21 as well as high-abundant miR-1-3p and miR-206 was observed in irradiated animals on day 3 and/or day 7. The data from this study could be used to develop a multi-marker panel with known tissue-specific origin that could be used for developing rapid assays for dose assessment and evaluation of radiation injury on multiple organs. Furthermore this approach may be

  13. HemaMax™, a Recombinant Human Interleukin-12, Is a Potent Mitigator of Acute Radiation Injury in Mice and Non-Human Primates

    PubMed Central

    Basile, Lena A.; Ellefson, Dolph; Gluzman-Poltorak, Zoya; Junes-Gill, Katiana; Mar, Vernon; Mendonca, Sarita; Miller, Joseph D.; Tom, Jamie; Trinh, Alice; Gallaher, Timothy K.

    2012-01-01

    HemaMax, a recombinant human interleukin-12 (IL-12), is under development to address an unmet medical need for effective treatments against acute radiation syndrome due to radiological terrorism or accident when administered at least 24 hours after radiation exposure. This study investigated pharmacokinetics, pharmacodynamics, and efficacy of m-HemaMax (recombinant murine IL-12), and HemaMax to increase survival after total body irradiation (TBI) in mice and rhesus monkeys, respectively, with no supportive care. In mice, m-HemaMax at an optimal 20 ng/mouse dose significantly increased percent survival and survival time when administered 24 hours after TBI between 8–9 Gy (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by increases in plasma interferon-γ (IFN-γ) and erythropoietin levels, recovery of femoral bone hematopoiesis characterized with the presence of IL-12 receptor β2 subunit–expressing myeloid progenitors, megakaryocytes, and osteoblasts. Mitigation of jejunal radiation damage was also examined. At allometrically equivalent doses, HemaMax showed similar pharmacokinetics in rhesus monkeys compared to m-HemaMax in mice, but more robustly increased plasma IFN-γ levels. HemaMax also increased plasma erythropoietin, IL-15, IL-18, and neopterin levels. At non-human primate doses pharmacologically equivalent to murine doses, HemaMax (100 ng/Kg and 250 ng/Kg) administered at 24 hours after TBI (6.7 Gy/LD50/30) significantly increased percent survival of HemaMax groups compared to vehicle (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by a significantly higher leukocyte (neutrophils and lymphocytes), thrombocyte, and reticulocyte counts during nadir (days 12–14) and significantly less weight loss at day 12 compared to vehicle. These findings indicate successful interspecies dose conversion and provide proof of concept that HemaMax increases survival in irradiated rhesus monkeys by promoting

  14. The adjuvanticity of an O. volvulus-derived rOv-ASP-1 protein in mice using sequential vaccinations and in non-human primates.

    PubMed

    Wang, Jing; Tricoche, Nancy; Du, Lanying; Hunter, Meredith; Zhan, Bin; Goud, Gaddam; Didier, Elizabeth S; Liu, Jing; Lu, Lu; Marx, Preston A; Jiang, Shibo; Lustigman, Sara

    2012-01-01

    Adjuvants potentiate antigen-specific protective immune responses and can be key elements promoting vaccine effectiveness. We previously reported that the Onchocerca volvulus recombinant protein rOv-ASP-1 can induce activation and maturation of naïve human DCs and therefore could be used as an innate adjuvant to promote balanced Th1 and Th2 responses to bystander vaccine antigens in mice. With a few vaccine antigens, it also promoted a Th1-biased response based on pronounced induction of Th1-associated IgG2a and IgG2b antibody responses and the upregulated production of Th1 cytokines, including IL-2, IFN-γ, TNF-α and IL-6. However, because it is a protein, the rOv-ASP-1 adjuvant may also induce anti-self-antibodies. Therefore, it was important to verify that the host responses to self will not affect the adjuvanticity of rOv-ASP-1 when it is used in subsequent vaccinations with the same or different vaccine antigens. In this study, we have established rOv-ASP-1's adjuvanticity in mice during the course of two sequential vaccinations using two vaccine model systems: the receptor-binding domain (RBD) of SARS-CoV spike protein and a commercial influenza virus hemagglutinin (HA) vaccine comprised of three virus strains. Moreover, the adjuvanticity of rOv-ASP-1 was retained with an efficacy similar to that obtained when it was used for a first vaccination, even though a high level of anti-rOv-ASP-1 antibodies was present in the sera of mice before the administration of the second vaccine. To further demonstrate its utility as an adjuvant for human use, we also immunized non-human primates (NHPs) with RBD plus rOv-ASP-1 and showed that rOv-ASP-1 could induce high titres of functional and protective anti-RBD antibody responses in NHPs. Notably, the rOv-ASP-1 adjuvant did not induce high titer antibodies against self in NHPs. Thus, the present study provided a sound scientific foundation for future strategies in the development of this novel protein adjuvant.

  15. Inhibition of miR-33a/b in non-human primates raises plasma HDL and reduces VLDL triglycerides

    PubMed Central

    Rayner, Katey J.; Esau, Christine C.; Hussain, Farah N.; McDaniel, Allison L.; Marshall, Stephanie M.; van Gils, Janine M.; Ray, Tathagat D.; Sheedy, Frederick J.; Goedeke, Leigh; Liu, Xueqing; Khatsenko, Oleg G.; Kaimal, Vivek; Lees, Cynthia J.; Fernandez-Hernando, Carlos; Fisher, Edward A.; Temel, Ryan E.; Moore, Kathryn J.

    2011-01-01

    Cardiovascular disease (CVD) remains the leading cause of mortality in westernized countries, despite optimum medical therapy to lower LDL cholesterol. The pursuit of novel therapies to target this residual risk has focused on raising levels of HDL cholesterol in order to exploit its atheroprotective effects1. MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and are thus a new class of targets for therapeutic intervention2. MicroRNA-33a and b (miR-33a/b) are intronic microRNAs embedded in the sterol response element binding protein genes SREBF2 and SREBF13–5, respectively, that repress expression of the cholesterol transporter ABCA1, a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL3–5 and protecting from atherosclerosis6, however extrapolation of these findings to humans is complicated by the fact that mice lack miR-33b which is present only in the SREBF1 gene of higher mammals. Here we show in African green monkeys that systemic delivery of an anti-miR oligonucleotide that targets both miR-33a and miR-33b increases hepatic expression of ABCA1 and induces a sustained increase in plasma HDL over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in the oxidation of fatty acids (CROT, CPT1A, HADHB, PRKAA1) and reduced genes involved in fatty acid synthesis (SREBF1, FASN, ACLY, ACACA), resulting in a marked suppression of plasma VLDL triglyceride levels, a finding not previously observed in mice. These data establish, in a model highly relevant to humans, that pharmacological inhibition of miR-33a and b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglycerides for the treatment of dyslipidemias that increase cardiovascular disease risk. PMID:22012398

  16. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides.

    PubMed

    Rayner, Katey J; Esau, Christine C; Hussain, Farah N; McDaniel, Allison L; Marshall, Stephanie M; van Gils, Janine M; Ray, Tathagat D; Sheedy, Frederick J; Goedeke, Leigh; Liu, Xueqing; Khatsenko, Oleg G; Kaimal, Vivek; Lees, Cynthia J; Fernandez-Hernando, Carlos; Fisher, Edward A; Temel, Ryan E; Moore, Kathryn J

    2011-10-19

    Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition

  17. Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells.

    PubMed

    Cong, Yu; McArthur, Monica A; Cohen, Melanie; Jahrling, Peter B; Janosko, Krisztina B; Josleyn, Nicole; Kang, Kai; Zhang, Tengfei; Holbrook, Michael R

    2016-05-01

    Humans infected with yellow fever virus (YFV), a mosquito-borne flavivirus, can develop illness ranging from a mild febrile disease to hemorrhagic fever and death. The 17D vaccine strain of YFV was developed in the 1930s, has been used continuously since development and has proven very effective. Genetic differences between vaccine and wild-type viruses are few, yet viral or host mechanisms associated with protection or disease are not fully understood. Over the past 20 years, a number of cases of vaccine-associated disease have been identified following vaccination with 17D; these cases have been correlated with reduced immune status at the time of vaccination. Recently, several studies have evaluated T cell responses to vaccination in both humans and non-human primates, but none have evaluated the response to wild-type virus infection. In the studies described here, monocyte-derived macrophages (MDM) and dendritic cells (MoDC) from both humans and rhesus macaques were evaluated for their ability to support infection with either wild-type Asibi virus or the 17D vaccine strain and the host cytokine and chemokine response characterized. Human MoDC and MDM were also evaluated for their ability to stimulate CD4+ T cells. It was found that MoDC and MDM supported viral replication and that there were differential cytokine responses to infection with either wild-type or vaccine viruses. Additionally, MoDCs infected with live 17D virus were able to stimulate IFN-γ and IL-2 production in CD4+ T cells, while cells infected with Asibi virus were not. These data demonstrate that wild-type and vaccine YFV stimulate different responses in target antigen presenting cells and that wild-type YFV can inhibit MoDC activation of CD4+ T cells, a critical component in development of protective immunity. These data provide initial, but critical insight into regulatory capabilities of wild-type YFV in development of disease.

  18. Telemetry video-electroencephalography (EEG) in rats, dogs and non-human primates: methods in follow-up safety pharmacology seizure liability assessments.

    PubMed

    Bassett, Leanne; Troncy, Eric; Pouliot, Mylene; Paquette, Dominique; Ascah, Alexis; Authier, Simon

    2014-01-01

    required by regulators. Non-human primates represent an important model in seizure liability assessments given similarities to humans and a high translational potential. Copyright © 2014. Published by Elsevier Inc.

  19. Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells

    PubMed Central

    Cong, Yu; McArthur, Monica A.; Cohen, Melanie; Jahrling, Peter B.; Janosko, Krisztina B.; Josleyn, Nicole; Kang, Kai; Zhang, Tengfei; Holbrook, Michael R.

    2016-01-01

    Humans infected with yellow fever virus (YFV), a mosquito-borne flavivirus, can develop illness ranging from a mild febrile disease to hemorrhagic fever and death. The 17D vaccine strain of YFV was developed in the 1930s, has been used continuously since development and has proven very effective. Genetic differences between vaccine and wild-type viruses are few, yet viral or host mechanisms associated with protection or disease are not fully understood. Over the past 20 years, a number of cases of vaccine-associated disease have been identified following vaccination with 17D; these cases have been correlated with reduced immune status at the time of vaccination. Recently, several studies have evaluated T cell responses to vaccination in both humans and non-human primates, but none have evaluated the response to wild-type virus infection. In the studies described here, monocyte-derived macrophages (MDM) and dendritic cells (MoDC) from both humans and rhesus macaques were evaluated for their ability to support infection with either wild-type Asibi virus or the 17D vaccine strain and the host cytokine and chemokine response characterized. Human MoDC and MDM were also evaluated for their ability to stimulate CD4+ T cells. It was found that MoDC and MDM supported viral replication and that there were differential cytokine responses to infection with either wild-type or vaccine viruses. Additionally, MoDCs infected with live 17D virus were able to stimulate IFN-γ and IL-2 production in CD4+ T cells, while cells infected with Asibi virus were not. These data demonstrate that wild-type and vaccine YFV stimulate different responses in target antigen presenting cells and that wild-type YFV can inhibit MoDC activation of CD4+ T cells, a critical component in development of protective immunity. These data provide initial, but critical insight into regulatory capabilities of wild-type YFV in development of disease. PMID:27191161

  20. The Adjuvanticity of an O. volvulus-Derived rOv-ASP-1 Protein in Mice Using Sequential Vaccinations and in Non-Human Primates

    PubMed Central

    Wang, Jing; Tricoche, Nancy; Du, Lanying; Hunter, Meredith; Zhan, Bin; Goud, Gaddam; Didier, Elizabeth S.; Liu, Jing; Lu, Lu; Marx, Preston A.; Jiang, Shibo; Lustigman, Sara

    2012-01-01

    Adjuvants potentiate antigen-specific protective immune responses and can be key elements promoting vaccine effectiveness. We previously reported that the Onchocerca volvulus recombinant protein rOv-ASP-1 can induce activation and maturation of naïve human DCs and therefore could be used as an innate adjuvant to promote balanced Th1 and Th2 responses to bystander vaccine antigens in mice. With a few vaccine antigens, it also promoted a Th1-biased response based on pronounced induction of Th1-associated IgG2a and IgG2b antibody responses and the upregulated production of Th1 cytokines, including IL-2, IFN-γ, TNF-α and IL-6. However, because it is a protein, the rOv-ASP-1 adjuvant may also induce anti-self-antibodies. Therefore, it was important to verify that the host responses to self will not affect the adjuvanticity of rOv-ASP-1 when it is used in subsequent vaccinations with the same or different vaccine antigens. In this study, we have established rOv-ASP-1's adjuvanticity in mice during the course of two sequential vaccinations using two vaccine model systems: the receptor-binding domain (RBD) of SARS-CoV spike protein and a commercial influenza virus hemagglutinin (HA) vaccine comprised of three virus strains. Moreover, the adjuvanticity of rOv-ASP-1 was retained with an efficacy similar to that obtained when it was used for a first vaccination, even though a high level of anti-rOv-ASP-1 antibodies was present in the sera of mice before the administration of the second vaccine. To further demonstrate its utility as an adjuvant for human use, we also immunized non-human primates (NHPs) with RBD plus rOv-ASP-1 and showed that rOv-ASP-1 could induce high titres of functional and protective anti-RBD antibody responses in NHPs. Notably, the rOv-ASP-1 adjuvant did not induce high titer antibodies against self in NHPs. Thus, the present study provided a sound scientific foundation for future strategies in the development of this novel protein adjuvant. PMID

  1. A collection of non-human primate computed tomography scans housed in MorphoSource, a repository for 3D data

    PubMed Central

    Copes, Lynn E.; Lucas, Lynn M.; Thostenson, James O.; Hoekstra, Hopi E.; Boyer, Doug M.

    2016-01-01

    A dataset of high-resolution microCT scans of primate skulls (crania and mandibles) and certain postcranial elements was collected to address questions about primate skull morphology. The sample consists of 489 scans taken from 431 specimens, representing 59 species of most Primate families. These data have transformative reuse potential as such datasets are necessary for conducting high power research into primate evolution, but require significant time and funding to collect. Similar datasets were previously only available to select research groups across the world. The physical specimens are vouchered at Harvard’s Museum of Comparative Zoology. The data collection took place at the Center for Nanoscale Systems at Harvard. The dataset is archived on MorphoSource.org. Though this is the largest high fidelity comparative dataset yet available, its provisioning on a web archive that allows unlimited researcher contributions promises a future with vastly increased digital collections available at researchers’ finger tips. PMID:26836025

  2. Evaluation of replication, immunogenicity and protective efficacy of a live attenuated cold-adapted pandemic H1N1 influenza virus vaccine in non-human primates.

    PubMed

    Boonnak, Kobporn; Paskel, Myeisha; Matsuoka, Yumiko; Vogel, Leatrice; Subbarao, Kanta

    2012-08-17

    We studied the replication of influenza A/California/07/09 (H1N1) wild type (CA09wt) virus in two non-human primate species and used one of these models to evaluate the immunogenicity and protective efficacy of a live attenuated cold-adapted vaccine, which contains the hemagglutinin and neuraminidase from the H1N1 wild type (wt) virus and six internal protein gene segments of the A/Ann Arbor/6/60 cold-adapted (ca) master donor virus. We infected African green monkeys (AGMs) and rhesus macaques with 2×10(6) TCID(50) of CA09wt and CA09ca influenza viruses. The virus CA09wt replicated in the upper respiratory tract of all animals but the titers in upper respiratory tract tissues of rhesus macaques were significant higher than in AGMs (mean peak titers 10(4.5) TCID(50)/g and 10(2.0) TCID(50)/g on days 4 and 2 post-infection, respectively; p<0.01). Virus replication was observed in the lungs of all rhesus macaques (10(2.0)-10(5.4) TCID(50)/g) whereas only 2 out of 4 AGMs had virus recovered from the lungs (10(2.5)-10(3.5) TCID(50)/g). The CA09ca vaccine virus was attenuated and highly restricted in replication in both AGMs and rhesus macaques. We evaluated the immunogenicity and protective efficacy of the CA09ca vaccine in rhesus macaques because CA09wt virus replicated more efficiently in this species. One or two doses of vaccine were administered intranasally and intratracheally to rhesus macaques. For the two-dose group, the vaccine was administered 4-weeks apart. Immunogenicity was assessed by measuring hemagglutination-inhibiting (HAI) antibodies in the serum and specific IgA antibodies to CA09wt virus in the nasal wash. One or two doses of the vaccine elicited a significant rise in HAI titers (range 40-320). Two doses of CA09ca elicited higher pH1N1-specific IgA titers than in the mock-immunized group (p<0.01). Vaccine efficacy was assessed by comparing titers of CA09wt challenge virus in the respiratory tract of mock-immunized and CA09ca vaccinated monkeys

  3. Vertical ridge augmentation using an equine bone and collagen block infused with recombinant human platelet-derived growth factor-BB: a randomized single-masked histologic study in non-human primates.

    PubMed

    Nevins, Myron; Al Hezaimi, Khalid; Schupbach, Peter; Karimbux, Nadeem; Kim, David M

    2012-07-01

    This study tests the effectiveness of hydroxyapatite and collagen bone blocks of equine origin (eHAC), infused with recombinant human platelet-derived growth factor-BB (rhPDGF-BB), to augment localized posterior mandibular defects in non-human primates (Papio hamadryas). Bilateral critical-sized defects simulating severe atrophy were created at the time of the posterior teeth extraction. Test and control blocks (without growth factor) were randomly grafted into the respective sites in each non-human primate. All sites exhibited vertical ridge augmentation, with physiologic hard- and soft-tissue integration of the blocks when clinical and histologic examinations were done at 4 months after the vertical ridge augmentation procedure. There was a clear, although non-significant, tendency to increased regeneration in the test sites. As in the first two preclinical studies in this series using canines, experimental eHAC blocks infused with rhPDGF-BB proved to be a predictable and technically viable method to predictably regenerate bone and soft tissue in critical-sized defects. This investigation supplies additional evidence that eHAC blocks infused with rhPDGF-BB growth factor is a predictable and technically feasible option for vertical augmentation of severely resorbed ridges.

  4. Integrated Safety Assessment of 2′-O-Methoxyethyl Chimeric Antisense Oligonucleotides in NonHuman Primates and Healthy Human Volunteers

    PubMed Central

    Crooke, Stanley T; Baker, Brenda F; Kwoh, T Jesse; Cheng, Wei; Schulz, Dan J; Xia, Shuting; Salgado, Nelson; Bui, Huynh-Hoa; Hart, Christopher E; Burel, Sebastien A; Younis, Husam S; Geary, Richard S; Henry, Scott P; Bhanot, Sanjay

    2016-01-01

    The common chemical and biological properties of antisense oligonucleotides provide the opportunity to identify and characterize chemical class effects across species. The chemical class that has proven to be the most versatile and best characterized is the 2′-O-methoxyethyl chimeric antisense oligonucleotides. In this report we present an integrated safety assessment of data obtained from controlled dose-ranging studies in nonhuman primates (macaques) and healthy human volunteers for 12 unique 2′-O-methoxyethyl chimeric antisense oligonucleotides. Safety was assessed by the incidence of safety signals in standardized laboratory tests for kidney and liver function, hematology, and complement activation; as well as by the mean test results as a function of dose level over time. At high doses a number of toxicities were observed in nonhuman primates. However, no class safety effects were identified in healthy human volunteers from this integrated data analysis. Effects on complement in nonhuman primates were not observed in humans. Nonhuman primates predicted safe doses in humans, but over predicted risk of complement activation and effects on platelets. Although limited to a single chemical class, comparisons from this analysis are considered valid and accurate based on the carefully controlled setting for the specified study populations and within the total exposures studied. PMID:27357629

  5. Effect of body mass distribution on the ontogeny of positional behaviors in non-human primates: Longitudinal follow-up of infant captive olive baboons (Papio anubis).

    PubMed

    Druelle, François; Aerts, Peter; Berillon, Gilles

    2016-11-01

    The diversity of primates' positional capabilities is unique among mammals. Indeed, they exhibit a daily repertoire composed of various locomotor and postural modes that may be linked to their particular morphological pattern. Because ontogeny undergoes parallel behavioral and morphological modifications, it may be useful to investigate the biomechanical consequences of the changing body shape. We, therefore, collected accurate quantitative and longitudinal data on positional behaviors, body mass distribution patterns, activities, and environment on a sample of six infant olive baboons, Papio anubis. These baboons are kept at the Primatology Station of the CNRS, France, where they live within the same social group. Individual behaviors were quantified using the focal sampling method. The body mass distribution was estimated according to a geometric model based on direct external measurements. Multivariate analysis enabled us to analyze the interactions between the data. Our results show that body mass distribution changes together with the ontogenetic changes in positional behaviors. At an early age, individuals have distally heavy segment masses in the limbs and an important fraction of the behavioral repertoire involves efficient grasping abilities. At the end of infancy, the same individuals have relatively more mass in proximal segments of the limbs and the proportion of quadrupedal walking is significantly higher while other climbing and suspensory behaviors decreased substantially. The present study experimentally confirms the association between body mass distribution and the positional repertoire of primates. These relationships, when interpreted in the context of basic biomechanical concepts, may improve our understanding of primate locomotion. We discuss further the implications of these functional relationships when modeling the evolutionary pathway of primates. Am. J. Primatol. 78:1201-1221, 2016. © 2016 Wiley Periodicals, Inc.

  6. Study of the role of novel RF-amide neuropeptides in affecting growth hormone secretion in a representative non-human primate (Macaca mulatta).

    PubMed

    Qaiser, Fatima; Wahab, Fazal; Wiqar, Muhammad Amin; Hashim, Rizwan; Leprince, Jerome; Vaudry, Hubert; Tena-Sempere, Manuel; Shahab, Muhammad

    2012-12-01

    RF amide peptide family with distinctive terminal -Arg-Phe-NH(2) signature is evolutionarily conserved from invertebrates to mammals. These neuropeptides have been shown to affect diverse functions in invertebrates and vertebrates including influencing pituitary hormone secretion. More recently, two members of this family 26-amino acid and 43-amino acid RF amide peptide (26RFa and 43RFa, respectively) originally isolated from frog have been cloned in rats and humans. Actions of these peptides on hormone secretion have not been studied in primates. In the present study, effect of iv administration of three different doses of human 26RFa and 43RFa on GH secretion was studied in a representative higher primate, the rhesus monkey. As control against these two peptides, normal saline and a scrambled sequence of 26RFa was administered. A set of four intact adult male monkeys received the administration in a random order. Peripheral blood samples were obtained from the chairrestrained but fully conscious animals for a period of 30 min before and 240 min after the administration at 15-min intervals. For quantitative measurement of GH concentration, a human GH chemiluminescent immunometric assay was used. Peripheral administration of 38 and 76 nmol doses of 26RFa significantly (P < 0.05) stimulated GH AUC during a 0-120 min period after injection of 26RFa. In contrast to 26RFa, administration of 43RFa appeared to suppress GH levels during the later stages of the sampling i.e. from 120 to 240 min period. Mean AUC during the period was significantly (P < 0.05) reduced by 76 nmol dose of 43RFa, while 38 nmol dose of 43RFa also had similar effect but lacked full statistical significance (P = 0.058). To our knowledge present study reports for the first time-specific stimulatory effect of 26RFa on the GH secretion and a novel inhibitory and delayed effect of 43RFa on the GH secretion in higher primates. In conclusion, present findings extend evidence for endocrine actions of RF

  7. Chikungunya antibodies detected in non-human primates and rats in three Indian Ocean islands after the 2006 ChikV outbreak

    PubMed Central

    2014-