WorldWideScience

Sample records for aged nonhuman primates

  1. Demand for nonhuman primate resources in the age of biodefense.

    Science.gov (United States)

    Patterson, Jean L; Carrion, Richardo

    2005-01-01

    The demand for nonhuman primates will undoubtedly increase to meet biomedical needs in this current age of biodefense. The availability of funding has increased the research on select agents and has created a requirement to validate results in relevant primate models. This review provides a description of current and potential biological threats that are likely to require nonhuman primates for the development of vaccines and therapeutics. Primates have been an invaluable resource in the dissection of viral disease pathogenesis as well as in testing vaccine efficacy. DNA vaccine approaches have been studied successfully for Ebola, Lassa, and anthrax in nonhuman primate models. Nonhuman primate research with monkeypox has provided insight into the role of cytokines in limiting disease severity. Biodefense research that has focused on select agents of bacterial origin has also benefited from nonhuman primate studies. Rhesus macaques have traditionally been the model of choice for anthrax research and have yielded successful findings in vaccine development. In plague research, African green monkeys have contributed to vaccine development. However, the disadvantages of current vaccines will undoubtedly require the generation of new vaccines, thus increasing the need for nonhuman primate research. Unfortunately, the current biosafety level (BSL)-3 and BSL-4 facilities equipped to perform this research are limited, which may ultimately impede progress in this era of biodefense.

  2. Property in Nonhuman Primates

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    Brosnan, Sarah F.

    2011-01-01

    Property is rare in most nonhuman primates, most likely because their lifestyles are not conducive to it. Nonetheless, just because these species do not frequently maintain property does not mean that they lack the propensity to do so. Primates show respect for possession, as well as behaviors related to property, such as irrational decision…

  3. Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Jean-Michel eVERDIER

    2015-03-01

    Full Text Available Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer’s and prion diseases or motor deficits (Parkinson’s and related diseases.

  4. Doublecortin-expressing cells persist in the associative cerebral cortex and amygdala in aged nonhuman primates

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    Xue-mei Zhang

    2009-10-01

    Full Text Available A novel population of cells that express typical immature neuronal markers including doublecortin (DCX+ has been recently identified throughout the adult cerebral cortex of relatively large mammals (guinea pig, rabbit, cat, monkey and human. These cells are more common in the associative relative to primary cortical areas and appear to develop into interneurons including type II nitrinergic neurons. Here we further describe these cells in the cerebral cortex and amygdala, in comparison with DCX+ cells in the hippocampal dentate gyrus, in 3 age groups of rhesus monkeys: young adult (12.3±0.2 yrs, n=3, mid-age (21.2±1.9 yrs, n=3 and aged (31.3±1.8 yrs, n=4. DCX+ cells with a heterogeneous morphology persisted in layers II/III primarily over the associative cortex and amygdala in all groups (including in two old animals with cerebral amyloid pathology, showing a parallel decline in cell density with age across regions. In contrast to the cortex and amygdala, DCX+ cells in the subgranular zone diminished in the mid-age and aged groups. DCX+ cortical cells might arrange as long tangential migratory chains in the mid-age and aged animals, with apparently distorted cell clusters seen in the aged group. Cortical DCX+ cells colocalized commonly with polysialylated neural cell adhesion molecule (PSA-NCAM and partially with neuron-specific nuclear protein (NeuN and γ-aminobutyric acid (GABA, suggesting a potential differentiation of these cells into interneuron phenotype. These data suggest a life-long role for immature interneuron-like cells in the associative cerebral cortex and amygdala in nonhuman primates.

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

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    Kofler Julia

    2012-05-01

    Full Text Available Abstract 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  Conclusions Our results indicate that preventive Aβ immunization is a safe therapeutic approach lacking adverse CNS immune system

  6. Nuclear transfer in nonhuman primates.

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    Mitalipov, Shoukhrat M; Wolf, Don P

    2006-01-01

    The nonhuman primate is a highly relevant model for the study of human diseases, and currently there is a significant need for populations of animals with specific genotypes that can not be satisfied by the capture of animals from the wild or by conventional breeding. There is an even greater need for genetically identical animals in vaccine development or tissue transplantation research, where immune system function is under study. Efficient somatic cell nuclear transfer (SCNT) procedures could provide a source for genetically identical nonhuman primates for biomedical research. SCNT offers the possibility of cloning animals using cultured cells and potentially provides an alternative approach for the genetic modification of primates. The opportunity to introduce precise genetic modifications into cultured cells by gene targeting procedures, and then use these cells as nuclear donors in SCNT, has potential application in the production of loss-of-function monkey models of human diseases. We were initially successful in producing monkeys by NT using embryonic blastomeres as the source of donor nuclei and have repeated that success. However, when somatic cells are used as nuclear donor cells, the developmental potential of monkey SCNT embryos is limited, and somatic cell cloning has not yet been accomplished in primates. High rates of in vitro development to blastocysts, comparable with in vitro fertilization controls, and successful production of rhesus monkeys by NT from embryonic blastomeres suggests that basic cloning procedures, including enucleation, fusion, and activation, are consistent with the production of viable embryos. Although modifications or additional steps in SCNT are clearly warranted, the basic procedures will likely be similar to those extant for embryonic cell NT. In this chapter, we describe detailed protocols for rhesus macaque embryonic cell NT, including oocyte and embryo production, micromanipulation, and embryo transfer in nonhuman

  7. Old world monkeys and new age science: the evolution of nonhuman primate systems virology.

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    Palermo, Robert E; Tisoncik-Go, Jennifer; Korth, Marcus J; Katze, Michael G

    2013-01-01

    Nonhuman primate (NHP) biomedical models are critical to our understanding of human health and disease, yet we are still in the early stages of developing sufficient tools to support primate genomic research that allow us to better understand the basis of phenotypic traits in NHP models of disease. A mere 7 years ago, the limited NHP transcriptome profiling that was being performed was done using complementary DNA arrays based on human genome sequences, and the lack of NHP genomic information and immunologic reagents precluded the use of NHPs in functional genomic studies. Since then, significant strides have been made in developing genomics capabilities for NHP research, from the rhesus macaque genome sequencing project to the construction of the first macaque-specific high-density oligonucleotide microarray, paving the way for further resource development and additional primate sequencing projects. Complete published draft genome sequences are now available for the chimpanzee ( Chimpanzee Sequencing Analysis Consortium 2005), bonobo ( Prufer et al. 2012), gorilla ( Scally et al. 2012), and baboon ( Ensembl.org 2013), along with the recently completed draft genomes for the cynomolgus macaque and Chinese rhesus macaque. Against this backdrop of both expanding sequence data and the early application of sequence-derived DNA microarrays tools, we will contextualize the development of these community resources and their application to infectious disease research through a literature review of NHP models of acquired immune deficiency syndrome and models of respiratory virus infection. In particular, we will review the use of -omics approaches in studies of simian immunodeficiency virus and respiratory virus pathogenesis and vaccine development, emphasizing the acute and innate responses and the relationship of these to the course of disease and to the evolution of adaptive immunity.

  8. Biokinetics of Plutonium in Nonhuman Primates.

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    Poudel, Deepesh; Guilmette, Raymond A; Gesell, Thomas F; Harris, Jason T; Brey, Richard R

    2016-10-01

    A major source of data on metabolism, excretion and retention of plutonium comes from experimental animal studies. Although old world monkeys are one of the closest living relatives to humans, certain physiological differences do exist between these nonhuman primates and humans. The objective of this paper was to describe the metabolism of plutonium in nonhuman primates using the bioassay and retention data obtained from macaque monkeys injected with plutonium citrate. A biokinetic model for nonhuman primates was developed by adapting the basic model structure and adapting the transfer rates described for metabolism of plutonium in adult humans. Significant changes to the parameters were necessary to explain the shorter retention of plutonium in liver and skeleton of the nonhuman primates, differences in liver to bone partitioning ratio, and significantly higher excretion of plutonium in feces compared to that in humans.

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

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    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

  10. Nonhuman primate models of polycystic ovary syndrome

    OpenAIRE

    David H Abbott; Nicol, Lindsey E.; Levine, Jon E; Xu, Ning; Goodarzi, Mark O.; Dumesic, Daniel A.

    2013-01-01

    With close genomic and phenotypic similarity to humans, nonhuman primate models provide comprehensive epigenetic mimics of polycystic ovary syndrome (PCOS), suggesting early life targeting for prevention. Fetal exposure to testosterone (T), of all nonhuman primate emulations, provides the closest PCOS-like phenotypes, with early-to-mid gestation T-exposed female rhesus monkeys exhibiting adult reproductive, endocrinological and metabolic dysfunctional traits that are co-pathologies of PCOS. L...

  11. Operant nociception in nonhuman primates.

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    Kangas, Brian D; Bergman, Jack

    2014-09-01

    The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. Most current in vivo procedures (eg, tail flick, hot plate, warm water tail withdrawal) assay the effects of nociceptive stimuli on simple spinal reflexes or unconditioned behavioral reactions. However, clinical treatment goals may include the restoration of previous behavioral activities, which can be limited by medication-related side effects that are not measured in such procedures. The present studies describe an apparatus and procedure to study the disruptive effects of nociceptive stimuli on voluntary behavior in nonhuman primates, and the ability of drugs to restore such behavior through their analgesic actions. Squirrel monkeys were trained to pull a cylindrical thermode for access to a highly palatable food. Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d-amphetamine or Δ(9)-THC, produced dose-related increases in threshold that were antagonist sensitive and efficacy dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex-based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.

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

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    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.

  13. Nonhuman primate models of polycystic ovary syndrome.

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    Abbott, David H; Nicol, Lindsey E; Levine, Jon E; Xu, Ning; Goodarzi, Mark O; Dumesic, Daniel A

    2013-07-01

    With close genomic and phenotypic similarity to humans, nonhuman primate models provide comprehensive epigenetic mimics of polycystic ovary syndrome (PCOS), suggesting early life targeting for prevention. Fetal exposure to testosterone (T), of all nonhuman primate emulations, provides the closest PCOS-like phenotypes, with early-to-mid gestation T-exposed female rhesus monkeys exhibiting adult reproductive, endocrinological and metabolic dysfunctional traits that are co-pathologies of PCOS. Late gestational T exposure, while inducing adult ovarian hyperandrogenism and menstrual abnormalities, has less dysfunctional metabolic accompaniment. Fetal exposures to dihydrotestosterone (DHT) or diethylstilbestrol (DES) suggest androgenic and estrogenic aspects of fetal programming. Neonatal exposure to T produces no PCOS-like outcome, while continuous T treatment of juvenile females causes precocious weight gain and early menarche (high T), or high LH and weight gain (moderate T). Acute T exposure of adult females generates polyfollicular ovaries, while chronic T exposure induces subtle menstrual irregularities without metabolic dysfunction.

  14. [Experimental whooping cough of nonhuman primate].

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    Kubrava, D T; Medkova, A Iu; Siniashina, L N; Shevtsova, Z V; Matua, A Z; Kondzharia, I G; Barkaia, V S; Elistratova, Zh V; Karataev, G I; Mikvabia, Z Ia; Gintsburg, A L

    2013-01-01

    Despite considerable success in study of Bordetella pertussis virulence factors, pathogenesis of whooping cough, duration of B. pertussis bacteria persistence, types and mechanisms of immune response are still keep underinvestigated. It can be explained by the absence ofadequate experimental animal model for pertussis study. Our study estimates clinical and laboratory parameters of whooping cough in non-human primates of the Old World in the process of intranasan infection by virulent B. pertussis bacteria. Also the duration of B. pertussis bacteria persistence in animals was investigated. 14 animal units of 4 species of non-human primates of the Old World were used for intranasal infection. The examination of infect animals included: visual exploration of nasopharynx, thermometry, clinical and biochemical blood analyses, identification ofB. pertussis, using microbiologic and molecular genetic analyses, estimation of innate and adoptive immune factors. The development of infectious process was accompanied by generation of B. pertussis bacteria, catarrhal inflammation of nasopharyngeal mucosa, leucocytosis, hypoglycemia specific for pertussis, and activation of innate and adaptive immunity for all primates regardless of specie were seen. While repeated experimental infection in primates single bacterial colonies were registered during only first week after challenge. It occurs like the absence of inflammation of nasopharyngeal mucosa and the lack of laboratory marks of whooping cough, recorded after first challenge. The evident booster effect of humoral immunity was observed. As a model for investigation of B. pertussis bacteria persistence and immune response against whooping cough we suggest the usage of rhesus macaque as more available to experiments.

  15. Progress with nonhuman primate embryonic stem cells.

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    Wolf, Don P; Kuo, Hung-Chih; Pau, K-Y Francis; Lester, Linda

    2004-12-01

    Embryonic stem cells hold potential in the fields of regenerative medicine, developmental biology, tissue regeneration, disease pathogenicity, and drug discovery. Embryonic stem (ES) cell lines are now available in primates, including man, rhesus, and cynomologous monkeys. Monkey ES cells serve as invaluable clinically relevant models for studies that can't be conducted in humans because of practical or ethical limitations, or in rodents because of differences in physiology and anatomy. Here, we review the current status of nonhuman primate research with ES cells, beginning with a description of their isolation, characterization, and availability. Substantial limitations still plague the use of primate ES cells, such as their required growth on feeder layers, poor cloning efficiency, and restricted availability. The ability to produce homogenous populations of both undifferentiated as well as differentiated phenotypes is an important challenge, and genetic approaches to achieving these objectives are discussed. Finally, safety, efficiency, and feasibility issues relating to the transplantation of ES-derived cells are considered.

  16. Alopecia: possible causes and treatments, particularly in captive nonhuman primates.

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    Novak, Melinda A; Meyer, Jerrold S

    2009-02-01

    Alopecia (hair loss) occurs in some nonhuman primates housed in captivity and is of concern to colony managers and veterinarians. Here we review the characteristics, potential causes, and treatments for this condition. Although we focus on nonhuman primates, relevant research on other mammalian species is discussed also, due to the relative paucity of studies on alopecia in the primate literature. We first discuss the cycle of hair growth and explain how this cycle can be disrupted to produce alopecia. Numerous factors may be related to hair loss and range from naturally occurring processes (for example, seasonality, aging) to various biologic dysfunctions, including vitamin and mineral imbalances, endocrine disorders, immunologic diseases, and genetic mutations. We also address bacterial and fungal infections, infestation by parasites, and atopic dermatitis as possible causes of alopecia. Finally, we examine the role of psychogenic factors, such as stress. Depending on the presumed cause of the hair loss, various treatment strategies can be pursued. Alopecia in nonhuman primates is a multifaceted disorder with many potential sources. For this reason, appropriate testing for various disease conditions should be completed before alopecia is considered to be related to stress.

  17. Nonhuman primate models in translational regenerative medicine.

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    Daadi, Marcel M; Barberi, Tiziano; Shi, Qiang; Lanford, Robert E

    2014-12-01

    Humans and nonhuman primates (NHPs) are similar in size, behavior, physiology, biochemistry, structure and function of organs, and complexity of the immune system. Research on NHPs generates complementary data that bridge translational research from small animal models to humans. NHP models of human disease offer unique opportunities to develop stem cell-based therapeutic interventions that directly address relevant and challenging translational aspects of cell transplantation therapy. These include the use of autologous induced pluripotent stem cell-derived cellular products, issues related to the immune response in autologous and allogeneic setting, pros and cons of delivery techniques in a clinical setting, as well as the safety and efficacy of candidate cell lines. The NHP model allows the assessment of complex physiological, biochemical, behavioral, and imaging end points, with direct relevance to human conditions. At the same time, the value of using primates in scientific research must be carefully evaluated and timed due to expense and the necessity for specialized equipment and highly trained personnel. Often it is more efficient and useful to perform initial proof-of-concept studies for new therapeutics in rodents and/or other species before the pivotal studies in NHPs that may eventually lead to first-in-human trials. In this report, we present how the Southwest National Primate Research Center, one of seven NIH-funded National Primate Research Centers, may help the global community in translating promising technologies to the clinical arena.

  18. Alopecia: Possible Causes and Treatments, Particularly in Captive Nonhuman Primates

    OpenAIRE

    2009-01-01

    Alopecia (hair loss) occurs in some nonhuman primates housed in captivity and is of concern to colony managers and veterinarians. Here we review the characteristics, potential causes, and treatments for this condition. Although we focus on nonhuman primates, relevant research on other mammalian species is discussed also, due to the relative paucity of studies on alopecia in the primate literature. We first discuss the cycle of hair growth and explain how this cycle can be disrupted to produce...

  19. Mediodorsal thalamus and cognition in nonhuman primates

    Directory of Open Access Journals (Sweden)

    Mark G Baxter

    2013-08-01

    Full Text Available Several recent studies in nonhuman 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.

  20. Transgenic nonhuman primates for neurodegenerative diseases

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    Chan Anthony WS

    2004-06-01

    Full Text Available Abstract Animal models that represent human diseases constitute an important tool in understanding the pathogenesis of the diseases, and in developing effective therapies. Neurodegenerative diseases are complex disorders involving neuropathologic and psychiatric alterations. Although transgenic and knock-in mouse models of Alzheimer's disease, (AD, Parkinson's disease (PD and Huntington's disease (HD have been created, limited representation in clinical aspects has been recognized and the rodent models lack true neurodegeneration. Chemical induction of HD and PD in nonhuman primates (NHP has been reported, however, the role of intrinsic genetic factors in the development of the diseases is indeterminable. Nonhuman primates closely parallel humans with regard to genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly, the development of NHP models for neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Therefore, a transgenic NHP carrying a mutant gene similar to that of patients will help to clarify our understanding of disease onset and progression. Additionally, monitoring disease onset and development in the transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in the NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will also be possible to compare the neurologic syndrome observed in the NHP model to that in patients. Understanding the correlation between genetic defects and physiologic changes (e.g. oxidative damage will lead to a better understanding of disease progression and the development of patient treatments, medications and preventive approaches for high risk individuals. The impact of the transgenic NHP model in understanding the role which

  1. Calorie restriction and resveratrol supplementation prevent age-related DNA and RNA oxidative damage in a non-human primate.

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    Marchal, J; Dal-Pan, A; Epelbaum, J; Blanc, S; Mueller, S; Wittig Kieffer, M; Metzger, F; Aujard, F

    2013-09-01

    Oxidative stress is a key factor in the aging process and in the development of age-related diseases. Because nutritional interventions such as caloric restriction (CR) delay the onset of age-related diseases and increase the lifespan of many species, the impact of a moderate CR was tested on male grey mouse lemur (Microcebus murinus), which have a median survival time of 5.7 years in captivity. The effects of CR on these lemurs were compared with a potential mimetic, resveratrol (RSV), a polyphenol naturally found in grapes. We hypothesized that both CR and RSV impact oxidative DNA and RNA damage compared to standard-fed control (CTL) animals. Adult (3-4 years old) male mouse lemurs were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day(-1)·kg(-1)). Oxidative stress was estimated after 3, 9, 15 and 21 months of treatment using the measurement of oxidized nucleosides in urine samples by mass spectrometry. The resting metabolic rate, adjusted for changes in body composition, was also measured to assess the potential relationship between oxygen consumption and oxidative damage markers. This study provides evidence for oxidative stress accumulation with age in grey mouse lemur. Dietary interventions resulted in a short-term increase in oxidative stress levels followed by reduced levels with increasing age. Moreover, in this photoperiod-dependent heterotherm primate, seasonal variations in oxidative stress were observed, which was likely due to a season-dependent, cost-benefit trade-off between torpor use and oxidative stress.

  2. Nonhuman Primates Prefer Slow Tempos but Dislike Music Overall

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    McDermott, Josh; Hauser, Marc D.

    2007-01-01

    Human adults generally find fast tempos more arousing than slow tempos, with tempo frequently manipulated in music to alter tension and emotion. We used a previously published method [McDermott, J., & Hauser, M. (2004). Are consonant intervals music to their ears? Spontaneous acoustic preferences in a nonhuman primate. Cognition, 94(2), B11-B21]…

  3. Evolutionary Developmental Psychology: Contributions from Comparative Research with Nonhuman Primates

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    Maestripieri, Dario; Roney, James R.

    2006-01-01

    Evolutionary developmental psychology is a discipline that has the potential to integrate conceptual approaches to the study of behavioral development derived from psychology and biology as well as empirical data from humans and animals. Comparative research with animals, and especially with nonhuman primates, can provide evidence of adaptation in…

  4. Distinct Lineages of Bufavirus in Wild Shrews and Nonhuman Primates.

    Science.gov (United States)

    Sasaki, Michihito; Orba, Yasuko; Anindita, Paulina D; Ishii, Akihiro; Ueno, Keisuke; Hang'ombe, Bernard M; Mweene, Aaron S; Ito, Kimihito; Sawa, Hirofumi

    2015-07-01

    Viral metagenomic analysis identified a new parvovirus genome in the intestinal contents of wild shrews in Zambia. Related viruses were detected in spleen tissues from wild shrews and nonhuman primates. Phylogenetic analyses showed that these viruses are related to human bufaviruses, highlighting the presence and genetic diversity of bufaviruses in wildlife.

  5. Human parainfluenza virus type 3 in wild nonhuman primates, Zambia.

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    Sasaki, Michihito; Ishii, Akihiro; Orba, Yasuko; Thomas, Yuka; Hang'ombe, Bernard M; Moonga, Ladslav; Mweene, Aaron S; Ogawa, Hirohito; Nakamura, Ichiro; Kimura, Takashi; Sawa, Hirofumi

    2013-01-01

    Human parainfluenza virus type 3 (HPIV3) genome was detected in 4 baboons in Zambia. Antibody for HPIV3 was detected in 13 baboons and 6 vervet monkeys in 2 distinct areas in Zambia. Our findings suggest that wild nonhuman primates are susceptible to HPIV3 infection.

  6. 42 CFR 71.53 - Nonhuman primates.

    Science.gov (United States)

    2010-10-01

    ... for use in breeding colonies is also permitted provided that all offspring will be used only for... cause(s) of deaths. If any primates in the shipment are sold or otherwise distributed within 90...

  7. Matrix factorization reveals aging-specific co-expression gene modules in the fat and muscle tissues in nonhuman primates

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    Wang, Yongcui; Zhao, Weiling; Zhou, Xiaobo

    2016-10-01

    Accurate identification of coherent transcriptional modules (subnetworks) in adipose and muscle tissues is important for revealing the related mechanisms and co-regulated pathways involved in the development of aging-related diseases. Here, we proposed a systematically computational approach, called ICEGM, to Identify the Co-Expression Gene Modules through a novel mathematical framework of Higher-Order Generalized Singular Value Decomposition (HO-GSVD). ICEGM was applied on the adipose, and heart and skeletal muscle tissues in old and young female African green vervet monkeys. The genes associated with the development of inflammation, cardiovascular and skeletal disorder diseases, and cancer were revealed by the ICEGM. Meanwhile, genes in the ICEGM modules were also enriched in the adipocytes, smooth muscle cells, cardiac myocytes, and immune cells. Comprehensive disease annotation and canonical pathway analysis indicated that immune cells, adipocytes, cardiomyocytes, and smooth muscle cells played a synergistic role in cardiac and physical functions in the aged monkeys by regulation of the biological processes associated with metabolism, inflammation, and atherosclerosis. In conclusion, the ICEGM provides an efficiently systematic framework for decoding the co-expression gene modules in multiple tissues. Analysis of genes in the ICEGM module yielded important insights on the cooperative role of multiple tissues in the development of diseases.

  8. Quality management for the international transportation of non-human primates

    Directory of Open Access Journals (Sweden)

    David B. Elmore

    2008-03-01

    Full Text Available Safe and humane transportation of live animals requires dedicated, informed personnel who carefully plan and attend to the details of appropriate animal care and handling throughout the shipping process. Specifically, although transportation of non-human primates shares goals common to all live animal transport, it also poses unique challenges stemming from the nature of these animals. Some of these unique challenges of transporting non-human primates, include the impact of public perception of non-human primates as cargo, maintaining biosecurity of non-human primate cargo, safety of both the non-human primate and public contacts, meeting the vital husbandry needs of varying species of non-human primates and compliance with numerous regulatory agencies, which may have overlapping responsibilities. This discussion will focus on these important considerations, as they relate to the legal international transportation of non-human primates for scientific use.

  9. Non-Human Primate Models of Orthopoxvirus Infections

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    Anne Schmitt

    2014-06-01

    Full Text Available Smallpox, one of the most destructive diseases, has been successfully eradicated through a worldwide vaccination campaign. Since immunization programs have been stopped, the number of people with vaccinia virus induced immunity is declining. This leads to an increase in orthopoxvirus (OPXV infections in humans, as well as in animals. Additionally, potential abuse of Variola virus (VARV, the causative agent of smallpox, or monkeypox virus, as agents of bioterrorism, has renewed interest in development of antiviral therapeutics and of safer vaccines. Due to its high risk potential, research with VARV is restricted to two laboratories worldwide. Therefore, numerous animal models of other OPXV infections have been developed in the last decades. Non-human primates are especially suitable due to their close relationship to humans. This article provides a review about on non-human primate models of orthopoxvirus infections.

  10. The origins of non-human primates' manual gestures.

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    Liebal, Katja; Call, Josep

    2012-01-12

    The increasing body of research into human and non-human primates' gestural communication reflects the interest in a comparative approach to human communication, particularly possible scenarios of language evolution. One of the central challenges of this field of research is to identify appropriate criteria to differentiate a gesture from other non-communicative actions. After an introduction to the criteria currently used to define non-human primates' gestures and an overview of ongoing research, we discuss different pathways of how manual actions are transformed into manual gestures in both phylogeny and ontogeny. Currently, the relationship between actions and gestures is not only investigated on a behavioural, but also on a neural level. Here, we focus on recent evidence concerning the differential laterality of manual actions and gestures in apes in the framework of a functional asymmetry of the brain for both hand use and language.

  11. Tolerance in Nonhuman Primates by Delayed Mixed Chimerism

    Science.gov (United States)

    2015-10-01

    vascularized bone marrow component that could be clearly seen; the NHP Pathology report showed that the animal had developed post-transplant...days post-transplant with neither clinical nor histological evidence of rejection (Figure 3). The animal developed a suspicious looking lesion around...Model in Non-Human Primates. Oral Presentation. New England Society of Plastic & Reconstructive Surgeons. Sebasco, Maine. June 2014. Leonard DA

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

    Energy Technology Data Exchange (ETDEWEB)

    Alvarez, V.; Coto, E.; Gonzalez-Roces, S.; Lopez-Larrea, C. [Hospital Central de Asturias, Oviedo (Spain)] [and others

    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.

  13. Longitudinal characterization of Escherichia coli in healthy captive nonhuman primates

    Directory of Open Access Journals (Sweden)

    Jonathan B Clayton

    2014-11-01

    Full Text Available The gastrointestinal (GI tracts of nonhuman primates are well known to harbor Escherichia coli, a known commensal of humans 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 the urogenital tract. Diarrhea in captive nonhuman primates (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 in correlation with diarrhea in captive primates; therefore, a study was performed during the summer of 2009 in collaboration with a zoo in Saint Paul, MN, which was 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 towards the sharing of enteric bacteria between such animals.

  14. Nonhuman Primate Induced Pluripotent Stem Cells in Regenerative Medicine

    Directory of Open Access Journals (Sweden)

    Yuehong Wu

    2012-01-01

    Full Text Available Among the various species from which induced pluripotent stem cells have been derived, nonhuman primates (NHPs have a unique role as preclinical models. Their relatedness to humans and similar physiology, including central nervous system, make them ideal for translational studies. We review here the progress made in deriving and characterizing iPS cell lines from different NHP species. We focus on iPS cell lines from the marmoset, a small NHP in which several human disease states can be modeled. The marmoset can serve as a model for the implementation of patient-specific autologous cell therapy in regenerative medicine.

  15. Cocaine is pharmacologically active in the nonhuman primate fetal brain

    DEFF Research Database (Denmark)

    Benveniste, Helene; Fowler, Joanna S; Rooney, William D

    2010-01-01

    Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third......-trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (approximately 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide...... evidence that cocaine use by a pregnant mother will also affect the function of the fetal brain. We are also unique in showing that cocaine's effects in brain glucose metabolism differed in pregnant (increased) and nonpregnant (decreased) animals, which suggests that the psychoactive effects of cocaine...

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

    Science.gov (United States)

    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…

  17. Pollical oblique ligament in humans and non-human primates.

    Science.gov (United States)

    Shrewsbury, Marvin

    2003-04-01

    A morphological study of the oblique ligament in the thumb is presented. The ligament was consistently described in human specimens and compared with dissections of non-human primates from different species. The oblique ligament was found in some, but not all, specimens in each of the following species examined: chimpanzee, orangutan, gibbon, anubis baboon, hamadryas baboon, squirrel monkey, lemur and marmoset. A revised identity of the oblique ligament is proposed as a reinforced distal border of a fibro-osseous annular pollical flexor sheath and whose function is not independent of the flexor sheath. The constant presence and tendinous trait of the pollical oblique ligament in humans, when compared with non-human primates, supports the notion that the oblique ligament strengthens the pollical flexor sheath in humans for restraint of the flexor pollicis longus tendon during forceful precision pinching. A derivation of the pollical oblique ligament is considered as representing a vestigial radial limb of a flexor pollicis superficialis tendon in the thumb.

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

    Directory of Open Access Journals (Sweden)

    Bernard Le Foll

    Full Text Available 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.

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

    Science.gov (United States)

    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

  20. Secondary expansion of the transient subplate zone in the developing cerebrum of human and nonhuman primates.

    Science.gov (United States)

    Duque, Alvaro; Krsnik, Zeljka; Kostović, Ivica; Rakic, Pasko

    2016-08-30

    The subplate (SP) was the last cellular compartment added to the Boulder Committee's list of transient embryonic zones [Bystron I, Blakemore C, Rakic P (2008) Nature Rev Neurosci 9(2):110-122]. It is highly developed in human and nonhuman primates, but its origin, mode, and dynamics of development, resolution, and eventual extinction are not well understood because human postmortem tissue offers only static descriptive data, and mice cannot serve as an adequate experimental model for the distinct regional differences in primates. Here, we take advantage of the large and slowly developing SP in macaque monkey to examine the origin, settling pattern, and subsequent dispersion of the SP neurons in primates. Monkey embryos exposed to the radioactive DNA replication marker tritiated thymidine ([(3)H]dT, or TdR) at early embryonic ages were killed at different intervals postinjection to follow postmitotic cells' positional changes. As expected in primates, most SP neurons generated in the ventricular zone initially migrate radially, together with prospective layer 6 neurons. Surprisingly, mostly during midgestation, SP cells become secondarily displaced and widespread into the expanding SP zone, which becomes particularly wide subjacent to the association cortical areas and underneath the summit of its folia. We found that invasion of monoamine, basal forebrain, thalamocortical, and corticocortical axons is mainly responsible for this region-dependent passive dispersion of the SP cells. Histologic and immunohistochemical comparison with the human SP at corresponding fetal ages indicates that the same developmental events occur in both primate species.

  1. Caloric restriction or resveratrol supplementation and ageing in a non-human primate: first-year outcome of the RESTRIKAL study in Microcebus murinus.

    Science.gov (United States)

    Dal-Pan, Alexandre; Terrien, Jérémy; Pifferi, Fabien; Botalla, Roger; Hardy, Isabelle; Marchal, Julia; Zahariev, Alexandre; Chery, Isabelle; Zizzari, Philippe; Perret, Martine; Picq, Jean Luc; Epelbaum, Jacques; Blanc, Stéphane; Aujard, Fabienne

    2011-03-01

    A life-long follow-up of physiological and behavioural functions was initiated in 38-month-old mouse lemurs (Microcebus murinus) to test whether caloric restriction (CR) or a potential mimetic compound, resveratrol (RSV), can delay the ageing process and the onset of age-related diseases. Based on their potential survival of 12 years, mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake and a RSV group (200 mg/kg.day(-1)) fed ad libitum. Since this prosimian primate exhibits a marked annual rhythm in body mass gain during winter, animals were tested throughout the year to assess body composition, daily energy expenditure (DEE), resting metabolic rate (RMR), physical activity and hormonal levels. After 1 year, all mouse lemurs seemed in good health. CR animals showed a significantly decreased body mass compared with the other groups during long day period only. CR or RSV treatments did not affect body composition. CR induced a decrease in DEE without changes in RMR, whereas RSV induced a concomitant increase in DEE and RMR without any obvious modification of locomotor activity in both groups. Hormonal levels remained similar in each group. In summary, after 1 year of treatment CR and RSV induced differential metabolic responses but animals successfully acclimated to their imposed diets. The RESTRIKAL study can now be safely undertaken on a long-term basis to determine whether age-associated alterations in mouse lemurs are delayed with CR and if RSV can mimic these effects.

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

    Science.gov (United States)

    Luo, Xin; Li, Min; Su, Bing

    2016-07-18

    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.

  3. Seroprevalence of Hepatitis A virus infection in non-human primates in Assam, India

    Directory of Open Access Journals (Sweden)

    B.G. Nath

    2013-08-01

    Full Text Available The present study investigated 37 serum samples of non-human primates in Assam State Zoo and the Department of Forest and Environment, Govt. of Assam for seroprevalence of hepatitis A virus infection during the period from December, 2007 to November, 2009. Four serum samples were also collected from animal keepers of the zoo to investigate transmission of the disease to the attendants working with these primates. Competitive ELISA was performed using hepatitis A virus ELISA kit (Wanti Hep. AV to detect hepatitis A virus antibody in serum samples. Ten (27.21% of the non-human primate samples and three (75% human samples had detectable anti-hepatitis A virus antibodies. Living status of the non-human primates (Free living was a high potential risk for hepatitis A virus infection. Seroprevalence of hepatitis A virus infection had significant difference between free living non-human primates and captive non-human primates (P less than 0.05. No significant difference (p=0.86 was seen between male and female non-human primates

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

    Science.gov (United States)

    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.

  5. Non-human primate regulatory T cells: Current biology and implications for transplantation

    NARCIS (Netherlands)

    E.M. Dons (Eefje); G. Raimondi (Giorgio); D.K.C. Cooper (David); A.W. Thomson (Angus)

    2010-01-01

    textabstractRegulatory T cells (Treg) offer potential for improving long-term outcomes in cell and organ transplantation. The non-human primate model is a valuable resource for addressing issues concerning the transfer of Treg therapy to the clinic. Herein, we discuss the properties of non-human pri

  6. Refractive power and biometric properties of the nonhuman primate isolated crystalline lens.

    Science.gov (United States)

    Borja, David; Manns, Fabrice; Ho, Arthur; Ziebarth, Noel M; Acosta, Ana Carolina; Arrieta-Quintera, Esdras; Augusteyn, Robert C; Parel, Jean-Marie

    2010-04-01

    Purpose. To characterize the age dependence of shape, refractive power, and refractive index of isolated lenses from nonhuman primates. Methods. Measurements were performed on ex vivo lenses from cynomolgus monkeys (cyno: n = 120; age, 2.7-14.3 years), rhesus monkeys (n = 61; age, 0.7-13.3 years), and hamadryas baboons (baboon: n = 16; age, 1.7-27.3 years). Lens thickness, diameter, and surface curvatures were measured with an optical comparator. Lens refractive power was measured with a custom optical system based on the Scheiner principle. The refractive contributions of the gradient, the surfaces, and the equivalent refractive index were calculated with optical ray-tracing software. The age dependence of the optical and biometric parameters was assessed. Results. Over the measured age range isolated lens thickness decreased (baboon: -0.04, cyno: -0.05, and rhesus: -0.06 mm/y) and equatorial diameter increased (logarithmically for the baboon and rhesus, and linearly for cyno: 0.07 mm/y). The isolated lens surfaces flattened and the corresponding refractive power from the surfaces decreased with age (-0.33, -0.48, and -0.68 D/y). The isolated lens equivalent refractive index decreased (only significant for the baboon, -0.001 D/y), and as a result the total isolated lens refractive power decreased with age (baboon: -1.26, cyno: -0.97, and rhesus: -1.76 D/y). Conclusions. The age-dependent trends in the optical and biometric properties, growth, and aging, of nonhuman primate lenses are similar to those of the pre-presbyopic human lens. As the lens ages, the decrease in refractive contributions from the gradient refractive index causes a rapid age-dependent decrease in maximally accommodated lens refractive power.

  7. Comparison of experimental respiratory tularemia in three nonhuman primate species.

    Science.gov (United States)

    Glynn, Audrey R; Alves, Derron A; Frick, Ondraya; Erwin-Cohen, Rebecca; Porter, Aimee; Norris, Sarah; Waag, David; Nalca, Aysegul

    2015-04-01

    Tularemia is a zoonotic disease caused by Francisella tularensis, which is transmitted to humans most commonly by contact with infected animals, tick bites, or inhalation of aerosolized bacteria. F. tularensis is highly infectious via the aerosol route; inhalation of as few as 10-50 organisms can cause pneumonic tularemia. Left untreated, the pneumonic form has more than >30% case-fatality rate but with early antibiotic intervention can be reduced to 3%. This study compared tularemia disease progression across three species of nonhuman primates [African green monkey (AGM), cynomolgus macaque (CM), and rhesus macaque (RM)] following aerosolized F. tularensis Schu S4 exposure. Groups of the animals exposed to various challenge doses were observed for clinical signs of infection and blood samples were analyzed to characterize the disease pathogenesis. Whereas the AGMs and CMs succumbed to disease following challenge doses of 40 and 32 colony forming units (CFU), respectively, the RM lethal dose was 276,667 CFU. Following all challenge doses that caused disease, the NHPs experienced weight loss, bacteremia, fever as early as 4 days post exposure, and tissue burden. Necrotizing-to-pyogranulomatous lesions were observed most commonly in the lung, lymph nodes, spleen, and bone marrow. Overall, the CM model consistently manifested pathological responses similar to those resulting from inhalation of F. tularensis in humans and thereby most closely emulates human tularemia disease. The RM model displayed a higher tolerance to infection and survived exposures of up to 15,593 CFU of aerosolized F. tularensis.

  8. Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

    Science.gov (United States)

    Ljungberg, Karl; Kümmerer, Beate M.; Gosse, Leslie; Dereuddre-Bosquet, Nathalie; Tchitchek, Nicolas; Hallengärd, David; García-Arriaza, Juan; Meinke, Andreas; Esteban, Mariano; Merits, Andres

    2017-01-01

    Chikungunya virus (CHIKV) is rapidly spreading across the globe, and millions are infected. Morbidity due to this virus is a serious threat to public health, but at present, there is no vaccine against this debilitating disease. We have recently developed a number of vaccine candidates, and here we have evaluated 3 of them in a nonhuman primate model. A single immunization with an attenuated strain of CHIKV (Δ5nsP3), a homologous prime-boost immunization with a DNA-launched RNA replicon encoding CHIKV envelope proteins (DREP-E), and a DREP-E prime followed by a recombinant modified vaccinia virus Ankara encoding CHIKV capsid and envelope (MVA-CE) boost all induced protection against WT CHIKV infection. The attenuated Δ5nsP3 virus proved to be safe and did not show any clinical signs typically associated with WT CHIKV infections such as fever, skin rash, lymphopenia, or joint swelling. These vaccines are based on an East/Central/South African strain of Indian Ocean lineage, but they also generated neutralizing antibodies against an isolate of the Asian genotype that now is rapidly spreading across the Americas. These results form the basis for clinical development of an efficacious CHIKV vaccine that generates both humoral and cellular immunity with long-term immunological memory. PMID:28352649

  9. African Non-Human Primates Host Diverse Enteroviruses

    Science.gov (United States)

    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

  10. Foodborne transmission of bovine spongiform encephalopathy to nonhuman primates.

    Science.gov (United States)

    Holznagel, Edgar; Yutzy, Barbara; Schulz-Schaeffer, Walter; Kruip, Carina; Hahmann, Uwe; Bierke, Pär; Torres, Juan-Maria; Kim, Yong-Sun; Thomzig, Achim; Beekes, Michael; Hunsmann, Gerhard; Loewer, Johannes

    2013-05-01

    Risk for human exposure to bovine spongiform encephalopathy (BSE)-inducing agent was estimated in a nonhuman primate model. To determine attack rates, incubation times, and molecular signatures, we orally exposed 18 macaques to 1 high dose of brain material from cattle with BSE. Several macaques were euthanized at regular intervals starting at 1 year postinoculation, and others were observed until clinical signs developed. Among those who received ≥5 g BSE-inducing agent, attack rates were 100% and prions could be detected in peripheral tissues from 1 year postinoculation onward. The overall median incubation time was 4.6 years (3.7-5.3). However, for 3 macaques orally exposed on multiple occasions, incubation periods were at least 7-10 years. Before clinical signs were noted, we detected a non-type 2B signature, indicating the existence of atypical prion protein during the incubation period. This finding could affect diagnosis of variant Creutzfeldt-Jakob disease in humans and might be relevant for retrospective studies of positive tonsillectomy or appendectomy specimens because time of infection is unknown.

  11. Identification of skin immune cells in non-human primates.

    Science.gov (United States)

    Adam, Lucille; Rosenbaum, Pierre; Cosma, Antonio; Le Grand, Roger; Martinon, Frédéric

    2015-11-01

    The skin is a valuable target for vaccine delivery because it contains many immune cell populations, notably antigen presenting cells. Skin immune cells have been extensively described in mice and humans but not in non-human primates, which are pertinent models for immunological research in vaccination. The aim of this work was to describe immune cell populations in the epidermis, dermis and skin draining lymph nodes in cynomolgus macaques by a single 12-parameter flow cytometry protocol. Given that skin cells share several markers, we defined a gating strategy to identify accurately immune cells and to limit contamination of one immune cell population by another. The epidermis contained CD1a(+)CD1c(-) Langerhans cells (LCs), CD3(+) T cells and putative NK cells. The dermis contained CD1a(+)CD1c(-) cells, which were similar to LCs, CD1a(+)CD1c(+) dermal dendritic cells (DDCs), CD163(high)CD11b(+) resident macrophages, CD3(+) T cells and putative NK cells. The skin also contained CD66(+) polymorphonuclear cells in some animals. Thus, immune cell populations in the macaque are similar to those in humans despite some differences in phenotype. In skin draining lymph nodes, we identified migratory LCs, CD1a(+)CD1c(+) DDCs and macrophages. The simultaneous identification of these different immune cells with one panel of markers avoids the use of large amounts of precious sample and may improve the understanding of immune mechanisms in the skin after treatment or vaccination.

  12. Optogenetics through windows on the brain in the nonhuman primate.

    Science.gov (United States)

    Ruiz, Octavio; Lustig, Brian R; Nassi, Jonathan J; Cetin, Ali; Reynolds, John H; Albright, Thomas D; Callaway, Edward M; Stoner, Gene R; Roe, Anna W

    2013-09-01

    Optogenetics combines optics and genetics to control neuronal activity with cell-type specificity and millisecond temporal precision. Its use in model organisms such as rodents, Drosophila, and Caenorhabditis elegans is now well-established. However, application of this technology in nonhuman primates (NHPs) has been slow to develop. One key challenge has been the delivery of viruses and light to the brain through the thick dura mater of NHPs, which can only be penetrated with large-diameter devices that damage the brain. The opacity of the NHP dura prevents visualization of the underlying cortex, limiting the spatial precision of virus injections, electrophysiological recordings, and photostimulation. Here, we describe a new optogenetics approach in which the native dura is replaced with an optically transparent artificial dura. This artificial dura can be penetrated with fine glass micropipettes, enabling precisely targeted injections of virus into brain tissue with minimal damage to cortex. The expression of optogenetic agents can be monitored visually over time. Most critically, this optical window permits targeted, noninvasive photostimulation and concomitant measurements of neuronal activity via intrinsic signal imaging and electrophysiological recordings. We present results from both anesthetized-paralyzed (optical imaging) and awake-behaving NHPs (electrophysiology). The improvements over current methods made possible by the artificial dura should enable the widespread use of optogenetic tools in NHP research, a key step toward the development of therapies for neuropsychiatric and neurological diseases in humans.

  13. Experimental gastric carcinogenesis in Cebus apella nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Joana de Fátima Ferreira Borges da Costa

    Full Text Available The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU. Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9(th day though on the 14(th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940(th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the

  14. A novel nonhuman primate model for influenza transmission.

    Directory of Open Access Journals (Sweden)

    Louise H Moncla

    Full Text Available Studies of influenza transmission are necessary to predict the pandemic potential of emerging influenza viruses. Currently, both ferrets and guinea pigs are used in such studies, but these species are distantly related to humans. Nonhuman primates (NHP share a close phylogenetic relationship with humans and may provide an enhanced means to model the virological and immunological events in influenza virus transmission. Here, for the first time, it was demonstrated that a human influenza virus isolate can productively infect and be transmitted between common marmosets (Callithrix jacchus, a New World monkey species. We inoculated four marmosets with the 2009 pandemic virus A/California/07/2009 (H1N1pdm and housed each together with a naïve cage mate. We collected bronchoalveolar lavage and nasal wash samples from all animals at regular intervals for three weeks post-inoculation to track virus replication and sequence evolution. The unadapted 2009 H1N1pdm virus replicated to high titers in all four index animals by 1 day post-infection. Infected animals seroconverted and presented human-like symptoms including sneezing, nasal discharge, labored breathing, and lung damage. Transmission occurred in one cohabitating pair. Deep sequencing detected relatively few genetic changes in H1N1pdm viruses replicating in any infected animal. Together our data suggest that human H1N1pdm viruses require little adaptation to replicate and cause disease in marmosets, and that these viruses can be transmitted between animals. Marmosets may therefore be a viable model for studying influenza virus transmission.

  15. Experimental Gastric Carcinogenesis in Cebus apella Nonhuman Primates

    Science.gov (United States)

    Silva, Tanielly Cristina Raiol; Andrade Junior, Edilson Ferreira; Rezende, Alexandre Pingarilho; Carneiro Muniz, José Augusto Pereira; Lacreta Junior, Antonio Carlos Cunha; Assumpção, Paulo Pimentel; Calcagno, Danielle Queiroz; Demachki, Samia; Rabenhorst, Silvia Helena Barem; Smith, Marília de Arruda Cardoso; Burbano, Rommel Rodriguez

    2011-01-01

    The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU). Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9th day though on the 14th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the tolerability and

  16. Resveratrol Metabolism in a Non-Human Primate, the Grey Mouse Lemur (Microcebus murinus), Using Ultra-High-Performance Liquid Chromatography–Quadrupole Time of Flight

    OpenAIRE

    Marie-Claude Menet; Julia Marchal; Alexandre Dal-Pan; Méryam Taghi; Valérie Nivet-Antoine; Delphine Dargère; Olivier Laprévote; Jean-Louis Beaudeux; Fabienne Aujard; Jacques Epelbaum; Charles-Henry Cottart

    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), c...

  17. Translational In Vivo Models for Women's Health: The Nonhuman Primate Endometrium--A Predictive Model for Assessing Steroid Receptor Modulators.

    Science.gov (United States)

    Slayden, Ov Daniel

    2016-01-01

    Macaques and baboons display physiological responses to steroid hormones that are similar to those of women. Herein, we describe various uses of nonhuman primates for preclinical studies on menstruation, endometriosis, and as a model system to evaluate reproductive therapies and contraceptives. Our goal is to outline the strengths of the nonhuman primate model for studies leading to improved therapies for women.

  18. An Evaluation of Twenty Years of EU Framework Programme-funded Immune-mediated Inflammatory Translational Research in Non-human Primates

    Directory of Open Access Journals (Sweden)

    Krista Geraldine Haanstra

    2016-11-01

    Full Text Available Ageing 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 primate can help to bridge the gap between drug discovery and drug prescription.Translational research covers various stages of drug development of which pre-clinical efficacy tests in valid animal models is usually the last stage. Pre-clinical 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 (EC 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. The data illustrate value of translational non-human primate research for the development of new therapies and emphasize the importance of EU FP funding

  19. Trypanosomes of non-human primates from the National Centre of Primates, Ananindeua, State of Pará, Brazil

    Directory of Open Access Journals (Sweden)

    Ziccardi Mariangela

    2000-01-01

    Full Text Available Trypanosome infections were sought in 46 non-human primates captured principally in Amazonian Brazil. Twenty-two (47.8% were infected with four Trypanosoma species: T. cruzi, T. minasense, T. devei and T. rangeli. These preliminary results confirmed the high prevalence and diversity of natural infections with trypanosomes in primates from Brazilian Amazon and were the first formal record of simian infections with trypanosomes in the State of Acre. The presence of T. cruzi-like and T. rangeli-like parasites are recorded in four new hosts.

  20. The value of non-human primates in the development of therapeutic monoclonal antibodies

    NARCIS (Netherlands)

    Van Meer, P.J.K.; Kooijman, M.; Van Der Laan, J.W.; Moors, E.H.M.; Schellekens, H.

    2011-01-01

    The pharmaceutical industry is increasingly focusing on the development of biological therapeutics. These molecules generally cause no off-target toxicity and are highly species specific. Therefore, non-human primates (NHPs) are often the only relevant species in which to conduct regulatory safety t

  1. Basic neuroscience research with nonhuman primates : a small but indispensable component of biomedical research

    NARCIS (Netherlands)

    Roelfsema, Pieter R; Treue, Stefan

    2014-01-01

    Research with nonhuman primates represents a small component of neuroscience with far-reaching relevance that is irreplaceable for essential insights into cognitive functions, brain disease, and therapy. Transparency and widespread information about this research and its importance is central to ens

  2. Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques

    DEFF Research Database (Denmark)

    Yan, Guangmei; Zhang, Guojie; Fang, Xiaodong;

    2011-01-01

    The nonhuman primates most commonly used in medical research are from the genus Macaca. To better understand the genetic differences between these animal models, we present high-quality draft genome sequences from two macaque species, the cynomolgus/crab-eating macaque and the Chinese rhesus...

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

    Science.gov (United States)

    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…

  4. A review of lateralization of spatial functioning in nonhuman primates

    NARCIS (Netherlands)

    Oleksiak, Anna; Postma, Albert; van der Ham, Ineke J. M.; Klink, P. Christiaan; van Wezel, Richard J. A.

    2011-01-01

    The majority of research on functional cerebral lateralization in primates revolves around vocal abilities, addressing the evolutionary origin of the human language faculty and its predominance in the left hemisphere of the brain. Right hemisphere specialization in spatial cognition is commonly repo

  5. A review of lateralization of spatial functioning in nonhuman primates

    NARCIS (Netherlands)

    Oleksiak, Anna; Postma, Albert; Ham, van der Ineke J.M.; Klink, P. Christiaan; Wezel, van Richard J.A.

    2010-01-01

    The majority of research on functional cerebral lateralization in primates revolves around vocal abilities, addressing the evolutionary origin of the human language faculty and its predominance in the left hemisphere of the brain. Right hemisphere specialization in spatial cognition is commonly repo

  6. A review of lateralization of spatial functioning in nonhuman primates.

    NARCIS (Netherlands)

    Oleksiak, A.; Postma, A.; Ham, I.J. van der; Klink, P.C.; Wezel, R.J.A. van

    2011-01-01

    The majority of research on functional cerebral lateralization in primates revolves around vocal abilities, addressing the evolutionary origin of the human language faculty and its predominance in the left hemisphere of the brain. Right hemisphere specialization in spatial cognition is commonly repo

  7. The evolution of female social relationships in nonhuman primates

    NARCIS (Netherlands)

    Sterck, E.H.M.; Watts, David P.; Schaik, C.P. van

    2002-01-01

    Considerable interspecifc variation in female social relationships occurs in gregarious primates, par- ticularly with regard to agonism and cooperation be- tween females and to the quality of female relationships with males. This variation exists alongside variation in female philopatry and dispersa

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

    Science.gov (United States)

    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.

  9. Enhancing nonhuman primate care and welfare through the use of positive reinforcement training.

    Science.gov (United States)

    Laule, Gail; Whittaker, Margaret

    2007-01-01

    Nonhuman primates are excellent subjects for the enhancement of care and welfare through training. The broad range of species offers tremendous behavioral diversity, and individual primates show varying abilities to cope with the stressors of captivity, which differ depending on the venue. Biomedical facilities include small single cages, pair housing, and breeding corrals with large social groups. Zoos have social groupings of differing sizes, emphasizing public display and breeding. Sanctuaries have nonbreeding groups of varying sizes and often of mixed species. In every venue, the primary objective is to provide good quality care, with minimal stress. Positive reinforcement training improves care and reduces stress by enlisting a primate's voluntary cooperation with targeted activities, including both husbandry and medical procedures. It can also improve socialization, reduce abnormal behaviors, and increase species-typical behaviors. This article reviews the results already achieved with positive reinforcement training and suggests further possibilities for enhancing primate care and welfare.

  10. Curing color blindness--mice and nonhuman primates.

    Science.gov (United States)

    Neitz, Maureen; Neitz, Jay

    2014-08-21

    It has been possible to use viral-mediated gene therapy to transform dichromatic (red-green color-blind) primates to trichromatic. Even though the third cone type was added after the end of developmental critical periods, treated animals acquired red-green color vision. What happened in the treated animals may represent a recapitulation of the evolution of trichromacy, which seems to have evolved with the acquisition of a third cone type without the need for subsequent modification to the circuitry. Some transgenic mice in which a third cone type was added also acquired trichromacy. However, compared with treated primates, red-green color vision in mice is poor, indicating large differences between mice and monkeys in their ability to take advantage of the new input. These results have implications for understanding the limits and opportunities for using gene therapy to treat vision disorders caused by defects in cone function.

  11. Learning of spatial statistics in nonhuman primates: contextual cueing in baboons (Papio papio).

    Science.gov (United States)

    Goujon, Annabelle; Fagot, Joel

    2013-06-15

    A growing number of theories of cognition suggest that many of our behaviors result from the ability to implicitly extract and use statistical redundancies present in complex environments. In an attempt to develop an animal model of statistical learning mechanisms in humans, the current study investigated spatial contextual cueing (CC) in nonhuman primates. Twenty-five baboons (Papio papio) were trained to search for a target (T) embedded within configurations of distrators (L) that were either predictive or non-predictive of the target location. Baboons exhibited an early CC effect, which remained intact after a 6-week delay and stable across extensive training of 20,000 trials. These results demonstrate the baboons' ability to learn spatial contingencies, as well as the robustness of CC as a cognitive phenomenon across species. Nevertheless, in both the youngest and oldest baboons, CC required many more trials to emerge than in baboons of intermediate age. As a whole, these results reveal strong similarities between CC in humans and baboons, suggesting similar statistical learning mechanisms in these two species. Therefore, baboons provide a valid model to investigate how statistical learning mechanisms develop and/or age during the life span, as well as how these mechanisms are implemented in neural networks, and how they have evolved throughout the phylogeny.

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

    Directory of Open Access Journals (Sweden)

    Xiao-Feng Li

    2016-10-01

    Full Text Available 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 10 days 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.

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

    Science.gov (United States)

    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.

  14. Evolution of Multilevel Social Systems in Nonhuman Primates and Humans.

    Science.gov (United States)

    Grueter, Cyril C; Chapais, Bernard; Zinner, Dietmar

    2012-10-01

    Multilevel (or modular) societies are a distinct type of primate social system whose key features are single-male-multifemale, core units nested within larger social bands. They are not equivalent to fission-fusion societies, with the latter referring to routine variability in associations, either on an individual or subunit level. The purpose of this review is to characterize and operationalize multilevel societies and to outline their putative evolutionary origins. Multilevel societies are prevalent in three primate clades: papionins, Asian colobines, and hominins. For each clade, we portray the most parsimonious phylogenetic pathway leading to a modular system and then review and discuss likely socioecological conditions promoting the establishment and maintenance of these societies. The multilevel system in colobines (most notably Rhinopithecus and Nasalis) has likely evolved as single-male harem systems coalesced, whereas the multilevel system of papionins (Papio hamadryas, Theropithecus gelada) and hominins most likely arose as multimale-multifemale groups split into smaller units. We hypothesize that, although ecological conditions acted as preconditions for the origin of multilevel systems in all three clades, a potentially important catalyst was intraspecific social threat, predominantly bachelor threat in colobines and female coercion/infanticide in papionins and humans. We emphasize that female transfers within bands or genetic relationships among leader males help to maintain modular societies by facilitating interunit tolerance. We still lack a good or even basic understanding of many facets of multilevel sociality. Key remaining questions are how the genetic structure of a multilevel society matches the observed social effort of its members, to what degree cooperation of males of different units is manifest and contributes to band cohesion, and how group coordination, communication, and decision making are achieved. Affiliative and cooperative

  15. Cocaine is pharmacologically active in the nonhuman primate fetal brain

    DEFF Research Database (Denmark)

    Benveniste, Helene; Fowler, Joanna S; Rooney, William D;

    2010-01-01

    Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third...... are influenced by the state of pregnancy. Our findings have clinical implications because they imply that the adverse effects of prenatal cocaine exposure to the newborn child include not only cocaine's deleterious effects to the placental circulation, but also cocaine's direct pharmacological effect...

  16. Marburg virus infection in nonhuman primates: Therapeutic treatment by lipid-encapsulated siRNA.

    Science.gov (United States)

    Thi, Emily P; Mire, Chad E; Ursic-Bedoya, Raul; Geisbert, Joan B; Lee, Amy C H; Agans, Krystle N; Robbins, Marjorie; Deer, Daniel J; Fenton, Karla A; MacLachlan, Ian; Geisbert, Thomas W

    2014-08-20

    Marburg virus (MARV) and the closely related filovirus Ebola virus cause severe and often fatal hemorrhagic fever (HF) in humans and nonhuman primates with mortality rates up to 90%. There are no vaccines or drugs approved for human use, and no postexposure treatment has completely protected nonhuman primates against MARV-Angola, the strain associated with the highest rate of mortality in naturally occurring human outbreaks. Studies performed with other MARV strains assessed candidate treatments at times shortly after virus exposure, before signs of disease are detectable. We assessed the efficacy of lipid nanoparticle (LNP) delivery of anti-MARV nucleoprotein (NP)-targeting small interfering RNA (siRNA) at several time points after virus exposure, including after the onset of detectable disease in a uniformly lethal nonhuman primate model of MARV-Angola HF. Twenty-one rhesus monkeys were challenged with a lethal dose of MARV-Angola. Sixteen of these animals were treated with LNP containing anti-MARV NP siRNA beginning at 30 to 45 min, 1 day, 2 days, or 3 days after virus challenge. All 16 macaques that received LNP-encapsulated anti-MARV NP siRNA survived infection, whereas the untreated or mock-treated control subjects succumbed to disease between days 7 and 9 after infection. These results represent the successful demonstration of therapeutic anti-MARV-Angola efficacy in nonhuman primates and highlight the substantial impact of an LNP-delivered siRNA therapeutic as a countermeasure against this highly lethal human disease.

  17. Progress and Prospects for Genetic Modification of Nonhuman Primate Models in Biomedical Research

    OpenAIRE

    Chan, Anthony W. S.

    2013-01-01

    The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and...

  18. Recent studies of iron deficiency during brain development in nonhuman primates

    OpenAIRE

    Golub, Mari S.

    2010-01-01

    Recent studies of the effects of developmental iron deficiency and iron deficiency anemia in nonhuman primates have provided new insights into this widespread and well-recognized human nutritional deficiency. The rhesus monkey was the animal model in these experiments which used extensive hematological and behavioral evaluations in addition to noninvasive brain measures. Two important findings were (1) different behavioral consequences depending on the timing of iron deficiency relative to br...

  19. Frequent Simian Foamy Virus Infection in Persons Occupationally Exposed to Nonhuman Primates

    OpenAIRE

    SWITZER, WILLIAM M.; Bhullar, Vinod; Shanmugam, Vedapuri; Cong, Mian-er; Parekh, Bharat; Lerche, Nicholas W; Yee, JoAnn L.; Ely, John J.; Boneva, Roumiana; Chapman, Louisa E.; Folks, Thomas M.; Heneine, Walid

    2004-01-01

    The recognition that AIDS originated as a zoonosis heightens public health concerns associated with human infection by simian retroviruses endemic in nonhuman primates (NHPs). These retroviruses include simian immunodeficiency virus (SIV), simian T-cell lymphotropic virus (STLV), simian type D retrovirus (SRV), and simian foamy virus (SFV). Although occasional infection with SIV, SRV, or SFV in persons occupationally exposed to NHPs has been reported, the characteristics and significance of t...

  20. Lessons in Nonhuman Primate Models for AIDS Vaccine Research: From Minefields to Milestones

    OpenAIRE

    Jeffrey D Lifson; Nancy L Haigwood

    2012-01-01

    Nonhuman primate (NHP) disease models for AIDS have made important contributions to the search for effective vaccines for AIDS. Viral diversity, persistence, capacity for immune evasion, and safety considerations have limited development of conventional approaches using killed or attenuated vaccines, necessitating the development of novel approaches. Here we highlight the knowledge gained and lessons learned in testing vaccine concepts in different virus/NHP host combinations.

  1. Autologous Transplantation of Lentivector/Acid Ceramidase–Transduced Hematopoietic Cells in Nonhuman Primates

    OpenAIRE

    Walia, Jagdeep S; Neschadim, Anton; Lopez-Perez, Orlay; Alayoubi, Abdulfatah; Fan, Xin; Carpentier, Stéphane; Madden, Melissa; Lee, Chyan-Jang; Cheung, Fred; Jaffray, David A.; Levade, Thierry; McCart, J. Andrea; Medin, Jeffrey A

    2011-01-01

    Farber disease is a rare lysosomal storage disorder (LSD) that manifests due to acid ceramidase (AC) deficiencies and ceramide accumulation. We present a preclinical gene therapy study for Farber disease employing a lentiviral vector (LV-huAC/huCD25) in three enzymatically normal nonhuman primates. Autologous, mobilized peripheral blood (PB) cells were transduced and infused into fully myelo-ablated recipients with tracking for at least 1 year. Outcomes were assessed by measuring the AC speci...

  2. From sweeping to the caress: similarities and discrepancies between human and non-human primates' pleasant touch

    Directory of Open Access Journals (Sweden)

    Laura Clara Grandi

    2016-09-01

    Full Text Available 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. Lymphoid neogenesis in skin of human hand, nonhuman primate, and rat vascularized composite allografts.

    Science.gov (United States)

    Hautz, Theresa; Zelger, Bettina G; Nasr, Isam W; Mundinger, Gerhard S; Barth, Rolf N; Rodriguez, Eduardo D; Brandacher, Gerald; Weissenbacher, Annemarie; Zelger, Bernhard; Cavadas, Pedro; Margreiter, Raimund; Lee, W P Andrew; Pratschke, Johann; Lakkis, Fadi G; Schneeberger, Stefan

    2014-09-01

    The mechanisms of skin rejection in vascularized composite allotransplantation (VCA) remain incompletely understood. The formation of tertiary lymphoid organs (TLO) in hand transplantation has been recently described. We assess this phenomenon in experimental and clinical VCA rejection. Skin biopsies of human (n = 187), nonhuman primate (n = 11), and rat (n = 15) VCAs were analyzed for presence of TLO. A comprehensive immunohistochemical assessment (characterization of the cell infiltrate, expression of adhesion molecules) including staining for peripheral node addressin (PNAd) was performed and correlated with rejection and time post-transplantation. TLO were identified in human, nonhuman primate, and rat skin samples. Expression of PNAd was increased in the endothelium of vessels upon rejection in human skin (P = 0.003) and correlated with B- and T-lymphocyte numbers and LFA-1 expression. PNAd expression was observed at all time-points after transplantation and increased significantly after year 5. In nonhuman primate skin, PNAd expression was found during inflammatory conditions early and late after transplantation. In rat skin, PNAd expression was strongly associated with acute rejection and time post-transplantation. Lymphoid neogenesis and TLO formation can be uniformly found in experimental and human VCA. PNAd expression in vascular endothelium correlates with skin rejection and T- and B-cell infiltration.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

  6. Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

    Science.gov (United States)

    Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

    2016-01-01

    The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

  7. Heterogeneity of life histories in a nonhuman primate population

    DEFF Research Database (Denmark)

    Hernández Pacheco, Raisa; Steiner, Uli

    2014-01-01

    Identifying the sources of variation in life histories, whether fixed (heritable) and/or dynamic differences, remains a fundamental task to address in order to understand the meaning and significance of phenotypic variation within populations. To test whether the variation among individual life...... histories within a primate population is generated by density-dependent dynamics, the demographic data of Cayo Santiago rhesus macaques over 40 years and 7000 individuals was used. A multi-stage model using a first-order Markov process describing reproductive dynamics was constructed and annual entropy...... estimated. Entropy was moderately high (0.71), ranging from 0.59 to 0.88. Variation in annual entropy does not relate to variation in survival nor directly relates to density-dependent effects. However, variation in entropy was related to transition probabilities among non-breeders. This multistage model...

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

    Directory of Open Access Journals (Sweden)

    Katherine A Leighty

    Full Text Available 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.

  9. Human and non-human primate genomes share hotspots of positive selection.

    Directory of Open Access Journals (Sweden)

    David Enard

    2010-02-01

    Full Text Available 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.

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

    Directory of Open Access Journals (Sweden)

    Damiana F Ravasi

    Full Text Available 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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  13. Caring for nonhuman primates in biomedical research facilities: scientific, moral and emotional considerations.

    Science.gov (United States)

    Coleman, Kristine

    2011-03-01

    Animal care for nonhuman primates (NHPs) in biomedical facilities has undergone major changes in the past few decades. Today, most primate facilities have dedicated and highly trained animal care technicians who go to great efforts to ensure the physiological and psychological well being of the primates in their charge. These caretakers work closely with the animals and, as a result, often develop strong relationships with them. Once discouraged and considered a potential threat to scientific objectivity, such positive relationships are now seen as important components to animal care. Positive interactions between caretakers and primates can benefit the primates by reducing their stress and improving their overall well being which can, in turn, help the scientific endeavor. Further, providing the best possible care is our moral responsibility. However, there can also be emotional costs associated with caring for NHPs in research facilities, particularly when animals become ill or have to be euthanized. Facilities can do much to help ease this conflict. High-quality and conscientious animal care is good for the animals, science, and public perception of research facilities.

  14. Olfactory responsiveness to two odorous steroids in three species of nonhuman primates.

    Science.gov (United States)

    Laska, Matthias; Wieser, Alexandra; Hernandez Salazar, Laura Teresa

    2005-07-01

    Social communication by means of odor signals is widespread among mammals. In pigs, for example, the C19-steroids 5-alpha-androst-16-en-3-one and 5-alpha-androst-16-en-3-ol are secreted by the boar and induce the mating stance in the sow. In humans, the same substances have been shown to be compounds of body odor and are presumed to affect human behavior. Using an instrumental conditioning paradigm, we here show that squirrel monkeys, spider monkeys and pigtail macaques are able to detect androstenone at concentrations in the micromolar range and thus at concentrations at least as low as those reported in pigs and humans. All three species of nonhuman primates were considerably less sensitive to androstenol, which was detected at concentrations in the millimolar range. Additional tests, using a habituation-dishabituation paradigm, showed that none of the 10 animals tested per species was anosmic to the two odorous steroids. These results suggest that androstenone and androstenol may be involved in olfactory communication in the primate species tested and that the specific anosmia to these odorants found in approximately 30% of human subjects may be due to their reduced number of functional olfactory receptor genes compared with nonhuman primates.

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

    Science.gov (United States)

    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.

  16. Leveraging human genomic information to identify nonhuman primate sequences for expression array development

    Directory of Open Access Journals (Sweden)

    Boyle Nicholas F

    2005-11-01

    Full Text Available Abstract Background Nonhuman primates (NHPs are essential for biomedical research due to their similarities to humans. The utility of NHPs will be greatly increased by the application of genomics-based approaches such as gene expression profiling. Sequence information from the 3' end of genes is the key resource needed to create oligonucleotide expression arrays. Results We have developed the algorithms and procedures necessary to quickly acquire sequence information from the 3' end of nonhuman primate orthologs of human genes. To accomplish this, we identified terminal exons of over 15,000 human genes by aligning mRNA sequences with genomic sequence. We found the mean length of complete last exons to be approximately 1,400 bp, significantly longer than previous estimates. We designed primers to amplify genomic DNA, which included at least 300 bp of the terminal exon. We cloned and sequenced the PCR products representing over 5,500 Macaca mulatta (rhesus monkey orthologs of human genes. This sequence information has been used to select probes for rhesus gene expression profiling. We have also tested 10 sets of primers with genomic DNA from Macaca fascicularis (Cynomolgus monkey, Papio hamadryas (Baboon, and Chlorocebus aethiops (African green monkey, vervet. The results indicate that the primers developed for this study will be useful for acquiring sequence from the 3' end of genes for other nonhuman primate species. Conclusion This study demonstrates that human genomic DNA sequence can be leveraged to obtain sequence from the 3' end of NHP orthologs and that this sequence can then be used to generate NHP oligonucleotide microarrays. Affymetrix and Agilent used sequences obtained with this approach in the design of their rhesus macaque oligonucleotide microarrays.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  19. Recent studies of iron deficiency during brain development in nonhuman primates.

    Science.gov (United States)

    Golub, Mari S

    2010-01-01

    Recent studies of the effects of developmental iron deficiency (ID) and iron deficiency anemia in nonhuman primates have provided new insights into this widespread and well-recognized human nutritional deficiency. The rhesus monkey was the animal model in these experiments, which used extensive hematological and behavioral evaluations in addition to noninvasive brain measures. Two important findings were as follows: 1) different behavioral consequences depending on the timing of ID relative to brain developmental stages and 2) the potential for long-lasting changes in brain iron regulatory systems. Further work in this model, including integration with studies in humans and in laboratory rodents, is ongoing.

  20. A Critical Role for CD8 T Cells in a Nonhuman Primate Model of Tuberculosis

    OpenAIRE

    2009-01-01

    The role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell–mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytoto...

  1. Stereotaxic Surgical Targeting of the Nonhuman Primate Caudate and Putamen: Gene Therapy for Huntington's Disease.

    Science.gov (United States)

    McBride, Jodi L; Clark, Randall L

    2016-01-01

    Stereotaxic surgery is an invaluable tool to deliver a variety of gene therapy constructs to the nonhuman primate caudate and putamen in preclinical studies for the genetic, neurodegenerative disorder, Huntington's disease (HD). Here we describe in detail how to perform this technique beginning with a pre-surgical magnetic resonance imaging scan to determine surgical coordinates followed by the stereotaxic surgical injection technique. In addition, we include methodology of a full necropsy including brain and peripheral tissue removal and a standard immunohistochemical technique to visualize the injected gene therapy agent.

  2. Recombinant vesicular stomatitis virus vector mediates postexposure protection against Sudan Ebola hemorrhagic fever in nonhuman primates.

    Science.gov (United States)

    Geisbert, Thomas W; Daddario-DiCaprio, Kathleen M; Williams, Kinola J N; Geisbert, Joan B; Leung, Anders; Feldmann, Friederike; Hensley, Lisa E; Feldmann, Heinz; Jones, Steven M

    2008-06-01

    Recombinant vesicular stomatitis virus (VSV) vectors expressing homologous filoviral glycoproteins can completely protect rhesus monkeys against Marburg virus when administered after exposure and can partially protect macaques after challenge with Zaire ebolavirus. Here, we administered a VSV vector expressing the Sudan ebolavirus (SEBOV) glycoprotein to four rhesus macaques shortly after exposure to SEBOV. All four animals survived SEBOV challenge, while a control animal that received a nonspecific vector developed fulminant SEBOV hemorrhagic fever and succumbed. This is the first demonstration of complete postexposure protection against an Ebola virus in nonhuman primates and provides further evidence that postexposure vaccination may have utility in treating exposures to filoviruses.

  3. Oral and Conjunctival Exposure of Nonhuman Primates to Low Doses of Ebola Makona Virus

    Science.gov (United States)

    Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Deer, Daniel J.; Fenton, Karla A.; Geisbert, Thomas W.

    2016-01-01

    Nonhuman primate (NHP) models of Ebola virus (EBOV) infection primarily use parenteral or aerosol routes of exposure. Uniform lethality can be achieved in these models at low doses of EBOV (≤100 plaque-forming units [PFU]). Here, we exposed NHPs to low doses of EBOV (Makona strain) by the oral or conjunctival routes. Surprisingly, animals exposed to 10 PFU by either route showed no signs of disease. Exposure to 100 PFU resulted in illness and/or lethal infection. These results suggest that these more natural routes require higher doses of EBOV to produce disease or that there may be differences between Makona and historical strains. PMID:27284090

  4. Absence of frequent herpesvirus transmission in a nonhuman primate predator-prey system in the wild.

    Science.gov (United States)

    Murthy, Sripriya; Couacy-Hymann, Emmanuel; Metzger, Sonja; Nowak, Kathrin; De Nys, Helene; Boesch, Christophe; Wittig, Roman; Jarvis, Michael A; Leendertz, Fabian H; Ehlers, Bernhard

    2013-10-01

    Emergence of viruses into the human population by transmission from nonhuman primates (NHPs) represents a serious potential threat to human health that is primarily associated with the increased bushmeat trade. Transmission of RNA viruses across primate species appears to be relatively frequent. In contrast, DNA viruses appear to be largely host specific, suggesting low transmission potential. Herein, we use a primate predator-prey system to study the risk of herpesvirus transmission between different primate species in the wild. The system was comprised of western chimpanzees (Pan troglodytes verus) and their primary (western red colobus, Piliocolobus badius badius) and secondary (black-and-white colobus, Colobus polykomos) prey monkey species. NHP species were frequently observed to be coinfected with multiple beta- and gammaherpesviruses (including new cytomegalo- and rhadinoviruses). However, despite frequent exposure of chimpanzees to blood, organs, and bones of their herpesvirus-infected monkey prey, there was no evidence for cross-species herpesvirus transmission. These findings suggest that interspecies transmission of NHP beta- and gammaherpesviruses is, at most, a rare event in the wild.

  5. Search for CEA-like molecules in polymorphonuclear leukocytes of non-human primates using monoclonal antibodies.

    Science.gov (United States)

    Jantscheff, P; Indzhiia, L V; Micheel, B

    1986-01-01

    The monoclonal anti-CEA antibody ZIK-A42-A/C1 which reacts with NCA of human polymorphonuclear leukocytes was found to bind also to polymorphonuclear blood leukocytes of the following non-human primates tested: hamadryas baboon (Papio hamadryas), stump-tailed monkey (Macaca arctoides), pig-tailed monkey (Macaca nemestrina), and rhesus monkey (Macaca mulata). No binding was observed to mononuclear blood leukocytes. It was concluded that non-human primates contain CEA-like substances in their polymorphonuclear leukocytes as humans do and that these substances carry some identical epitopes.

  6. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates.

    Science.gov (United States)

    Blin, Guillaume; Nury, David; Stefanovic, Sonia; Neri, Tui; Guillevic, Oriane; Brinon, Benjamin; Bellamy, Valérie; Rücker-Martin, Catherine; Barbry, Pascal; Bel, Alain; Bruneval, Patrick; Cowan, Chad; Pouly, Julia; Mitalipov, Shoukhrat; Gouadon, Elodie; Binder, Patrice; Hagège, Albert; Desnos, Michel; Renaud, Jean-François; Menasché, Philippe; Pucéat, Michel

    2010-04-01

    Cell therapy holds promise for tissue regeneration, including in individuals with advanced heart failure. However, treatment of heart disease with bone marrow cells and skeletal muscle progenitors has had only marginal positive benefits in clinical trials, perhaps because adult stem cells have limited plasticity. The identification, among human pluripotent stem cells, of early cardiovascular cell progenitors required for the development of the first cardiac lineage would shed light on human cardiogenesis and might pave the way for cell therapy for cardiac degenerative diseases. Here, we report the isolation of an early population of cardiovascular progenitors, characterized by expression of OCT4, stage-specific embryonic antigen 1 (SSEA-1), and mesoderm posterior 1 (MESP1), derived from human pluripotent stem cells treated with the cardiogenic morphogen BMP2. This progenitor population was multipotential and able to generate cardiomyocytes as well as smooth muscle and endothelial cells. When transplanted into the infarcted myocardium of immunosuppressed nonhuman primates, an SSEA-1+ progenitor population derived from Rhesus embryonic stem cells differentiated into ventricular myocytes and reconstituted 20% of the scar tissue. Notably, primates transplanted with an unpurified population of cardiac-committed cells, which included SSEA-1- cells, developed teratomas in the scar tissue, whereas those transplanted with purified SSEA-1+ cells did not. We therefore believe that the SSEA-1+ progenitors that we have described here have the potential to be used in cardiac regenerative medicine.

  7. Durability of a vesicular stomatitis virus-based marburg virus vaccine in nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Chad E Mire

    Full Text Available The filoviruses, Marburg virus (MARV and Ebola virus, causes severe hemorrhagic fever with high mortality in humans and nonhuman primates. A promising filovirus vaccine under development is based on a recombinant vesicular stomatitis virus (rVSV that expresses individual filovirus glycoproteins (GPs in place of the VSV glycoprotein (G. These vaccines have shown 100% efficacy against filovirus infection in nonhuman primates when challenge occurs 28-35 days after a single injection immunization. Here, we examined the ability of a rVSV MARV-GP vaccine to provide protection when challenge occurs more than a year after vaccination. Cynomolgus macaques were immunized with rVSV-MARV-GP and challenged with MARV approximately 14 months after vaccination. Immunization resulted in the vaccine cohort of six animals having anti-MARV GP IgG throughout the pre-challenge period. Following MARV challenge none of the vaccinated animals showed any signs of clinical disease or viremia and all were completely protected from MARV infection. Two unvaccinated control animals exhibited signs consistent with MARV infection and both succumbed. Importantly, these data are the first to show 100% protective efficacy against any high dose filovirus challenge beyond 8 weeks after final vaccination. These findings demonstrate the durability of VSV-based filovirus vaccines.

  8. Durability of a vesicular stomatitis virus-based marburg virus vaccine in nonhuman primates.

    Science.gov (United States)

    Mire, Chad E; Geisbert, Joan B; Agans, Krystle N; Satterfield, Benjamin A; Versteeg, Krista M; Fritz, Elizabeth A; Feldmann, Heinz; Hensley, Lisa E; Geisbert, Thomas W

    2014-01-01

    The filoviruses, Marburg virus (MARV) and Ebola virus, causes severe hemorrhagic fever with high mortality in humans and nonhuman primates. A promising filovirus vaccine under development is based on a recombinant vesicular stomatitis virus (rVSV) that expresses individual filovirus glycoproteins (GPs) in place of the VSV glycoprotein (G). These vaccines have shown 100% efficacy against filovirus infection in nonhuman primates when challenge occurs 28-35 days after a single injection immunization. Here, we examined the ability of a rVSV MARV-GP vaccine to provide protection when challenge occurs more than a year after vaccination. Cynomolgus macaques were immunized with rVSV-MARV-GP and challenged with MARV approximately 14 months after vaccination. Immunization resulted in the vaccine cohort of six animals having anti-MARV GP IgG throughout the pre-challenge period. Following MARV challenge none of the vaccinated animals showed any signs of clinical disease or viremia and all were completely protected from MARV infection. Two unvaccinated control animals exhibited signs consistent with MARV infection and both succumbed. Importantly, these data are the first to show 100% protective efficacy against any high dose filovirus challenge beyond 8 weeks after final vaccination. These findings demonstrate the durability of VSV-based filovirus vaccines.

  9. Homologous and heterologous protection of nonhuman primates by Ebola and Sudan virus-like particles.

    Directory of Open Access Journals (Sweden)

    Kelly L Warfield

    Full Text Available Filoviruses cause hemorrhagic fever resulting in significant morbidity and mortality in humans. Several vaccine platforms that include multiple virus-vectored approaches and virus-like particles (VLPs have shown efficacy in nonhuman primates. Previous studies have shown protection of cynomolgus macaques against homologous infection for Ebola virus (EBOV and Marburg virus (MARV following a three-dose vaccine regimen of EBOV or MARV VLPs, as well as heterologous protection against Ravn Virus (RAVV following vaccination with MARV VLPs. The objectives of the current studies were to determine the minimum number of vaccine doses required for protection (using EBOV as the test system and then demonstrate protection against Sudan virus (SUDV and Taï Forest virus (TAFV. Using the EBOV nonhuman primate model, we show that one or two doses of VLP vaccine can confer protection from lethal infection. VLPs containing the SUDV glycoprotein, nucleoprotein and VP40 matrix protein provide complete protection against lethal SUDV infection in macaques. Finally, we demonstrate protective efficacy mediated by EBOV, but not SUDV, VLPs against TAFV; this is the first demonstration of complete cross-filovirus protection using a single component heterologous vaccine within the Ebolavirus genus. Along with our previous results, this observation provides strong evidence that it will be possible to develop and administer a broad-spectrum VLP-based vaccine that will protect against multiple filoviruses by combining only three EBOV, SUDV and MARV components.

  10. Biosafety in Ex Vivo Gene Therapy and Conditional Ablation of Lentivirally Transduced Hepatocytes in Nonhuman Primates

    Science.gov (United States)

    Menzel, Olivier; Birraux, Jacques; Wildhaber, Barbara E; Jond, Caty; Lasne, Françoise; Habre, Walid; Trono, Didier; Nguyen, Tuan H; Chardot, Christophe

    2009-01-01

    Ex vivo gene therapy is an interesting alternative to orthotopic liver transplantation (OLT) for treating metabolic liver diseases. In this study, we investigated its efficacy and biosafety in nonhuman primates. Hepatocytes isolated from liver lobectomy were transduced in suspension with a bicistronic liver-specific lentiviral vector and immediately autotransplanted (SLIT) into three cynomolgus monkeys. The vector encoded cynomolgus erythropoietin (EPO) and the conditional suicide gene herpes simplex virus-thymidine kinase (HSV-TK). Survival of transduced hepatocytes and vector dissemination were evaluated by detecting transgene expression and vector DNA. SLIT was safely performed within a day in all three subjects. Serum EPO and hematocrit rapidly increased post-SLIT and their values returned to baseline within about 1 month. Isoforms of EPO detected in monkeys' sera differed from the physiological renal EPO. In liver biopsies at months 8 and 15, we detected EPO protein, vector mRNA and DNA, demonstrating long-term survival and functionality of transplanted lentivirally transduced hepatocytes. Valganciclovir administration resulted in complete ablation of the transduced hepatocytes. We demonstrated the feasibility and biosafety of SLIT, and the long term (>1 year) functionality of lentivirally transduced hepatocytes in nonhuman primates. The HSV-TK/valganciclovir suicide strategy can increase the biosafety of liver gene therapy protocols by safely and completely ablating transduced hepatocytes on demand. PMID:19568222

  11. A critical role for CD8 T cells in a nonhuman primate model of tuberculosis.

    Science.gov (United States)

    Chen, Crystal Y; Huang, Dan; Wang, Richard C; Shen, Ling; Zeng, Gucheng; Yao, Shuyun; Shen, Yun; Halliday, Lisa; Fortman, Jeff; McAllister, Milton; Estep, Jim; Hunt, Robert; Vasconcelos, Daphne; Du, George; Porcelli, Steven A; Larsen, Michelle H; Jacobs, William R; Haynes, Barton F; Letvin, Norman L; Chen, Zheng W

    2009-04-01

    The role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell-mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytotoxic/bactericidal protein granulysin. Employing a more relevant nonhuman primate model of human tuberculosis, we examined the contribution of BCG- or M. tuberculosis-elicited CD8 T cells to vaccine-induced immunity against tuberculosis. CD8 depletion compromised BCG vaccine-induced immune control of M. tuberculosis replication in the vaccinated rhesus macaques. Depletion of CD8 T cells in BCG-vaccinated rhesus macaques led to a significant decrease in the vaccine-induced immunity against tuberculosis. Consistently, depletion of CD8 T cells in rhesus macaques that had been previously infected with M. tuberculosis and cured by antibiotic therapy also resulted in a loss of anti-tuberculosis immunity upon M. tuberculosis re-infection. The current study demonstrates a major role for CD8 T cells in anti-tuberculosis immunity, and supports the view that CD8 T cells should be included in strategies for development of new tuberculosis vaccines and immunotherapeutics.

  12. A critical role for CD8 T cells in a nonhuman primate model of tuberculosis.

    Directory of Open Access Journals (Sweden)

    Crystal Y Chen

    2009-04-01

    Full Text Available The role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell-mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytotoxic/bactericidal protein granulysin. Employing a more relevant nonhuman primate model of human tuberculosis, we examined the contribution of BCG- or M. tuberculosis-elicited CD8 T cells to vaccine-induced immunity against tuberculosis. CD8 depletion compromised BCG vaccine-induced immune control of M. tuberculosis replication in the vaccinated rhesus macaques. Depletion of CD8 T cells in BCG-vaccinated rhesus macaques led to a significant decrease in the vaccine-induced immunity against tuberculosis. Consistently, depletion of CD8 T cells in rhesus macaques that had been previously infected with M. tuberculosis and cured by antibiotic therapy also resulted in a loss of anti-tuberculosis immunity upon M. tuberculosis re-infection. The current study demonstrates a major role for CD8 T cells in anti-tuberculosis immunity, and supports the view that CD8 T cells should be included in strategies for development of new tuberculosis vaccines and immunotherapeutics.

  13. Social isolation disrupts hippocampal neurogenesis in young non-human primates

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    Simone M Cinini

    2014-03-01

    Full Text Available Social relationships are crucial for the development and maintenance of normal behavior in non-human primates. Animals that are raised in isolation develop abnormal patterns of behavior that persist even when they are later reunited with their parents. In rodents, social isolation is a stressful event and is associated with a decrease in hippocampal neurogenesis but considerably less is known about the effects of social isolation in non-human primates during the transition from adolescence to adulthood. To investigate how social isolation affects young marmosets, these were isolated from other members of the colony for one or three weeks and evaluated for alterations in their behavior and hippocampal cell proliferation. We found that anxiety-related behaviors like scent-marking and locomotor activity increased after social isolation when compared to baseline levels. In agreement, grooming - an indicative of attenuation of tension - was reduced among isolated marmosets. These results were consistent with increased cortisol levels after one and three weeks of isolation. After social isolation (one or three weeks, reduced proliferation of neural cells in the subgranular zone of dentate granule cell layer was identified and a smaller proportion of BrdU-positive cells underwent neuronal fate (doublecortin labeling. Our data is consistent with the notion that social deprivation during the transition from adolescence to adulthood leads to stress and produces anxiety-like behaviors that in turn might affect neurogenesis and contribute to the deleterious consequences of prolonged stressful conditions.

  14. Homologous and heterologous protection of nonhuman primates by Ebola and Sudan virus-like particles.

    Science.gov (United States)

    Warfield, Kelly L; Dye, John M; Wells, Jay B; Unfer, Robert C; Holtsberg, Frederick W; Shulenin, Sergey; Vu, Hong; Swenson, Dana L; Bavari, Sina; Aman, M Javad

    2015-01-01

    Filoviruses cause hemorrhagic fever resulting in significant morbidity and mortality in humans. Several vaccine platforms that include multiple virus-vectored approaches and virus-like particles (VLPs) have shown efficacy in nonhuman primates. Previous studies have shown protection of cynomolgus macaques against homologous infection for Ebola virus (EBOV) and Marburg virus (MARV) following a three-dose vaccine regimen of EBOV or MARV VLPs, as well as heterologous protection against Ravn Virus (RAVV) following vaccination with MARV VLPs. The objectives of the current studies were to determine the minimum number of vaccine doses required for protection (using EBOV as the test system) and then demonstrate protection against Sudan virus (SUDV) and Taï Forest virus (TAFV). Using the EBOV nonhuman primate model, we show that one or two doses of VLP vaccine can confer protection from lethal infection. VLPs containing the SUDV glycoprotein, nucleoprotein and VP40 matrix protein provide complete protection against lethal SUDV infection in macaques. Finally, we demonstrate protective efficacy mediated by EBOV, but not SUDV, VLPs against TAFV; this is the first demonstration of complete cross-filovirus protection using a single component heterologous vaccine within the Ebolavirus genus. Along with our previous results, this observation provides strong evidence that it will be possible to develop and administer a broad-spectrum VLP-based vaccine that will protect against multiple filoviruses by combining only three EBOV, SUDV and MARV components.

  15. No monkey business: why studying NK cells in nonhuman primates pays off

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    Henoch Sangjoon Hong

    2013-02-01

    Full Text Available Human NK cells play a key role in mediating host immune responses against various infectious diseases. For practical reasons, the majority of the data on human NK 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 human NK cell subpopulations in vivo. Although research in mice has elucidated a number of fundamental features of NK cell biology, mouse and human NK 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. Nonhuman 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 CD56bright and CD56dim NK cell subsets have phenotypically and functionally analogous counterparts in rhesus macaques. Thus, the use of nonhuman primate models offers the potential to substantially advance human NK cell research.

  16. Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models

    Directory of Open Access Journals (Sweden)

    Iskra Tuero

    2014-08-01

    Full Text Available An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV is transmitted primarily across mucosal surfaces, development of immunity at these sites is critical, but few clinical vaccine trials have targeted these sites or assessed vaccine-elicited mucosal immune responses. Pre-clinical studies in non-human primate models have facilitated progress in mucosal vaccine development by evaluating candidate vaccine approaches, developing methodologies for collecting and assessing mucosal samples, and providing clues to immune correlates of protective immunity for further investigation. In this review we have focused on non-human primate studies which have provided important information for future design of vaccine strategies, targeting of mucosal inductive sites, and assessment of mucosal immunity. Knowledge gained in these studies will inform mucosal vaccine design and evaluation in human clinical trials.

  17. Gene transfer to the nonhuman primate retina with recombinant feline immunodeficiency virus vectors.

    Science.gov (United States)

    Lotery, Andrew J; Derksen, Todd A; Russell, Stephen R; Mullins, Robert F; Sauter, Sybille; Affatigato, Louisa M; Stone, Edwin M; Davidson, Beverly L

    2002-04-10

    We hypothesize that recombinant feline immunodeficiency viral (rFIV) vectors may be useful for gene transfer to the nonhuman primate retina. We performed vitrectomies and subretinal injections in the right eyes of 11 cynomolgus monkeys. Vesicular stomatitis virus glycoprotein-pseudotyped rFIV that expressed the Escherichia coli beta-galactosidase gene was injected into eight eyes. Sham vehicle or lactose buffer injections were also performed in two of these eight study eyes. rFIV pseudotyped with an amphotropic envelope was used in two eyes, and in one animal injections of lactose buffer only were given. After surgery the animals were clinically evaluated by retinal photography and electroretinography. beta-Galactosidase expression was evaluated, at a final end point, in histological sections. We found photoreceptor and Müller cells to have the greatest transgene expression. Focal inflammatory responses localized to the injection site were seen histologically in all eyes. No difference in transduction efficiency was seen between injections near the macula and more peripheral injections. Visual function as assessed by electroretinography was not significantly affected by vector or vehicle injections. We conclude that rFIV vectors administered beneath the retina can transduce a variety of retinal cells in the nonhuman primate retina. rFIV vectors have therapeutic potential and could be exploited to develop gene therapy for the human eye.

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

    Science.gov (United States)

    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. Primate cognition: attention, episodic memory, prospective memory, self-control, and metacognition as examples of cognitive control in nonhuman primates.

    Science.gov (United States)

    Beran, Michael J; Menzel, Charles R; Parrish, Audrey E; Perdue, Bonnie M; Sayers, Ken; Smith, J David; Washburn, David A

    2016-09-01

    Primate Cognition is the study of cognitive processes, which represent internal mental processes involved in discriminations, decisions, and behaviors of humans and other primate species. Cognitive control involves executive and regulatory processes that allocate attention, manipulate and evaluate available information (and, when necessary, seek additional information), remember past experiences to plan future behaviors, and deal with distraction and impulsivity when they are threats to goal achievement. Areas of research that relate to cognitive control as it is assessed across species include executive attention, episodic memory, prospective memory, metacognition, and self-control. Executive attention refers to the ability to control what sensory stimuli one attends to and how one regulates responses to those stimuli, especially in cases of conflict. Episodic memory refers to memory for personally experienced, autobiographical events. Prospective memory refers to the formation and implementation of future-intended actions, such as remembering what needs to be done later. Metacognition consists of control and monitoring processes that allow individuals to assess what information they have and what information they still need, and then if necessary to seek information. Self-control is a regulatory process whereby individuals forego more immediate or easier to obtain rewards for more delayed or harder to obtain rewards that are objectively more valuable. The behavioral complexity shown by nonhuman primates when given tests to assess these capacities indicates psychological continuities with human cognitive control capacities. However, more research is needed to clarify the proper interpretation of these behaviors with regard to possible cognitive constructs that may underlie such behaviors. WIREs Cogn Sci 2016, 7:294-316. doi: 10.1002/wcs.1397 For further resources related to this article, please visit the WIREs website.

  20. Models of stress in nonhuman primates and their relevance for human psychopathology and endocrine dysfunction.

    Science.gov (United States)

    Meyer, Jerrold S; Hamel, Amanda F

    2014-01-01

    Stressful life events have been linked to the onset of severe psychopathology and endocrine dysfunction in many patients. Moreover, vulnerability to the later development of such disorders can be increased by stress or adversity during development (e.g., childhood neglect, abuse, or trauma). This review discusses the methodological features and results of various models of stress in nonhuman primates in the context of their potential relevance for human psychopathology and endocrine dysfunction, particularly mood disorders and dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Such models have typically examined the effects of stress on the animals' behavior, endocrine function (primarily the HPA and hypothalamic-pituitary-gonadal systems), and, in some cases, immune status. Manipulations such as relocation and/or removal of an animal from its current social group or, alternatively, formation of a new social group can have adverse effects on all of these outcome measures that may be either transient or more persistent depending on the species, sex, and other experimental conditions. Social primates may also experience significant stress associated with their rank in the group's dominance hierarchy. Finally, stress during prenatal development or during the early postnatal period may have long-lasting neurobiological and endocrine effects that manifest in an altered ability to cope behaviorally and physiologically with later challenges. Whereas early exposure to severe stress usually results in deficient coping abilities, certain kinds of milder stressors can promote subsequent resilience in the animal. We conclude that studies of stress in nonhuman primates can model many features of stress exposure in human populations and that such studies can play a valuable role in helping to elucidate the mechanisms underlying the role of stress in human psychopathology and endocrine dysfunction.

  1. Structural variations of the VWA locus in humans and comparison with non-human primates.

    Science.gov (United States)

    Minaguchi, K; Takenaka, O

    2000-09-11

    The HUMVWA locus was examined in 160 samples from the Japanese population. A total of 142 fragments were sequenced, and the counterpart sequences were also determined in non-human primates. In humans, 10 different alleles were found; they could be grouped into seven allelic classes based on the total number of repeats. No variation was observed in the alleles 17, 18 and 19, which showed consensus sequence structures and in the allele 14, which showed a different structure. New variation was found in alleles 15, 16, and 20, which had differences occurred in a basic (TCTA)(TCTG)(n) repeat in the 5' side. The counterpart fragments were successfully amplified in three species (chimpanzees, gorilla, and orangutan) out of four kinds of anthropoids, three species (rhesus macaques, Japanese macaques, and green monkey) out of four kinds of old world monkeys, but not in one species of either new world monkey or prosimian. The sizes of the fragments distributed from 92 to 180 bp in non-human primates and showed allelic size differences in four species. The sequence of the 5' flanking region followed by primer sequences in humans and anthropoids, which consisted of 19 bp, was identical in all, but differed from that in old world monkeys. The basic repeat motifs of humans and anthropoids consisted of TCTA, TCTG, and TCCA but that of old world monkeys consisted of TCTG, TCCG and TCCA The structures of humans and anthropoids were essentially similar, but with characteristic difference in each species. Differences in the allelic structures of old world monkeys were complex. Seven different alleles were observed in two rhesus and two Japanese macaques and one type of allele was observed in two green monkeys. Duplication of more than two repeat units of 4 bp was found in an allele of an old world monkey. These data illuminate interesting features of mutational changes in STRs during the long generations and also some insight into evolutional aspects of primates.

  2. Animal Welfares of Laboratory Non-Human Primates%非人灵长类动物实验中的动物福利

    Institute of Scientific and Technical Information of China (English)

    陈乾生

    2003-01-01

    While comparing non-human primates with human beings, it is not hard to conclude certain similarities between these two based on aspects such as morphological anatomy, biochemistry functioning and so on. As a result, nonhuman primates often play an important role in life scientific researches. These primates are always used as "Stand-Ins"for human beings. In the processes of toxicological testing of new drugs, some drugs, especially drugs of genic projects or biological medicines are requiring uses of primates as part of the new drug testing. Therefore, the morality and ethics of using non-human primates have to be emphasised by people. After all, this is one of the issues that concerns with the expectations of meeting the international scientific research standards by our national laboratory animal sciences.In fact, the moral and ethical problems of non-human primates experiments is related to the matters of animal welfares.

  3. Low prevalence of Chagas parasite infection in a nonhuman primate colony in Louisiana.

    Science.gov (United States)

    Dorn, Patricia L; Daigle, Megan E; Combe, Crescent L; Tate, Ashley H; Stevens, Lori; Phillippi-Falkenstein, Kathrine M

    2012-07-01

    Chagas disease, an important cause of heart disease in Latin America, is caused by the parasite Trypanosoma cruzi, which typically is transmitted to humans by triatomine insects. Although autochthonous transmission of the Chagas parasite to humans is rare in the United States, triatomines are common, and more than 20 species of mammals are infected with the Chagas parasite in the southern United States. Chagas disease has also been detected in colonies of nonhuman primates (NHP) in Georgia and Texas, and heart abnormalities consistent with Chagas disease have occurred at our NHP center in Louisiana. To determine the level of T. cruzi infection, we serologically tested 2157 of the approximately 4200 NHP at the center; 34 of 2157 primates (1.6%) tested positive. Presence of the T. cruzi parasite was confirmed by hemoculture in 4 NHP and PCR of the cultured parasites. These results strongly suggest local transmission of T. cruzi, because most of the infected NHP were born and raised at this site. All 3 species of NHP tested yielded infected animals, with significantly higher infection prevalence in pig-tailed macaques, suggesting possible exploration of this species as a model organism. The local T. cruzi strain isolated during this study would enhance such investigations. The NHP at this center are bred for use in scientific research, and the effects of the Chagas parasite on infected primates could confuse the interpretation of other studies.

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

    Science.gov (United States)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Best, Katharine [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Guedj, Jeremie [Univ. of Paris (France). IAME; Madelain, Vincent [Univ. of Paris (France); de Lamballerie, Xavier [Aix-Marseille Univ. (France); L, So-Yonim [Harvard Univ., Cambridge, MA (United States). Center for Virology and Vaccine Research; Osuna, Christa E [Harvard Univ., Cambridge, MA (United States). Center for Virology and Vaccine Research; Whitney, James [Harvard Univ., Cambridge, MA (United States). Center for Virology and Vaccine Research; Perelson, Alan S. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    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.

  6. Working on the 3 Rs: Utilization of refinement to enhance the value of translational research in nonhuman primates

    NARCIS (Netherlands)

    Graham, M.L.

    2011-01-01

    Studies in nonhuman primates are indicated in translating research results towards a clinical application, in particular to assess the safety and efficacy of immunosuppressives and cell therapy products. This requires a thorough consideration of animal well-being, i.e., the 3 Rs refinement, reductio

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

    Science.gov (United States)

    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.

  8. Macaques in farms and folklore: exploring the human-nonhuman primate interface in Sulawesi, Indonesia.

    Science.gov (United States)

    Riley, Erin P; Priston, Nancy E C

    2010-09-01

    The island of Sulawesi is an ecologically diverse and anthropogenically complex region in the Indonesian archipelago; it is home to multiple macaque species and a key locus of human-nonhuman primate interconnections. Here, we review the ethnoprimatology of Sulawesi by exploring two primary domains of the human-macaque interface: overlapping resource use and cultural perceptions of macaques. Crop raiding is the primary form of overlapping resource use. While the raiding of cacao plantations predominates in Central and South Sulawesi, subsistence crops (e.g., sweet potato and maize) are most vulnerable on Buton, Southeast Sulawesi. Despite this overlap levels of conflict are generally low, with farmers showing considerable tolerance. This tolerance can be explained by positive perceptions of the macaques despite their crop raiding behavior, and the finding that in some areas macaques figure prominently in local folklore, hence affording them protection. These findings provide some hope for the future management and conservation of these endemic macaques.

  9. Reward and decision processes in the brains of humans and nonhuman primates.

    Science.gov (United States)

    Sirigu, Angela; Duhamel, Jean-René

    2016-03-01

    Choice behavior requires weighing multiple decision variables, such as utility, uncertainty, delay, or effort, that combine to define a subjective value for each considered option or course of action. This capacity is based on prior learning about potential rewards (and punishments) that result from prior actions. When made in a social context, decisions can involve strategic thinking about the intentions of others and about the impact of others' behavior on one's own outcome. Valuation is also influenced by different emotions that serve to adaptively regulate our choices in order to, for example, stay away from excessively risky gambles, prevent future regrets, or avoid personal rejection or conflicts. Drawing on economic theory and on advances in the study of neuronal mechanisms, we review relevant recent experiments in nonhuman primates and clinical observations made in neurologically impaired patients suffering from impaired decision-making capacities.

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

    Energy Technology Data Exchange (ETDEWEB)

    Xiang, Z.Q. [The Wistar Institute of Anatomy and Biology, Philadelphia, PA (United States); Greenberg, L. [Centers for Disease Control and Prevention, Atlanta, GA (United States); Ertl, H.C., E-mail: ertl@wistar.upenn.edu [The Wistar Institute of Anatomy and Biology, Philadelphia, PA (United States); Rupprecht, C.E. [The Global Alliance for Rabies Control, Manhattan, KS (United States); Ross University School of Veterinary Medicine, Basseterre (Saint Kitts and Nevis)

    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.

  11. Sex-specific differences in olfactory sensitivity for putative human pheromones in nonhuman primates.

    Science.gov (United States)

    Laska, Matthias; Wieser, Alexandra; Salazar, Laura Teresa Hernandez

    2006-05-01

    In humans, the volatile C19-steroids androsta-4,16-dien-3-one (AND) and estra-1,3,5(10),16-tetraen-3-ol (EST) have been shown to modulate autonomic nervous system responses, and to cause hypothalamic activation in a gender-specific manner. Using two conditioning paradigms, the authors here show that pigtail macaques and squirrel monkeys of both sexes were able to detect AND and EST at concentrations in the micromolar and mM range, respectively. Male and female spider monkeys, in contrast, differed markedly in their sensitivity to these two odorous steroids, with males not showing any behavioral responses to the highest concentrations of AND tested and females not responding to the highest concentrations of EST. These data provide the first examples of sex-specific bimodal distributions of olfactory sensitivity in a nonhuman primate species.

  12. Non-human primate and rodent embryonic stem cells are differentially sensitive to embryotoxic compounds

    Directory of Open Access Journals (Sweden)

    Lauren Walker

    2015-01-01

    First, osteogenic capacity was compared between ESCs from the mouse and a New World monkey, the common marmoset. Then, cells were treated with compounds that have been previously reported to induce bone teratogenicity. Calcification and MTT assays evaluated effects on osteogenesis and cell viability, respectively. Our data indicated that marmoset ESCs responded differently than mouse ESCs in such embryotoxicity screens with no obvious dependency on chemical or compound classes and thus suggest that embryotoxicity screening results could be affected by species-driven response variation. In addition, ESCs derived from rhesus monkey, an Old World monkey, and phylogenetically closer to humans than the marmoset, were observed to respond differently to test compounds than marmoset ESCs. Together these results indicate that there are significant differences in the responses of non-human primate and mouse ESC to embryotoxic agents.

  13. Transgenic Nonhuman Primate Models for Human Diseases: Approaches and Contributing Factors

    Institute of Scientific and Technical Information of China (English)

    Yongchang Chen; Yuyu Niu; Weizhi Ji

    2012-01-01

    Nonhuman primates (NHPs) provide powerful experimental models to study human development,cognitive functions and disturbances as well as complex behavior,because of their genetic and physiological similarities to humans.Therefore,NHPs are appropriate models for the study of human diseases,such as neurodegenerative diseases including Parkinson's,Alzheimer's and Huntington's diseases,which occur as a result of genetic mutations.However,such diseass afflicting humans do not occur naturally in NHPs.So transgenic NHPs need to be established to understand the etiology of disease pathology and pathogenesis.Compared to rodent genetic models,the generation of transgenic NHPs for human diseases is inefficient,and only a transgenic monkey model for Huntington's disease has been reported.This review focuses on potential approaches and contributing factors for generating transgenic NHPs to study human diseases.

  14. Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates.

    Science.gov (United States)

    Nagaya, Yoko; Nozaki, Yoshitane; Kobayashi, Kazumasa; Takenaka, Osamu; Nakatani, Yosuke; Kusano, Kazutomi; Yoshimura, Tsutomu; Kusuhara, Hiroyuki

    2014-01-01

    In central nervous system drug discovery, cerebrospinal fluid (CSF) drug concentration (C(CSF)) has been widely used as a surrogate for unbound brain concentrations (C(u,brain)). However, previous rodent studies demonstrated that when drugs undergo active efflux by transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier, the C(CSF) overestimates the corresponding C(u,brain). To investigate the utility of C(CSF) as a surrogate for interstitial fluid (ISF) concentration (C(ISF)) in nonhuman primates, this study simultaneously determined the C(CSF) and C(ISF) of 12 compounds, including P-gp substrates, under steady-state conditions in cynomolgus monkeys using intracerebral microdialysis coupled with cisternal CSF sampling. Unbound plasma concentrations of non- or weak P-gp substrates were within 2.2-fold of the C(ISF) or C(CSF), whereas typical P-gp substrates (risperidone, verapamil, desloratadine, and quinidine) showed ISF-to-plasma unbound (K(p,uu,ISF)) and CSF-to-plasma unbound concentration ratios (K(p,uu,CSF)) that were appreciably lower than unity. Although the K(p,uu,CSF) of quinidine, verapamil, and desloratadine showed a trend of overestimating the K(p,uu,ISF), K(p,uu,CSF) showed a good agreement with K(p,uu,ISF) within 3-fold variations for all compounds examined. C(u,brain) of some basic compounds, as determined using brain homogenates, overestimated the C(ISF) and C(CSF). Therefore, C(CSF) could be used as a surrogate for C(ISF) in nonhuman primates.

  15. A novel highly reproducible and lethal nonhuman primate model for orthopox virus infection.

    Directory of Open Access Journals (Sweden)

    Marit Kramski

    Full Text Available The intentional re-introduction of Variola virus (VARV, the agent of smallpox, into the human population is of great concern due its bio-terroristic potential. Moreover, zoonotic infections with Cowpox (CPXV and Monkeypox virus (MPXV cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antiviral drugs for use in humans can only be demonstrated in animal models. The existing nonhuman primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously or intratracheally to induce a lethal infection in macaques. To overcome these drawbacks, the infectivity and pathogenicity of a particular CPXV was evaluated in the common marmoset (Callithrix jacchus.A CPXV named calpox virus was isolated from a lethal orthopox virus (OPV outbreak in New World monkeys. We demonstrated that marmosets infected with calpox virus, not only via the intravenous but also the intranasal route, reproducibly develop symptoms resembling smallpox in humans. Infected animals died within 1-3 days after onset of symptoms, even when very low infectious viral doses of 5x10(2 pfu were applied intranasally. Infectious virus was demonstrated in blood, saliva and all organs analyzed.We present the first characterization of a new OPV infection model inducing a disease in common marmosets comparable to smallpox in humans. Intranasal virus inoculation mimicking the natural route of smallpox infection led to reproducible infection. In vivo titration resulted in an MID(50 (minimal monkey infectious dose 50% of 8.3x10(2 pfu of calpox virus which is approximately 10,000-fold lower than MPXV and VARV doses applied in the macaque models. Therefore, the calpox virus/marmoset model is a suitable nonhuman primate model for the validation of vaccines and antiviral drugs. Furthermore, this model can help study mechanisms of OPV pathogenesis.

  16. Side-by-side comparison of gene-based smallpox vaccine with MVA in nonhuman primates.

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    Joseph W Golden

    Full Text Available Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA. We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV nonhuman primate (NHP challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA.

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

    Science.gov (United States)

    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.

  18. Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever.

    Science.gov (United States)

    Marzi, Andrea; Yoshida, Reiko; Miyamoto, Hiroko; Ishijima, Mari; Suzuki, Yasuhiko; Higuchi, Megumi; Matsuyama, Yukie; Igarashi, Manabu; Nakayama, Eri; Kuroda, Makoto; Saijo, Masayuki; Feldmann, Friederike; Brining, Douglas; Feldmann, Heinz; Takada, Ayato

    2012-01-01

    Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.

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

    Science.gov (United States)

    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. Positive reinforcement training as a technique to alter nonhuman primate behavior: quantitative assessments of effectiveness.

    Science.gov (United States)

    Schapiro, Steven J; Bloomsmith, Mollie A; Laule, Gail E

    2003-01-01

    Many suggest that operant conditioning techniques can be applied successfully to improve the behavioral management of nonhuman primates in research settings. However, relatively little empirical data exist to support this claim. This article is a review of several studies that discussed applied positive reinforcement training techniques (PRT) on breeding/research colonies of rhesus macaques (Macaca mulatta) and chimpanzees (Pan troglodytes) at The University of Texas M. D. Anderson Cancer Center and measured their effectiveness. Empirical analyses quantified the amount of time required to train rhesus monkeys to come up, station, target, and stay. Additionally, a study found that time spent affiliating by female rhesus was changed as a function of training low affiliators to affiliate more and high affiliators to affiliate less. Another study successfully trained chimpanzees to feed without fighting and to come inside on command. PRT is an important behavioral management tool that can improve the care and welfare of primates in captivity. Published empirical findings are essential for managers to assess objectively the utility of positive reinforcement training techniques in enhancing captive management and research procedures.

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

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    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.

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

    Directory of Open Access Journals (Sweden)

    Hugo eMerchant

    2014-01-01

    Full Text Available 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 nonhuman 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 nonhuman 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 nonhuman primates might be the reason why macaques cannot rhythmically entrain in the way humans do.

  3. On the scent of human olfactory orbitofrontal cortex: meta-analysis and comparison to non-human primates.

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    Gottfried, Jay A; Zald, David H

    2005-12-15

    It is widely accepted that the orbitofrontal cortex (OFC) represents the main neocortical target of primary olfactory cortex. In non-human primates, the olfactory neocortex is situated along the basal surface of the caudal frontal lobes, encompassing agranular and dysgranular OFC medially and agranular insula laterally, where this latter structure wraps onto the posterior orbital surface. Direct afferent inputs arrive from most primary olfactory areas, including piriform cortex, amygdala, and entorhinal cortex, in the absence of an obligatory thalamic relay. While such findings are almost exclusively derived from animal data, recent cytoarchitectonic studies indicate a close anatomical correspondence between non-human primate and human OFC. Given this cross-species conservation of structure, it has generally been presumed that the olfactory projection area in human OFC occupies the same posterior portions of OFC as seen in non-human primates. This review questions this assumption by providing a critical survey of the localization of primate and human olfactory neocortex. Based on a meta-analysis of human functional neuroimaging studies, the region of human OFC showing the greatest olfactory responsivity appears substantially rostral and in a different cytoarchitectural area than the orbital olfactory regions as defined in the monkey. While this anatomical discrepancy may principally arise from methodological differences across species, these results have implications for the interpretation of prior human lesion and neuroimaging studies and suggest constraints upon functional extrapolations from animal data.

  4. Primate Innovation: Sex, Age and Social Rank

    NARCIS (Netherlands)

    Reader, S.M.; Laland, K.N.

    2001-01-01

    Analysis of an exhaustive survey of primate behavior collated from the published literature revealed significant variation in rates of innovation among individuals of different sex, age and social rank. We searched approximately 1,000 articles in four primatology journals, together with other releva

  5. Can grey parrots (Psittacus erithacus) succeed on a "complex" foraging task failed by nonhuman primates (Pan troglodytes, Pongo abelii, Sapajus apella) but solved by wrasse fish (Labroides dimidiatus)?

    Science.gov (United States)

    Pepperberg, Irene M; Hartsfield, Leigh Ann

    2014-08-01

    Linking specific cognitive abilities of nonhuman species on a laboratory task to their evolutionary history-ecological niche can be a fruitful exercise in comparative psychology. Crucial issues, however, are the choice of task, the specific conditions of the task, and possibly the subjects' understanding or interpretation of the task. Salwiczek et al. (2012) compared cleaner wrasse fish (Labroides dimidaitus) to several nonhuman primate species (capuchins, Sapajus paella; chimpanzees, Pan troglodytes; orangutans, Pongo abelii) on a task purportedly related to the ecological demands of the fish, but not necessarily of the nonhuman primates; fish succeeded whereas almost all of the nonhuman primates that were tested failed. We replicated the two-choice paradigm of the task with three Grey parrots (Psittacus erithacus), whose ecology, evolutionary history, and cortical capacity are arguably more like those of nonhuman primates than fish. Greys succeeded at levels more like fish than all the nonhuman primates, suggesting possible alternative explanations for their success. Fish and nonhuman primate subjects also experienced a reversal of the initial conditions to test for generalization: Greys were similarly tested; they performed more like fish and capuchins (who now succeeded) than the apes (who continued to fail).

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

  9. Image-guided intracranial cannula placement for awake in vivo microdialysis in nonhuman primates

    Science.gov (United States)

    Chen, Antong; Bone, Ashleigh; Hines, Catherine D. G.; Dogdas, Belma; Montgomery, Tamara O.; Michener, Maria; Winkelmann, Christopher T.; Ghafurian, Soheil; Lubbers, Laura S.; Renger, John; Bagchi, Ansuman; Uslaner, Jason M.; Johnson, Colena; Zariwala, Hatim A.

    2016-03-01

    Intracranial microdialysis is used for sampling neurochemicals and large peptides along with their metabolites from the interstitial fluid (ISF) of the brain. The ability to perform this in nonhuman primates (NHP) e.g., rhesus could improve the prediction of pharmacokinetic (PK) and pharmacodynamics (PD) action of drugs in human. However, microdialysis in rhesus brains is not as routinely performed as in rodents. One challenge is that the precise intracranial probe placement in NHP brains is difficult due to the richness of the anatomical structure and the variability of the size and shape of brains across animals. Also, a repeatable and reproducible ISF sampling from the same animal is highly desirable when combined with cognitive behaviors or other longitudinal study end points. Toward that end, we have developed a semi-automatic flexible neurosurgical method employing MR and CT imaging to (a) derive coordinates for permanent guide cannula placement in mid-brain structures and (b) fabricate a customized recording chamber to implant above the skull for enclosing and safeguarding access to the cannula for repeated experiments. In order to place the intracranial guide cannula in each subject, the entry points in the skull and the depth in the brain were derived using co-registered images acquired from MR and CT scans. The anterior/posterior (A/P) and medial-lateral (M/L) rotation in the pose of the animal was corrected in the 3D image to appropriately represent the pose used in the stereotactic frame. An array of implanted fiducial markers was used to transform stereotactic coordinates to the images. The recording chamber was custom fabricated using computer-aided design (CAD), such that it would fit the contours of the individual skull with minimum error. The chamber also helped in guiding the cannula through the entry points down a trajectory into the depth of the brain. We have validated our method in four animals and our results indicate average placement error

  10. Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox).

    Science.gov (United States)

    Mucker, Eric M; Goff, Arthur J; Shamblin, Joshua D; Grosenbach, Douglas W; Damon, Inger K; Mehal, Jason M; Holman, Robert C; Carroll, Darin; Gallardo, Nadia; Olson, Victoria A; Clemmons, Cody J; Hudson, Paul; Hruby, Dennis E

    2013-12-01

    Naturally occurring smallpox has been eradicated but remains a considerable threat as a biowarfare/bioterrorist weapon (F. Fleck, Bull. World Health Organ. 81:917-918, 2003). While effective, the smallpox vaccine is currently not recommended for routine use in the general public due to safety concerns (http://www.bt.cdc.gov/agent/smallpox/vaccination). Safe and effective countermeasures, particularly those effective after exposure to smallpox, are needed. Currently, SIGA Technologies is developing the small-molecule oral drug, tecovirimat (previously known as ST-246), as a postexposure therapeutic treatment of orthopoxvirus disease, including smallpox. Tecovirimat has been shown to be efficacious in preventing lethal orthopoxviral disease in numerous animal models (G. Yang, D. C. Pevear, M. H. Davies, M. S. Collett, T. Bailey, et al., J. Virol. 79:13139-13149, 2005; D. C. Quenelle, R. M. Buller, S. Parker, K. A. Keith, D. E. Hruby, et al., Antimicrob. Agents Chemother., 51:689-695, 2007; E. Sbrana, R. Jordan, D. E. Hruby, R. I. Mateo, S. Y. Xiao, et al., Am. J. Trop. Med. Hyg. 76:768-773, 2007). Furthermore, in clinical trials thus far, the drug appears to be safe, with a good pharmacokinetic profile. In this study, the efficacy of tecovirimat was evaluated in both a prelesional and postlesional setting in nonhuman primates challenged intravenously with 1 × 10(8) PFU of Variola virus (VARV; the causative agent of smallpox), a model for smallpox disease in humans. Following challenge, 50% of placebo-treated controls succumbed to infection, while all tecovirimat-treated animals survived regardless of whether treatment was started at 2 or 4 days postinfection. In addition, tecovirimat treatment resulted in dramatic reductions in dermal lesion counts, oropharyngeal virus shedding, and viral DNA circulating in the blood. Although clinical disease was evident in tecovirimat-treated animals, it was generally very mild and appeared to resolve earlier than in placebo

  11. Molecular typing of Giardia duodenalis isolates from nonhuman primates housed IN a Brazilian zoo.

    Science.gov (United States)

    David, Érica Boarato; Patti, Mariella; Coradi, Silvana Torossian; Oliveira-Sequeira, Teresa Cristina Goulart; Ribolla, Paulo Eduardo Martins; Guimarães, Semíramis

    2014-01-01

    Giardia infections in captive nonhuman primates (NHP) housed at a Brazilian zoo were investigated in order to address their zoonotic potential. Fresh fecal samples were collected from the floors of 22 enclosures where 47 primates of 18 different species were housed. The diagnosis of intestinal parasites after concentration by sedimentation and flotation methods revealed the following parasites and their frequencies: Giardia (18%); Entamoeba spp. (18%); Endolimax nana (4.5%); Iodamoeba spp. (4.5%); Oxyurid (4.5%) and Strongylid (4.5%). Genomic DNA extracted from all samples was processed by PCR methods in order to amplify fragments of gdh and tpi genes of Giardia. Amplicons were obtained from samples of Ateles belzebuth, Alouatta caraya, Alouatta fusca and Alouatta seniculus. Clear sequences were only obtained for the isolates from Ateles belzebuth (BA1), Alouatta fusca (BA2) and Alouatta caraya (BA3). According to the phenetic analyses of these sequences, all were classified as assemblage A. For the tpi gene, all three isolates were grouped into sub-assemblage AII (BA1, BA2 and BA3) whereas for the gdh gene, only BA3 was sub-assemblage AII, and the BA1 and BA2 were sub-assemblage AI. Considering the zoonotic potential of the assemblage A, and that the animals of the present study show no clinical signs of infection, the data obtained here stresses that regular coproparasitological surveys are necessary to implement preventive measures and safeguard the health of the captive animals, of their caretakers and of people visiting the zoological gardens.

  12. A new non-human primate model of photochemically induced cerebral infarction.

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    Satoshi Ikeda

    Full Text Available BACKGROUND AND PURPOSE: Rat models of photochemically induced cerebral infarction have been readily studied, but to date there are no reports of transcranial photochemically induced infarctions in the marmoset. In this report, we used this non-human primate as a model of cerebral thrombosis and observed the recovery process. METHODS: Five common marmosets were used. Cerebral ischemia was produced via intravascular thrombosis induced by an intravenous injection of Rose Bengal and irradiation with green light. After inducing cerebral infarction, we observed the behavior of marmosets via a continuous video recording. We evaluated maximum speed, mean speed, and distance traveled in 1 min. In addition, we evaluated scores for feeding behavior, upper limb grip, and lower limb grip. We confirmed the infarct area after cerebral infarction using 2,3,5-triphenyltetrazolium chloride staining in a separate marmoset. RESULTS: We found functional decreases 2 days after creating the cerebral infarction in all measurements. Total distance traveled, average speed, upper limb score, and feeding behavior score did not recover to pre-infarction levels within 28 days. Maximum speed in 1 min and lower limb score recovered 28 days after infarction as compared to pre-infarction levels. We confirmed the infarct area of 11.4 mm × 6.8 mm as stained with 2,3,5-triphenyltetrazolium chloride. CONCLUSION: We were able to create a primate photothrombosis-induced cerebral infarction model using marmosets and observe functional recovery. We suggest that this is a useful model for basic research of cerebral infarction.

  13. Concealed fertility and extended female sexuality in a non-human primate (Macaca assamensis.

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    Ines Fürtbauer

    Full Text Available In numerous primates living in mixed-sex groups, females display probabilistic cues of fertility to simultaneously concentrate paternity to dominant males while diluting it amongst others as a means to reduce the risk of infanticide and to increase male care for offspring. A few species, however, lack these cues and potentially conceal fertility from males; yet, to date, little is known about mating patterns and their underlying proximate mechanisms in such species. Here, we investigated mating activity and sexual consortships relative to female reproductive state in wild Assamese macaques (Macaca assamensis, a species where females lack prominent anogenital swellings and copulation calls. During two mating seasons (2837 contact hours we recorded sexual and social behaviors, sexual consortships, and collected 1178 fecal samples (n = 15 females which were analyzed for progestogen concentrations to assess female reproductive state and to determine the timing of ovulation and conception. Although mostly conceiving in their first ovarian cycle, females were sexually receptive throughout the entire 4-month mating season, and within-cycle mating frequencies were not increased during fertile phases. Dominant males did not monopolize fertile matings, and consortships by high-ranking males lasted for long periods, which were not exclusively linked to female fertile phases. Furthermore, females copulated promiscuously but not randomly, i.e. for almost every female, matings were concentrated to a certain male, irrespective of male rank. Collectively, we demonstrate that fertility is undisclosed to males. The extreme extended female sexuality facilitated by concealed fertility may allow females to create differentiated mating relationships within a promiscuous mating system. Our study provides important new insight into the plasticity of female sexuality in non-human primates.

  14. Utility, limitations, and future of non-human primates for dengue research and vaccine development.

    Science.gov (United States)

    Sariol, Carlos A; White, Laura J

    2014-01-01

    Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately, there are no licensed dengue vaccines available or specific anti-viral drugs. The development of a dengue vaccine faces unique challenges. The four serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, non-human primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article, we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally, we propose some guidelines toward a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups.

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

    Directory of Open Access Journals (Sweden)

    Travis May

    Full Text Available 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.

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

    Science.gov (United States)

    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

  17. Performance of ESAT-6 for serodiagnosis of nonhuman primate tuberculosis: A meta-analysis

    Directory of Open Access Journals (Sweden)

    Fangui Min

    2015-06-01

    Full Text Available ESAT-6 is one of the most studied antigens in vaccine, diagnosis, and pathogenic mechanism of tuberculosis. In the present study, a meta-analysis was performed regarding the use of ESAT-6 based antibody detection test for diagnosing nonhuman primate (NHP tuberculosis. Studies in English and Chinese were searched and selected strictly. Quality of included studies was assessed using the standardized QUADAS-2 tool. Heterogeneity was explored through meta-regression. Finally, eight studies were included with high degree of homogeneity. Quality of included studies was general satisfied except the bias of “patient selection” for the majority of serum samples were from experimental infections. Estimates of sensitivity ranged from 69% to 82%, while specificity ranged from 96% to 99%. Area under ROC curves and Q were 0.9503 and 0.8909 respectively, indicating a high diagnostic accuracy. Current evidence suggests that ESAT-6 based serodiagnosis has the potential to become useful diagnostic tools for NHP tuberculosis.

  18. Non-Human Primates Harbor Diverse Mammalian and Avian Astroviruses Including Those Associated with Human Infections.

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    Erik A Karlsson

    Full Text Available Astroviruses (AstVs are positive sense, single-stranded RNA viruses transmitted to a wide range of hosts via the fecal-oral route. The number of AstV-infected animal hosts has rapidly expanded in recent years with many more likely to be discovered because of the advances in viral surveillance and next generation sequencing. Yet no study to date has identified human AstV genotypes in animals, although diverse AstV genotypes similar to animal-origin viruses have been found in children with diarrhea and in one instance of encephalitis. Here we provide important new evidence that non-human primates (NHP can harbor a wide variety of mammalian and avian AstV genotypes, including those only associated with human infection. Serological analyses confirmed that >25% of the NHP tested had antibodies to human AstVs. Further, we identified a recombinant AstV with parental relationships to known human AstVs. Phylogenetic analysis suggests AstVs in NHP are on average evolutionarily much closer to AstVs from other animals than are AstVs from bats, a frequently proposed reservoir. Our studies not only demonstrate that human astroviruses can be detected in NHP but also suggest that NHP are unique in their ability to support diverse AstV genotypes, further challenging the paradigm that astrovirus infection is species-specific.

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

    Science.gov (United States)

    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.

  20. Considerations in the Use of Nonhuman Primate Models of Ebola Virus and Marburg Virus Infection.

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    Geisbert, Thomas W; Strong, James E; Feldmann, Heinz

    2015-10-01

    The filoviruses, Ebola virus and Marburg virus, are zoonotic pathogens that cause severe hemorrhagic fever in humans and nonhuman primates (NHPs), with case-fatality rates ranging from 23% to 90%. The current outbreak of Ebola virus infection in West Africa, with >26 000 cases, demonstrates the long-underestimated public health danger that filoviruses pose as natural human pathogens. Currently, there are no vaccines or treatments licensed for human use. Licensure of any medical countermeasure may require demonstration of efficacy in the gold standard cynomolgus or rhesus macaque models of filovirus infection. Substantial progress has been made over the last decade in characterizing the filovirus NHP models. However, there is considerable debate over a variety of experimental conditions, including differences among filovirus isolates used, routes and doses of exposure, and euthanasia criteria, all of which may contribute to variability of results among different laboratories. As an example of the importance of understanding these differences, recent data with Ebola virus shows that an addition of a single uridine residue in the glycoprotein gene at the editing site attenuates the virus. Here, we draw on decades of experience working with filovirus-infected NHPs to provide a perspective on the importance of various experimental conditions.

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

    Science.gov (United States)

    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.

  2. Genome editing in nonhuman primates: approach to generating human disease models.

    Science.gov (United States)

    Chen, Y; Niu, Y; Ji, W

    2016-09-01

    Nonhuman primates (NHPs) are superior than rodents to be animal models for the study of human diseases, due to their similarities in terms of genetics, physiology, developmental biology, social behaviour and cognition. Transgenic animals have become a key tool in functional genomics to generate models for human diseases and validate new drugs. However, until now, progress in the field of transgenic NHPs has been slow because of technological limitations. Many human diseases, including neurodegenerative disorders, are caused by mutations in endogenous genes. Fortunately, recent developments in precision gene editing have led to the generation of NHP models for human diseases. Since 2014, there have been several reports of the generation of monkey models using transcription activator-like endonucleases (TALENs) or clustered regularly interspaced short palindromic repeats (CRISPR/Cas9); some of these NHP models showed symptoms that were much closer to those of human diseases than have been seen previously in mouse models. No off-targeting was observed in the NHP models, and multiple gene knockout and biallelic mutants were feasible with low efficiency. These findings suggest that there are many possibilities to establish NHP models for human diseases that can mimic human diseases more faithfully than rodent models.

  3. Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Green, Damian J.; Pagel, John M.; Nemecek, Eneida R.; Lin, Yukang; Kenoyer, Aimee L.; Pantelias, Anastasia; Hamlin, Donald K.; Wilbur, D. S.; Fisher, Darrell R.; Rajendran, Joseph G.; Gopal, Ajay K.; Park, Steven I.; Press, Oliver W.

    2009-08-06

    Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in nineteen nonhuman primates (M. fascicularis) the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation when compared to directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)4SA] produced markedly lower concentrations of radiation in non-target tissues when compared to conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung and liver (10.3:1, 18.9:1 and 9.9:1 respectively) when compared to the conventional RIT controls (2.6:1, 6.4:1 and 2.9:1 respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time-point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.

  4. Surface roughness enhances the osseointegration of titanium headposts in non-human primates.

    Science.gov (United States)

    Hacking, S A; Boyraz, P; Powers, B M; Sen-Gupta, E; Kucharski, W; Brown, C A; Cook, E P

    2012-11-15

    It is well recognized that micrometer and nanometer sized surface features enhance the skeletal attachment of implants within bone. However, little is known regarding the integration of implants placed outside the bone but in contact with the surface. Loosening of chronic skull anchored headposts in non-human primate based experiments can be a factor. The purpose of this study was to evaluate the effect of a simple and easily applied surface texture on bone apposition to titanium implants fixed to the periosteal surface of the skull. Implants possessed either a polished surface or a textured surface created by grit-basting followed by acid etching. The percent of bone in contact with the implant surface (bone apposition) to three polished and three textured implants was evaluated in one adult female monkey after 14 weeks. Upon harvest, implants were processed for undecalcified histology and regions of bone apposition were quantified using backscatter electron microscopy and digital image analysis. The bone apposition to textured implants was 62±20% and to polished implants was 42±21%. The application of a peak-and-pit like texture to the surface of titanium implants significantly increased bone apposition to titanium implants placed on the periosteal surface of the skull. This study demonstrates that titanium headposts can easily be modified to improve osseointegration using equipment and supplies available to most neurophysiological laboratories. In addition, implant texturing may have utility in areas including skeletal trauma and reconstruction where devices are placed in contact with the bone surface.

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

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    Tal Noy-Porat

    2016-03-01

    Full Text Available 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.

  6. Nonhuman primates: translational models for predicting antipsychotic-induced movement disorders.

    Science.gov (United States)

    Porsolt, Roger D; Castagné, Vincent; Hayes, Eric; Virley, David

    2013-12-01

    Repeated haloperidol treatment administered to nonhuman primates (NHPs) over several months or even years leads to the gradual appearance of drug-induced dystonic reactions in the orofacial region (mouth opening, tongue protrusion or retraction, bar biting) and in the whole body (writhing of the limbs and trunk, bar grasping). The propensity of antipsychotics to induce dystonia in NHPs is not correlated with their propensity to induce catalepsy in rodents, suggesting that the two types of effects are dissociated and may represent distinct aspects of the extrapyramidal symptoms induced by antipsychotics. In view of the clear homology to clinically observed phenomena, antipsychotic-induced dystonias in antipsychotic-primed NHPs would appear to possess a high degree of translational validity. These NHP phenomena could therefore serve as a useful model for predicting the occurrence of similar abnormal movements with novel substances developed for the treatment of schizophrenia or other psychotic disorders. Moreover, the NHP dystonia model could possibly serve as a biomarker for substances that will eventually cause tardive dyskinesia in patients.

  7. Recombinant vesicular stomatitis virus vaccine vectors expressing filovirus glycoproteins lack neurovirulence in nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Chad E Mire

    Full Text Available The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV that expresses an individual filovirus glycoprotein (GP in place of the VSV glycoprotein (G. The main concern with all replication-competent vaccines, including the rVSV filovirus GP vectors, is their safety. To address this concern, we performed a neurovirulence study using 21 cynomolgus macaques where the vaccines were administered intrathalamically. Seven animals received a rVSV vector expressing the Zaire ebolavirus (ZEBOV GP; seven animals received a rVSV vector expressing the Lake Victoria marburgvirus (MARV GP; three animals received rVSV-wild type (wt vector, and four animals received vehicle control. Two of three animals given rVSV-wt showed severe neurological symptoms whereas animals receiving vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP did not develop these symptoms. Histological analysis revealed major lesions in neural tissues of all three rVSV-wt animals; however, no significant lesions were observed in any animals from the filovirus vaccine or vehicle control groups. These data strongly suggest that rVSV filovirus GP vaccine vectors lack the neurovirulence properties associated with the rVSV-wt parent vector and support their further development as a vaccine platform for human use.

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

    Science.gov (United States)

    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.

  9. Exenatide Pretreatment Improved Graft Function in Nonhuman Primate Islet Recipients Compared to Treatment after Transplant Only

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    Jill L. Buss

    2012-01-01

    Full Text Available The GLP-1 receptor agonist, exenatide, has previously been shown to improve insulin secretion, protect beta cells from apoptosis, and promote beta cell regeneration. We propose that pretreatment with exenatide will promote islet graft survival and improve graft function. Pancreatectomized cynomolgus monkeys underwent islet allotransplantation and were treated with exenatide beginning on day 0 or day −2. A third group of animals was treated with an immunosuppressive regimen while a fourth group remained untreated. Fasting blood glucose (FBG was used to evaluate graft function along with intravenous glucose tolerance tests (IVGTTs performed at study endpoint (day 10 for untreated and posttransplant exenatide or day 90 for pretreatment exenatide and immunosuppression. The average FBG for pre-treated animals day 5 following transplant was 52.7±14.8 mg/dl, compared to 154.3±105.5 mg/dl for animals treated only following transplant, 59.4 mg/dl ±12.1 for animals treated with immunosuppression, and 265.5±172.3 mg/dl for untreated animals. IVGTTs performed at study endpoint showed normal glucose and insulin curves in the pre-treated exenatide and immunosuppression groups only, with beta cell function actually improving after transplant in the pre-treated group. We conclude, therefore, that exenatide pre-treatment can successfully maintain islet graft survival in nonhuman primates.

  10. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates.

    Science.gov (United States)

    Samaranch, Lluis; Salegio, Ernesto A; San Sebastian, Waldy; Kells, Adrian P; Foust, Kevin D; Bringas, John R; Lamarre, Clementine; Forsayeth, John; Kaspar, Brian K; Bankiewicz, Krystof S

    2012-04-01

    Widespread distribution of gene products at clinically relevant levels throughout the CNS has been challenging. Adeno-associated virus type 9 (AAV9) vector has been reported as a good candidate for intravascular gene delivery, but low levels of preexisting antibody titers against AAV in the blood abrogate cellular transduction within the CNS. In the present study we compared the effectiveness of vascular delivery and cerebrospinal fluid (CSF) delivery of AAV9 in transducing CNS tissue in nonhuman primates. Both delivery routes generated similar distribution patterns, although we observed a more robust level of transduction after CSF delivery. Consistent with previous reports administering AAV9, we found greater astrocytic than neuronal tropism via both routes, although we did find a greater magnitude of CNS transduction after CSF delivery compared with intravascular delivery. Last, we have demonstrated that delivery of AAV9 into the CSF does not shield against AAV antibodies. This has obvious implications when developing and/or implementing any clinical trial studies.

  11. Morphine Produces Immunosuppressive Effects in Nonhuman Primates at the Proteomic and Cellular Levels*

    Science.gov (United States)

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

    2012-01-01

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. To explore how these changes interact with lentiviral infections in vivo, animals from two nonhuman primate species (African green monkeys and pigtailed macaques) were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g. lymph node, colon, cerebrospinal fluid, 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 interorgan, interindividual, and interspecies 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 cell counts. Although 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 lymph nodes, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have direct relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the potential interplay between opioid abuse and the immunological response to an infective agent. PMID:22580588

  12. Morphine produces immunosuppressive effects in nonhuman primates at the proteomic and cellular levels.

    Science.gov (United States)

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

    2012-09-01

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. To explore how these changes interact with lentiviral infections in vivo, animals from two nonhuman primate species (African green monkeys and pigtailed macaques) were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g. lymph node, colon, cerebrospinal fluid, 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 interorgan, interindividual, and interspecies 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 cell counts. Although 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 lymph nodes, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have direct relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the potential interplay between opioid abuse and the immunological response to an infective agent.

  13. Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates.

    Science.gov (United States)

    Thi, Emily P; Mire, Chad E; Lee, Amy C H; Geisbert, Joan B; Zhou, Joy Z; Agans, Krystle N; Snead, Nicholas M; Deer, Daniel J; Barnard, Trisha R; Fenton, Karla A; MacLachlan, Ian; Geisbert, Thomas W

    2015-05-21

    The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.

  14. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates.

    Science.gov (United States)

    Lindholm, Marie W; Elmén, Joacim; Fisker, Niels; Hansen, Henrik F; Persson, Robert; Møller, Marianne R; Rosenbohm, Christoph; Ørum, Henrik; Straarup, Ellen M; Koch, Troels

    2012-02-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for the reduction of low-density lipoprotein cholesterol (LDL-C). PCSK9 increases the degradation of the LDL receptor, resulting in high LDL-C in individuals with high PCSK9 activity. Here, we show that two locked nucleic acid (LNA) antisense oligonucleotides targeting PCSK9 produce sustained reduction of LDL-C in nonhuman primates after a loading dose (20 mg/kg) and four weekly maintenance doses (5 mg/kg). PCSK9 messenger RNA (mRNA) and serum PCSK9 protein were reduced by 85% which resulted in a 50% reduction in circulating LDL-C. Serum total cholesterol (TC) levels were reduced to the same extent as LDL-C with no reduction in high-density lipoprotein levels, demonstrating a specific pharmacological effect on LDL-C. The reduction in hepatic PCSK9 mRNA correlated with liver LNA oligonucleotide content. This verified that anti-PCSK9 LNA oligonucleotides regulated LDL-C through an antisense mechanism. The compounds were well tolerated with no observed effects on toxicological parameters (liver and kidney histology, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine). The pharmacologic evidence and initial safety profile of the compounds used in this study indicate that LNA antisense oligonucleotides targeting PCSK9 provide a viable therapeutic strategy and are potential complements to statins in managing high LDL-C.

  15. Nonhuman Primate Models of Chikungunya Virus Infection and Disease (CHIKV NHP Model

    Directory of Open Access Journals (Sweden)

    Rebecca Broeckel

    2015-09-01

    Full Text Available Chikungunya virus (CHIKV is a positive-sense RNA virus transmitted by Aedes mosquitoes. CHIKV is a reemerging Alphavirus that causes acute febrile illness and severe and debilitating polyarthralgia of the peripheral joints. Huge epidemics and the rapid spread of CHIKV seen in India and the Indian Ocean region established CHIKV as a global health concern. This concern was further solidified by the recent incursion of the virus into the Western hemisphere, a region without pre-existing immunity. Nonhuman primates (NHPs serve as excellent animal models for understanding CHIKV pathogenesis and pre-clinical assessment of vaccines and therapeutics. NHPs present advantages over rodent models because they are a natural amplification host for CHIKV and they share significant genetic and physiological homology with humans. CHIKV infection in NHPs results in acute fever, rash, viremia and production of type I interferon. NHPs develop CHIKV-specific B and T-cells, generating neutralizing antibodies and CHIKV-specific CD4+ and CD8+ T-cells. CHIKV establishes a persistent infection in NHPs, particularly in cynomolgus macaques, because infectious virus could be recovered from spleen, liver, and muscle as late as 44 days post infection. NHPs are valuable models that are useful in preclinical testing of vaccines and therapeutics and uncovering the details of CHIKV pathogenesis.

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

    Science.gov (United States)

    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.

  17. Advantage of dichromats over trichromats in discrimination of color-camouflaged stimuli in nonhuman primates.

    Science.gov (United States)

    Saito, Atsuko; Mikami, Akichika; Kawamura, Shoji; Ueno, Yoshikazu; Hiramatsu, Chihiro; Widayati, Kanthi A; Suryobroto, Bambang; Teramoto, Migaku; Mori, Yusuke; Nagano, Kunitoshi; Fujita, Kazuo; Kuroshima, Hika; Hasegawa, Toshikazu

    2005-12-01

    Due to a middle- to long-wavelength-sensitive (M/LWS) cone opsin polymorphism, there is considerable phenotypic variation in the color vision of New World monkeys. Many females have trichromatic vision, whereas some females and all males have dichromatic vision. The selective pressures that maintain this polymorphism are unclear. In the present study we compared the performance of dichromats and trichromats in a discrimination task. We examined tri- and dichromatic individuals of two species: brown capuchin monkeys (Cebus apella) and long-tailed macaques (Macaca fascicularis). We also examined one protanomalous chimpanzee (Pan troglodytes). The subjects' task was to discriminate a circular pattern from other patterns in which textural elements differed in orientation and thickness from the background. After they were trained with stimuli of a single color, the subjects were presented with color-camouflaged stimuli with a green/red mosaic overlaid onto the pattern. The dichromatic monkeys and the protanomalous chimpanzee selected the correct stimulus under camouflaged conditions at rates significantly above chance levels, while the trichromats did not. These findings demonstrate that dichromatic nonhuman primates possess a superior visual ability to discriminate color-camouflaged stimuli, and that such an ability may confer selective advantages with respect to the detection of cryptic foods and/or predators.

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

    Science.gov (United States)

    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.

  19. Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates.

    Science.gov (United States)

    Careaga, Milo; Murai, Takeshi; Bauman, Melissa D

    2017-03-01

    A subset of women who are exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental or neuropsychiatric disorder. Although epidemiology studies have primarily focused on the association between maternal infection and an increased risk of offspring schizophrenia, mounting evidence indicates that maternal infection may also increase the risk of autism spectrum disorder. A number of factors, including genetic susceptibility, the intensity and timing of the infection, and exposure to additional aversive postnatal events, may influence the extent to which maternal infection alters fetal brain development and which disease phenotype (autism spectrum disorder, schizophrenia, other neurodevelopmental disorders) is expressed. Preclinical animal models provide a test bed to systematically evaluate the effects of maternal infection on fetal brain development, determine the relevance to human central nervous system disorders, and to evaluate novel preventive and therapeutic strategies. Maternal immune activation models in mice, rats, and nonhuman primates suggest that the maternal immune response is the critical link between exposure to infection during pregnancy and subsequent changes in brain and behavioral development of offspring. However, differences in the type, severity, and timing of prenatal immune challenge paired with inconsistencies in behavioral phenotyping approaches have hindered the translation of preclinical results to human studies. Here we highlight the promises and limitations of the maternal immune activation model as a preclinical tool to study prenatal risk factors for autism spectrum disorder, and suggest specific changes to improve reproducibility and maximize translational potential.

  20. Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates.

    Science.gov (United States)

    Jackowski, Andrea; Perera, Tarique D; Abdallah, Chadi G; Garrido, Griselda; Tang, Cheuk Y; Martinez, Jose; Mathew, Sanjay J; Gorman, Jack M; Rosenblum, Leonard A; Smith, Eric L P; Dwork, Andrew J; Shungu, Dikoma C; Kaffman, Arie; Gelernter, Joel; Coplan, Jeremy D; Kaufman, Joan

    2011-04-30

    Male bonnet monkeys (Macaca radiata) were subjected to the variable foraging demand (VFD) early stress paradigm as infants, MRI scans were completed an average of 4 years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of interest (ROI) hippocampus and whole brain voxel-based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. The animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.

  1. Development of the first marmoset-specific DNA microarray (EUMAMA): a new genetic tool for large-scale expression profiling in a non-human primate

    NARCIS (Netherlands)

    Datson, N.A.; Morsink, M.C.; Atanasova, S.; Armstrong, V.W.; Zischler, H.; Schlumbohm, C.; Dutilh, B.E.; Huynen, M.A.; Waegele, B.; Ruepp, A.; Kloet, E.R. de; Fuchs, E.

    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 marmo

  2. Efficient derivation of multipotent neural stem/progenitor cells from non-human primate embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Hiroko Shimada

    Full Text Available The common marmoset (Callithrix jacchus is a small New World primate that has been used as a non-human primate model for various biomedical studies. We previously demonstrated that transplantation of neural stem/progenitor cells (NS/PCs derived from mouse and human embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs promote functional locomotor recovery of mouse spinal cord injury models. However, for the clinical application of such a therapeutic approach, we need to evaluate the efficacy and safety of pluripotent stem cell-derived NS/PCs not only by xenotransplantation, but also allotransplantation using non-human primate models to assess immunological rejection and tumorigenicity. In the present study, we established a culture method to efficiently derive NS/PCs as neurospheres from common marmoset ESCs. Marmoset ESC-derived neurospheres could be passaged repeatedly and showed sequential generation of neurons and astrocytes, similar to that of mouse ESC-derived NS/PCs, and gave rise to functional neurons as indicated by calcium imaging. Although marmoset ESC-derived NS/PCs could not differentiate into oligodendrocytes under default culture conditions, these cells could abundantly generate oligodendrocytes by incorporating additional signals that recapitulate in vivo neural development. Moreover, principal component analysis of microarray data demonstrated that marmoset ESC-derived NS/PCs acquired similar gene expression profiles to those of fetal brain-derived NS/PCs by repeated passaging. Therefore, marmoset ESC-derived NS/PCs may be useful not only for accurate evaluation by allotransplantation of NS/PCs into non-human primate models, but are also applicable to analysis of iPSCs established from transgenic disease model marmosets.

  3. Knowledge-guided robust MRI brain extraction for diverse large-scale neuroimaging studies on humans and non-human primates.

    Science.gov (United States)

    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.

  4. Knowledge-guided robust MRI brain extraction for diverse large-scale neuroimaging studies on humans and non-human primates.

    Directory of Open Access Journals (Sweden)

    Yaping Wang

    Full Text Available 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.

  5. Immunogenicity of a prototype enterotoxigenic Escherichia coli adhesin vaccine in mice and nonhuman primates.

    Science.gov (United States)

    Sincock, Stephanie A; Hall, Eric R; Woods, Colleen M; O'Dowd, Aisling; Poole, Steven T; McVeigh, Annette L; Nunez, Gladys; Espinoza, Nereyda; Miller, Milagros; Savarino, Stephen J

    2016-01-01

    Enterotoxigenic Escherichia coli (ETEC) are the most common cause of bacterial diarrhea in young children in developing countries and in travelers. Efforts to develop an ETEC vaccine have intensified in the past decade, and intestinal colonization factors (CFs) are somatic components of most investigational vaccines. CFA/I and related Class 5 fimbrial CFs feature a major stalk-forming subunit and a minor, antigenically conserved tip adhesin. We hypothesized that the tip adhesin is critical for stimulating antibodies that specifically inhibit ETEC attachment to the small intestine. To address this, we compared the capacity of donor strand complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, and CFA/I fimbriae to elicit anti-adhesive antibodies in mice, using hemagglutination inhibition (HAI) as proxy for neutralization of intestinal adhesion. When given with genetically attenuated heat-labile enterotoxin LTR192G as adjuvant by intranasal (IN) or orogastric (OG) vaccination, dscCfaE exceeded CFA/I fimbriae in eliciting serum HAI titers and anti-CfaE antibody titers. Based on these findings, we vaccinated Aotus nancymaae nonhuman primates (NHP) with dscCfaE alone or admixed with one of two adjuvants, LTR192G and cholera toxin B-subunit, by IN and OG administration. Only IN vaccination with dscCfaE with either adjuvant elicited substantial serum HAI titers and IgA and IgG anti-adhesin responses, with the latter detectable a year after vaccination. In conclusion, we have shown that dscCfaE elicits robust HAI and anti-adhesin antibody responses in both mice and NHPs when given with adjuvant by IN vaccination, encouraging further evaluation of an ETEC adhesin-based vaccine approach.

  6. Multilocus sequence typing of Enterocytozoon bieneusi in nonhuman primates in China.

    Science.gov (United States)

    Karim, Md Robiul; Wang, Rongjun; He, Xiaoyi; Zhang, Longxian; Li, Jian; Rume, Farzana Islam; Dong, Haiju; Qi, Meng; Jian, Fuchun; Zhang, Sumei; Sun, Mingfei; Yang, Guangyou; Zou, Fengcai; Ning, Changshen; Xiao, Lihua

    2014-02-24

    To infer population genetics of Enterocytozoon bieneusi in nonhuman primates (NHPs), 126 positive specimens in 839 fecal specimens from 23 NHP species in China based on ITS locus were used, belonging to genotypes Type IV, D, Peru8, Henan V, Peru11, PigEBITS7 and 3 novel ones (CM1, CM2 and CM3). Multilocus sequence typing employing four micro and minisatellites (MS1, MS3, MS4 and MS7) and ITS were used to analyze population structure of 85 isolates successfully amplified at all five loci, which yielded 59 multilocus genotypes. Linkage disequilibrium (LD) was measured using both multilocus sequences and allelic profile data. The observation of strong and significant LD with limited recombination in multilocus sequence analysis indicated the presence of overall clonal population structure of E. bieneusi, which was supported by allelic profile data analysis. Fu's selective neutrality test demonstrated the absence of neutral mutations and molecular selection. The population structure of common ITS genotypes (CM1, Type IV and D) was compared. Strong LD in multilocus sequence analysis versus insignificant LD and/or LE in allelic profile data analysis implied epidemic population in common ITS genotypes. No significant genetic isolation was evidenced by either phylogenetic or substructural analyses. The population genetics was also compared among the sub-population 1 (contained mainly genotype Type IV), sub-population 2 (contained mainly genotypes CM1 and D), sub-population 3 (contained mixed genotypes) and sub-population 4 (contained genotype Henan V). The presence of strong LD in multilocus data analysis with insignificant LD and/or LE in allele profile data analysis suggested the epidemic population in sub-populations.

  7. Vesicular stomatitis virus-based vaccines protect nonhuman primates against Bundibugyo ebolavirus.

    Directory of Open Access Journals (Sweden)

    Chad E Mire

    Full Text Available Ebola virus (EBOV causes severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs. Currently, there are no licensed vaccines or therapeutics for human use. Recombinant vesicular stomatitis virus (rVSV-based vaccine vectors, which encode an EBOV glycoprotein in place of the VSV glycoprotein, have shown 100% efficacy against homologous Sudan ebolavirus (SEBOV or Zaire ebolavirus (ZEBOV challenge in NHPs. In addition, a single injection of a blend of three rVSV vectors completely protected NHPs against challenge with SEBOV, ZEBOV, the former Côte d'Ivoire ebolavirus, and Marburg virus. However, recent studies suggest that complete protection against the newly discovered Bundibugyo ebolavirus (BEBOV using several different heterologous filovirus vaccines is more difficult and presents a new challenge. As BEBOV caused nearly 50% mortality in a recent outbreak any filovirus vaccine advanced for human use must be able to protect against this new species. Here, we evaluated several different strategies against BEBOV using rVSV-based vaccines. Groups of cynomolgus macaques were vaccinated with a single injection of a homologous BEBOV vaccine, a single injection of a blended heterologous vaccine (SEBOV/ZEBOV, or a prime-boost using heterologous SEBOV and ZEBOV vectors. Animals were challenged with BEBOV 29-36 days after initial vaccination. Macaques vaccinated with the homologous BEBOV vaccine or the prime-boost showed no overt signs of illness and survived challenge. In contrast, animals vaccinated with the heterologous blended vaccine and unvaccinated control animals developed severe clinical symptoms consistent with BEBOV infection with 2 of 3 animals in each group succumbing. These data show that complete protection against BEBOV will likely require incorporation of BEBOV glycoprotein into the vaccine or employment of a prime-boost regimen. Fortunately, our results demonstrate that heterologous rVSV-based filovirus vaccine

  8. Targeting of deep-brain structures in nonhuman primates using MR and CT Images

    Science.gov (United States)

    Chen, Antong; Hines, Catherine; Dogdas, Belma; Bone, Ashleigh; Lodge, Kenneth; O'Malley, Stacey; Connolly, Brett; Winkelmann, Christopher T.; Bagchi, Ansuman; Lubbers, Laura S.; Uslaner, Jason M.; Johnson, Colena; Renger, John; Zariwala, Hatim A.

    2015-03-01

    In vivo gene delivery in central nervous systems of nonhuman primates (NHP) is an important approach for gene therapy and animal model development of human disease. To achieve a more accurate delivery of genetic probes, precise stereotactic targeting of brain structures is required. However, even with assistance from multi-modality 3D imaging techniques (e.g. MR and CT), the precision of targeting is often challenging due to difficulties in identification of deep brain structures, e.g. the striatum which consists of multiple substructures, and the nucleus basalis of meynert (NBM), which often lack clear boundaries to supporting anatomical landmarks. Here we demonstrate a 3D-image-based intracranial stereotactic approach applied toward reproducible intracranial targeting of bilateral NBM and striatum of rhesus. For the targeting we discuss the feasibility of an atlas-based automatic approach. Delineated originally on a high resolution 3D histology-MR atlas set, the NBM and the striatum could be located on the MR image of a rhesus subject through affine and nonrigid registrations. The atlas-based targeting of NBM was compared with the targeting conducted manually by an experienced neuroscientist. Based on the targeting, the trajectories and entry points for delivering the genetic probes to the targets could be established on the CT images of the subject after rigid registration. The accuracy of the targeting was assessed quantitatively by comparison between NBM locations obtained automatically and manually, and finally demonstrated qualitatively via post mortem analysis of slices that had been labelled via Evan Blue infusion and immunohistochemistry.

  9. Progress and prospects for genetic modification of nonhuman primate models in biomedical research.

    Science.gov (United States)

    Chan, Anthony W S

    2013-01-01

    The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and new therapies for many diseases. Biomedical research has not been the primary role of NHPs. They have mainly been used for safety evaluation and pharmacokinetics studies, rather than determining therapeutic efficacy. The development of the first transgenic rhesus macaque (2001) revolutionized the role of NHP models in biomedicine. Development of the transgenic NHP model of Huntington's disease (2008), with distinctive clinical features, further suggested the uniqueness of the model system; and the potential role of the NHP model for human genetic disorders. Modeling human genetic diseases using NHPs will continue to thrive because of the latest advances in molecular, genetic, and embryo technologies. NHPs rising role in biomedical research, specifically pre-clinical studies, is foreseeable. The path toward the development of transgenic NHPs and the prospect of transgenic NHPs in their new role in future biomedicine needs to be reviewed. This article will focus on the advancement of transgenic NHPs in the past decade, including transgenic technologies and disease modeling. It will outline new technologies that may have significant impact in future NHP modeling and will conclude with a discussion of the future prospects of the transgenic NHP model.

  10. Immunogenicity and protective efficacy of a live attenuated H5N1 vaccine in nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Shufang Fan

    2009-05-01

    Full Text Available The continued spread of highly pathogenic H5N1 influenza viruses among poultry and wild birds, together with the emergence of drug-resistant variants and the possibility of human-to-human transmission, has spurred attempts to develop an effective vaccine. Inactivated subvirion or whole-virion H5N1 vaccines have shown promising immunogenicity in clinical trials, but their ability to elicit protective immunity in unprimed human populations remains unknown. A cold-adapted, live attenuated vaccine with the hemagglutinin (HA and neuraminidase (NA genes of an H5N1 virus A/VN/1203/2004 (clade 1 was protective against the pulmonary replication of homologous and heterologous wild-type H5N1 viruses in mice and ferrets. In this study, we used reverse genetics to produce a cold-adapted, live attenuated H5N1 vaccine (AH/AAca that contains HA and NA genes from a recent H5N1 isolate, A/Anhui/2/05 virus (AH/05 (clade 2.3, and the backbone of the cold-adapted influenza H2N2 A/AnnArbor/6/60 virus (AAca. AH/AAca was attenuated in chickens, mice, and monkeys, and it induced robust neutralizing antibody responses as well as HA-specific CD4+ T cell immune responses in rhesus macaques immunized twice intranasally. Importantly, the vaccinated macaques were fully protected from challenge with either the homologous AH/05 virus or a heterologous H5N1 virus, A/bar-headed goose/Qinghai/3/05 (BHG/05; clade 2.2. These results demonstrate for the first time that a cold-adapted H5N1 vaccine can elicit protective immunity against highly pathogenic H5N1 virus infection in a nonhuman primate model and provide a compelling argument for further testing of double immunization with live attenuated H5N1 vaccines in human trials.

  11. Liposome-encapsulated hemoglobin ameliorates ischemic stroke in nonhuman primates: longitudinal observation.

    Science.gov (United States)

    Kawaguchi, Akira T; Haida, Munetaka; Ohba, Hiroyuki; Yamano, Mariko; Fukumoto, Dai; Tsukada, Hideo

    2013-10-01

    Liposome-encapsulated hemoglobin (LEH) is protective early after brain ischemia in rats and nonhuman primates, but it remains unclear whether the protection persists and confers any benefits beyond the acute phase of brain ischemia and reperfusion. Ten monkeys underwent middle cerebral artery occlusion, received LEH (2 mL/kg, n = 5) or saline (2 mL/kg, n = 5) 5 min later, and reperfusion 3 h later. Positron emission tomography studies were repeated for the cerebral metabolic rate of O2 (CMRO2 ) as well as glucose (CMRglc) up to 8 days after reperfusion, when the animals were euthanized for morphological studies. There was no difference in O2 metabolism until 3 h after reperfusion, when CMRO2 was significantly better preserved in the cortex, but not in basal ganglia, on Day 0 in LEH-treated monkeys. The extent of cortical infarction (saline 68 ± 10% vs. LEH 38 ± 9%, P < 0.05) and CMRO2 (mild suppression: saline 34 ± 10% vs. LEH 14 ± 4%, P < 0.05) remained significantly better preserved 8 days later, when CMRglc showed a similar pattern of cortical protection (mild suppression: saline 49 ± 15% vs. LEH 37 ± 4%, P < 0.05) in LEH-treated monkeys, together with regained body weight. Somatic weight control, morphological integrity, CMRO2 , and CMRglc were better preserved immediately, as well as 8 days after occlusion and reperfusion of the middle cerebral artery in monkeys receiving LEH early after onset of ischemia.

  12. Validation of serological tests for the detection of antibodies against Treponema pallidum in nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Sascha Knauf

    2015-03-01

    Full Text Available There is evidence to suggest that the yaws bacterium (Treponema pallidum ssp. pertenue may exist in non-human primate populations residing in regions where yaws is endemic in humans. Especially in light of the fact that the World Health Organizaiton (WHO recently launched its second yaws eradication campaign, there is a considerable need for reliable tools to identify treponemal infection in our closest relatives, African monkeys and great apes. It was hypothesized that commercially available serological tests detect simian anti-T. pallidum antibody in serum samples of baboons, with comparable sensitivity and specificity to their results on human sera. Test performances of five different treponemal tests (TTs and two non-treponemal tests (NTTs were evaluated using serum samples of 57 naturally T. pallidum-infected olive baboons (Papio anubis from Lake Manyara National Park in Tanzania. The T. pallidum particle agglutination assay (TP-PA was used as a gold standard for comparison. In addition, the overall infection status of the animals was used to further validate test performances. For most accurate results, only samples that originated from baboons of known infection status, as verified in a previous study by clinical inspection, PCR and immunohistochemistry, were included. All tests, TTs and NTTs, used in this study were able to reliably detect antibodies against T. pallidum in serum samples of infected baboons. The sensitivity of TTs ranged from 97.7-100%, while specificity was between 88.0-100.0%. The two NTTs detected anti-lipoidal antibodies in serum samples of infected baboons with a sensitivity of 83.3% whereas specificity was 100%. For screening purposes, the TT Espline TP provided the highest sensitivity and specificity and at the same time provided the most suitable format for use in the field. The enzyme immune assay Mastblot TP (IgG, however, could be considered as a confirmatory test.

  13. Validation of serological tests for the detection of antibodies against Treponema pallidum in nonhuman primates.

    Science.gov (United States)

    Knauf, Sascha; Dahlmann, Franziska; Batamuzi, Emmanuel K; Frischmann, Sieghard; Liu, Hsi

    2015-03-01

    There is evidence to suggest that the yaws bacterium (Treponema pallidum ssp. pertenue) may exist in non-human primate populations residing in regions where yaws is endemic in humans. Especially in light of the fact that the World Health Organizaiton (WHO) recently launched its second yaws eradication campaign, there is a considerable need for reliable tools to identify treponemal infection in our closest relatives, African monkeys and great apes. It was hypothesized that commercially available serological tests detect simian anti-T. pallidum antibody in serum samples of baboons, with comparable sensitivity and specificity to their results on human sera. Test performances of five different treponemal tests (TTs) and two non-treponemal tests (NTTs) were evaluated using serum samples of 57 naturally T. pallidum-infected olive baboons (Papio anubis) from Lake Manyara National Park in Tanzania. The T. pallidum particle agglutination assay (TP-PA) was used as a gold standard for comparison. In addition, the overall infection status of the animals was used to further validate test performances. For most accurate results, only samples that originated from baboons of known infection status, as verified in a previous study by clinical inspection, PCR and immunohistochemistry, were included. All tests, TTs and NTTs, used in this study were able to reliably detect antibodies against T. pallidum in serum samples of infected baboons. The sensitivity of TTs ranged from 97.7-100%, while specificity was between 88.0-100.0%. The two NTTs detected anti-lipoidal antibodies in serum samples of infected baboons with a sensitivity of 83.3% whereas specificity was 100%. For screening purposes, the TT Espline TP provided the highest sensitivity and specificity and at the same time provided the most suitable format for use in the field. The enzyme immune assay Mastblot TP (IgG), however, could be considered as a confirmatory test.

  14. Vesicular stomatitis virus-based ebola vaccine is well-tolerated and protects immunocompromised nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Thomas W Geisbert

    2008-11-01

    Full Text Available Ebola virus (EBOV is a significant human pathogen that presents a public health concern as an emerging/re-emerging virus and as a potential biological weapon. Substantial progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against EBOV. Among these prospects, a vaccine based on recombinant vesicular stomatitis virus (VSV is particularly robust, as it can also confer protection when administered as a postexposure treatment. A concern that has been raised regarding the replication-competent VSV vectors that express EBOV glycoproteins is how these vectors would be tolerated by individuals with altered or compromised immune systems such as patients infected with HIV. This is especially important as all EBOV outbreaks to date have occurred in areas of Central and Western Africa with high HIV incidence rates in the population. In order to address this concern, we evaluated the safety of the recombinant VSV vector expressing the Zaire ebolavirus glycoprotein (VSVDeltaG/ZEBOVGP in six rhesus macaques infected with simian-human immunodeficiency virus (SHIV. All six animals showed no evidence of illness associated with the VSVDeltaG/ZEBOVGP vaccine, suggesting that this vaccine may be safe in immunocompromised populations. While one goal of the study was to evaluate the safety of the candidate vaccine platform, it was also of interest to determine if altered immune status would affect vaccine efficacy. The vaccine protected 4 of 6 SHIV-infected macaques from death following ZEBOV challenge. Evaluation of CD4+ T cells in all animals showed that the animals that succumbed to lethal ZEBOV challenge had the lowest CD4+ counts, suggesting that CD4+ T cells may play a role in mediating protection against ZEBOV.

  15. Neuroanatomical study of the A11 diencephalospinal pathway in the non-human primate.

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    Quentin Barraud

    Full Text Available BACKGROUND: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP. We therefore characterized the anatomy of this pathway in the NHP. METHODS AND FINDINGS: In situ hybridization of spinal dopamine receptors showed that D1 receptor mRNA is absent while D2 and D5 receptor mRNAs are mainly expressed in the dorsal horn and D3 receptor mRNA in both the dorsal and ventral horns. Unilateral injections of the retrograde tracer Fluoro-Gold (FG into the cervical spinal enlargement labeled A11 hypothalamic neurons quasi-exclusively among dopamine areas. Detailed immunohistochemical analysis suggested that these FG-labeled A11 neurons are tyrosine hydroxylase-positive but dopa-decarboxylase and dopamine transporter-negative, suggestive of a L-DOPAergic nucleus. Stereological cell count of A11 neurons revealed that this group is composed by 4002±501 neurons per side. A 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP intoxication with subsequent development of a parkinsonian syndrome produced a 50% neuronal cell loss in the A11 group. CONCLUSION: The diencephalic A11 area could be the major source of L-DOPA in the NHP spinal cord, where it may play a role in the modulation of sensorimotor integration through D2 and D3 receptors either directly or indirectly via dopamine formation in spinal dopa-decarboxylase-positives cells.

  16. Frequent simian foamy virus infection in persons occupationally exposed to nonhuman primates.

    Science.gov (United States)

    Switzer, William M; Bhullar, Vinod; Shanmugam, Vedapuri; Cong, Mian-Er; Parekh, Bharat; Lerche, Nicholas W; Yee, JoAnn L; Ely, John J; Boneva, Roumiana; Chapman, Louisa E; Folks, Thomas M; Heneine, Walid

    2004-03-01

    The recognition that AIDS originated as a zoonosis heightens public health concerns associated with human infection by simian retroviruses endemic in nonhuman primates (NHPs). These retroviruses include simian immunodeficiency virus (SIV), simian T-cell lymphotropic virus (STLV), simian type D retrovirus (SRV), and simian foamy virus (SFV). Although occasional infection with SIV, SRV, or SFV in persons occupationally exposed to NHPs has been reported, the characteristics and significance of these zoonotic infections are not fully defined. Surveillance for simian retroviruses at three research centers and two zoos identified no SIV, SRV, or STLV infection in 187 participants. However, 10 of 187 persons (5.3%) tested positive for SFV antibodies by Western blot (WB) analysis. Eight of the 10 were males, and 3 of the 10 worked at zoos. SFV integrase gene (int) and gag sequences were PCR amplified from the peripheral blood lymphocytes available from 9 of the 10 persons. Phylogenetic analysis showed SFV infection originating from chimpanzees (n = 8) and baboons (n = 1). SFV seropositivity for periods of 8 to 26 years (median, 22 years) was documented for six workers for whom archived serum samples were available, demonstrating long-standing SFV infection. All 10 persons reported general good health, and secondary transmission of SFV was not observed in three wives available for WB and PCR testing. Additional phylogenetic analysis of int and gag sequences provided the first direct evidence identifying the source chimpanzees of the SFV infection in two workers. This study documents more frequent infection with SFV than with other simian retroviruses in persons working with NHPs and provides important information on the natural history and species origin of these infections. Our data highlight the importance of studies to better define the public health implications of zoonotic SFV infections.

  17. Differential effects of HOXB4 on nonhuman primate short- and long-term repopulating cells.

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    Xiao-Bing Zhang

    2006-05-01

    Full Text Available BACKGROUND: Hematopoietic stem cells (HSCs or repopulating cells are able to self-renew and differentiate into cells of all hematopoietic lineages, and they can be enriched using the CD34 cell surface marker. Because of this unique property, HSCs have been used for HSC transplantation and gene therapy applications. However, the inability to expand HSCs has been a significant limitation for clinical applications. Here we examine, in a clinically relevant nonhuman primate model, the ability of HOXB4 to expand HSCs to potentially overcome this limitation. METHODS AND FINDINGS: Using a competitive repopulation assay, we directly compared in six animals engraftment of HOXB4GFP (HOXB4 green fluorescent protein and control (yellow fluorescent protein [YFP]-transduced and expanded CD34+ cells. In three animals, cells were infused after a 3-d transduction culture, while in three other animals cells were infused after an additional 6-9 d of ex vivo expansion. We demonstrate that HOXB4 overexpression resulted in superior engraftment in all animals. The most dramatic effect of HOXB4 was observed early after transplantation, resulting in an up to 56-fold higher engraftment compared to the control cells. At 6 mo after transplantation, the proportion of marker gene-expressing cells in peripheral blood was still up to 5-fold higher for HOXB4GFP compared to YFP-transduced cells. CONCLUSIONS: These data demonstrate that HOXB4 overexpression in CD34+ cells has a dramatic effect on expansion and engraftment of short-term repopulating cells and a significant, but less pronounced, effect on long-term repopulating cells. These data should have important implications for the expansion and transplantation of HSCs, in particular for cord blood transplantations where often only suboptimal numbers of HSCs are available.

  18. Social complexity parallels vocal complexity: a comparison of three nonhuman primate species

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    Hélène eBOUCHET

    2013-07-01

    Full Text Available Social factors play a key role in the structuring of vocal repertoires at the individual level, notably in nonhuman 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

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

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    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).

  20. Chronic cortical and electromyographic recordings from a fully implantable device: preclinical experience in a nonhuman primate

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    Ryapolova-Webb, Elena; Afshar, Pedram; Stanslaski, Scott; Denison, Tim; de Hemptinne, Coralie; Bankiewicz, Krystof; Starr, Philip A.

    2014-02-01

    Objective. Analysis of intra- and perioperatively recorded cortical and basal ganglia local field potentials in human movement disorders has provided great insight into the pathophysiology of diseases such as Parkinson's, dystonia, and essential tremor. However, in order to better understand the network abnormalities and effects of chronic therapeutic stimulation in these disorders, long-term recording from a fully implantable data collection system is needed. Approach. A fully implantable investigational data collection system, the Activa® PC + S neurostimulator (Medtronic, Inc., Minneapolis, MN), has been developed for human use. Here, we tested its utility for extended intracranial recording in the motor system of a nonhuman primate. The system was attached to two quadripolar paddle arrays: one covering sensorimotor cortex, and one covering a proximal forelimb muscle, to study simultaneous cortical field potentials and electromyography during spontaneous transitions from rest to movement. Main results. Over 24 months of recording, movement-related changes in physiologically relevant frequency bands were readily detected, including beta and gamma signals at approximately 2.5 μV/\\sqrtHz and 0.7 μV/\\sqrt{Hz}, respectively. The system architecture allowed for flexible recording configurations and algorithm triggered data recording. In the course of physiological analyses, sensing artifacts were observed (˜1 μVrms stationary tones at fixed frequency), which were mitigated either with post-processing or algorithm design and did not impact the scientific conclusions. Histological examination revealed no underlying tissue damage; however, a fibrous capsule had developed around the paddles, demonstrating a potential mechanism for the observed signal amplitude reduction. Significance. This study establishes the usefulness of this system in measuring chronic brain and muscle signals. Use of this system may potentially be valuable in human trials of chronic brain

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

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    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.

  2. Effect of Synthetic Truncated Apolipoprotein C-I Peptide on Plasma Lipoprotein Cholesterol in Nonhuman Primates

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    Rampratap S. Kushwaha

    2004-01-01

    Full Text Available The present studies were conducted to determine whether a synthetic truncated apoC-I peptide that inhibits CETP activity in baboons would raise plasma HDL cholesterol levels in nonhuman primates with low HDL levels. We used 2 cynomolgus monkeys and 3 baboons fed a cholesterol- and fat-enriched diet. In cynomolgus monkeys, we injected synthetic truncated apoC-I inhibitor peptide at a dose of 20 mg/kg and, in baboons, at doses of 10, 15, and 20 mg/kg at weekly intervals. Blood samples were collected 3 times a week and VLDL + LDL and HDL cholesterol concentrations were measured. In cynomolgus monkeys, administration of the inhibitor peptide caused a rapid decrease in VLDL + LDL cholesterol concentrations (30%–60% and an increase in HDL cholesterol concentrations (10%–20%. VLDL + LDL cholesterol concentrations returned to baseline levels in approximately 15 days. In baboons, administration of the synthetic inhibitor peptide caused a decrease in VLDL + LDL cholesterol (20%–60% and an increase in HDL cholesterol (10%–20%. VLDL + LDL cholesterol returned to baseline levels by day 21, whereas HDL cholesterol concentrations remained elevated for up to 26 days. ApoA-I concentrations increased, whereas apoE and triglyceride concentrations decreased. Subcutaneous and intravenous administrations of the inhibitor peptide had similar effects on LDL and HDL cholesterol concentrations. There was no change in body weight, food consumption, or plasma IgG levels of any baboon during the study. These studies suggest that the truncated apoC-I peptide can be used to raise HDL in humans.

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

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    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.

  4. The early postnatal nonhuman primate neocortex contains self-renewing multipotent neural progenitor cells.

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    Jihane Homman-Ludiye

    Full Text Available The postnatal neocortex has traditionally been considered a non-neurogenic region, under non-pathological conditions. A few studies suggest, however, that a small subpopulation of neural cells born during postnatal life can differentiate into neurons that take up residence within the neocortex, implying that postnatal neurogenesis could occur in this region, albeit at a low level. Evidence to support this hypothesis remains controversial while the source of putative neural progenitors responsible for generating new neurons in the postnatal neocortex is unknown. Here we report the identification of self-renewing multipotent neural progenitor cells (NPCs derived from the postnatal day 14 (PD14 marmoset monkey primary visual cortex (V1, striate cortex. While neuronal maturation within V1 is well advanced by PD14, we observed cells throughout this region that co-expressed Sox2 and Ki67, defining a population of resident proliferating progenitor cells. When cultured at low density in the presence of epidermal growth factor (EGF and/or fibroblast growth factor 2 (FGF-2, dissociated V1 tissue gave rise to multipotent neurospheres that exhibited the ability to differentiate into neurons, oligodendrocytes and astrocytes. While the capacity to generate neurones and oligodendrocytes was not observed beyond the third passage, astrocyte-restricted neurospheres could be maintained for up to 6 passages. This study provides the first direct evidence for the existence of multipotent NPCs within the postnatal neocortex of the nonhuman primate. The potential contribution of neocortical NPCs to neural repair following injury raises exciting new possibilities for the field of regenerative medicine.

  5. Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.

    Science.gov (United States)

    Madelain, Vincent; Guedj, Jérémie; Mentré, France; Nguyen, Thi Huyen Tram; Jacquot, Frédéric; Oestereich, Lisa; Kadota, Takumi; Yamada, Koichi; Taburet, Anne-Marie; de Lamballerie, Xavier; Raoul, Hervé

    2017-01-01

    Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC50) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.

  6. The early postnatal nonhuman primate neocortex contains self-renewing multipotent neural progenitor cells.

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    Homman-Ludiye, Jihane; Merson, Tobias D; Bourne, James A

    2012-01-01

    The postnatal neocortex has traditionally been considered a non-neurogenic region, under non-pathological conditions. A few studies suggest, however, that a small subpopulation of neural cells born during postnatal life can differentiate into neurons that take up residence within the neocortex, implying that postnatal neurogenesis could occur in this region, albeit at a low level. Evidence to support this hypothesis remains controversial while the source of putative neural progenitors responsible for generating new neurons in the postnatal neocortex is unknown. Here we report the identification of self-renewing multipotent neural progenitor cells (NPCs) derived from the postnatal day 14 (PD14) marmoset monkey primary visual cortex (V1, striate cortex). While neuronal maturation within V1 is well advanced by PD14, we observed cells throughout this region that co-expressed Sox2 and Ki67, defining a population of resident proliferating progenitor cells. When cultured at low density in the presence of epidermal growth factor (EGF) and/or fibroblast growth factor 2 (FGF-2), dissociated V1 tissue gave rise to multipotent neurospheres that exhibited the ability to differentiate into neurons, oligodendrocytes and astrocytes. While the capacity to generate neurones and oligodendrocytes was not observed beyond the third passage, astrocyte-restricted neurospheres could be maintained for up to 6 passages. This study provides the first direct evidence for the existence of multipotent NPCs within the postnatal neocortex of the nonhuman primate. The potential contribution of neocortical NPCs to neural repair following injury raises exciting new possibilities for the field of regenerative medicine.

  7. Is alpha-synuclein loss-of-function a contributor to parkinsonian pathology? Evidence from non-human primates

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    Timothy J Collier

    2016-01-01

    Full Text Available 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 nonhuman primates reproduces the pattern of nigrostriatal degeneration characteristic of PD.

  8. Spontaneous abortion and preterm labor and delivery in nonhuman primates: evidence from a captive colony of chimpanzees (Pan troglodytes.

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    Derek E Wildman

    Full Text Available BACKGROUND: Preterm birth is a leading cause of perinatal mortality, yet the evolutionary history of this obstetrical syndrome is largely unknown in nonhuman primate species. METHODOLOGY/PRINCIPAL FINDINGS: We examined the length of gestation during pregnancies that occurred in a captive chimpanzee colony by inspecting veterinary and behavioral records spanning a total of thirty years. Upon examination of these records we were able to confidently estimate gestation length for 93 of the 97 (96% pregnancies recorded at the colony. In total, 78 singleton gestations resulted in live birth, and from these pregnancies we estimated the mean gestation length of normal chimpanzee pregnancies to be 228 days, a finding consistent with other published reports. We also calculated that the range of gestation in normal chimpanzee pregnancies is approximately forty days. Of the remaining fifteen pregnancies, only one of the offspring survived, suggesting viability for chimpanzees requires a gestation of approximately 200 days. These fifteen pregnancies constitute spontaneous abortions and preterm deliveries, for which the upper gestational age limit was defined as 2 SD from the mean length of gestation (208 days. CONCLUSIONS/SIGNIFICANCE: The present study documents that preterm birth occurred within our study population of captive chimpanzees. As in humans, pregnancy loss is not uncommon in chimpanzees, In addition, our findings indicate that both humans and chimpanzees show a similar range of normal variation in gestation length, suggesting this was the case at the time of their last common ancestor (LCA. Nevertheless, our data suggest that whereas chimpanzees' normal gestation length is ∼20-30 days after reaching viability, humans' normal gestation length is approximately 50 days beyond the estimated date of viability without medical intervention. Future research using a comparative evolutionary framework should help to clarify the extent to which

  9. Temporal evolution of ischemic lesions in nonhuman primates: a diffusion and perfusion MRI study.

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    Xiaodong Zhang

    Full Text Available Diffusion-weighted imaging (DWI and perfusion MRI were used to examine the spatiotemporal evolution of stroke lesions in adult macaques with ischemic occlusion.Permanent MCA occlusion was induced with silk sutures through an interventional approach via the femoral artery in adult rhesus monkeys (n = 8, 10-21 years old. The stroke lesions were examined with high-resolution DWI and perfusion MRI, and T2-weighted imaging (T2W on a clinical 3T scanner at 1-6, 48, and 96 hours post occlusion and validated with H&E staining.The stroke infarct evolved via a natural logarithmic pattern with the mean infarct growth rate = 1.38 ± 1.32 ml per logarithmic time scale (hours (n = 7 in the hyperacute phase (1-6 hours. The mean infarct volume after 6 hours post occlusion was 3.6±2.8 ml (n = 7, by DWI and increased to 3.9±2.9 ml (n = 5, by T2W after 48 hours, and to 4.7±2.2ml (n = 3, by T2W after 96 hours post occlusion. The infarct volumes predicted by the natural logarithmic function were correlated significantly with the T2W-derived lesion volumes (n = 5, r = 0.92, p = 0.01 at 48 hours post occlusion. The final infarct volumes derived from T2W were correlated significantly with those from H&E staining (r = 0.999, p < 0.0001, n = 4. In addition, the diffusion-perfusion mismatch was visible generally at 6 hours but nearly diminished at 48 hours post occlusion.The infarct evolution follows a natural logarithmic pattern in the hyperacute phase of stroke. The logarithmic pattern of evolution could last up to 48 hours after stroke onset and may be used to predict the infarct volume growth during the acute phase of ischemic stroke. The nonhuman primate model, MRI protocols, and post data processing strategy may provide an excellent platform for characterizing the evolution of acute stroke lesion in mechanistic studies and therapeutic interventions of stroke disease.

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

    Science.gov (United States)

    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

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

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

    2015-10-01

    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.

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

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    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".

  13. Venezuelan equine encephalitis virus replicon particle vaccine protects nonhuman primates from intramuscular and aerosol challenge with ebolavirus.

    Science.gov (United States)

    Herbert, Andrew S; Kuehne, Ana I; Barth, James F; Ortiz, Ramon A; Nichols, Donald K; Zak, Samantha E; Stonier, Spencer W; Muhammad, Majidat A; Bakken, Russell R; Prugar, Laura I; Olinger, Gene G; Groebner, Jennifer L; Lee, John S; Pratt, William D; Custer, Max; Kamrud, Kurt I; Smith, Jonathan F; Hart, Mary Kate; Dye, John M

    2013-05-01

    There are no vaccines or therapeutics currently approved for the prevention or treatment of ebolavirus infection. Previously, a replicon vaccine based on Venezuelan equine encephalitis virus (VEEV) demonstrated protective efficacy against Marburg virus in nonhuman primates. Here, we report the protective efficacy of Sudan virus (SUDV)- and Ebola virus (EBOV)-specific VEEV replicon particle (VRP) vaccines in nonhuman primates. VRP vaccines were developed to express the glycoprotein (GP) of either SUDV or EBOV. A single intramuscular vaccination of cynomolgus macaques with VRP expressing SUDV GP provided complete protection against intramuscular challenge with SUDV. Vaccination against SUDV and subsequent survival of SUDV challenge did not fully protect cynomolgus macaques against intramuscular EBOV back-challenge. However, a single simultaneous intramuscular vaccination with VRP expressing SUDV GP combined with VRP expressing EBOV GP did provide complete protection against intramuscular challenge with either SUDV or EBOV in cynomolgus macaques. Finally, intramuscular vaccination with VRP expressing SUDV GP completely protected cynomolgus macaques when challenged with aerosolized SUDV, although complete protection against aerosol challenge required two vaccinations with this vaccine.

  14. Maternal high fat diet is associated with decreased plasma n-3 fatty acids and fetal hepatic apoptosis in nonhuman primates.

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    Wilmon F Grant

    Full Text Available To begin to understand the contributions of maternal obesity and over-nutrition to human development and the early origins of obesity, we utilized a non-human primate model to investigate the effects of maternal high-fat feeding and obesity on breast milk, maternal and fetal plasma fatty acid composition and fetal hepatic development. While the high-fat diet (HFD contained equivalent levels of n-3 fatty acids (FA's and higher levels of n-6 FA's than the control diet (CTR, we found significant decreases in docosahexaenoic acid (DHA and total n-3 FA's in HFD maternal and fetal plasma. Furthermore, the HFD fetal plasma n-6:n-3 ratio was elevated and was significantly correlated to the maternal plasma n-6:n-3 ratio and maternal hyperinsulinemia. Hepatic apoptosis was also increased in the HFD fetal liver. Switching HFD females to a CTR diet during a subsequent pregnancy normalized fetal DHA, n-3 FA's and fetal hepatic apoptosis to CTR levels. Breast milk from HFD dams contained lower levels of eicosopentanoic acid (EPA and DHA and lower levels of total protein than CTR breast milk. This study links chronic maternal consumption of a HFD with fetal hepatic apoptosis and suggests that a potentially pathological maternal fatty acid milieu is replicated in the developing fetal circulation in the nonhuman primate.

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

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    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

  16. Reported analgesic administration to rabbits, pigs, sheep, dogs and non-human primates undergoing experimental surgical procedures.

    Science.gov (United States)

    Coulter, C A; Flecknell, P A; Richardson, C A

    2009-07-01

    Reported analgesic use following experimental surgery is low in rodents and there has been little published information on the frequency of analgesic use in other laboratory species. A structured literature review was conducted to examine analgesic administration in larger laboratory animals. The Scirus search engine was used to identify studies published in peer-reviewed journals that reported carrying out experimental surgery on 'large' laboratory animals, specifically rabbits, pigs, sheep, dogs and non-human primates. Seventy-four studies between 2000 and 2001 and 75 studies between 2005 and 2006 were included in the review. There was an increase in the reported administration of systemic analgesics to these species from 50% in 2000-2001 to 63% in 2005-2006. When all agents with analgesic properties were considered (systemic analgesics, local anaesthetics and anaesthetics with analgesic components), the proportion of papers that reported some form of analgesic administration to 'large' laboratory animals increased from 86% in 2000-2001 to 89% in 2005-2006. Overall rabbits, pigs, sheep, dogs and non-human primates were more likely to receive analgesics following potentially painful experimental procedures than has been reported in laboratory rodents but analgesic administration to 'large' laboratory species is still not optimal.

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

    Energy Technology Data Exchange (ETDEWEB)

    Naidoo-Variawa, S [Discipline of Medical Radiation Sciences, Faculty of Health Sciences, University of Sydney, PO Box 170, Lidcombe, NSW 1825, Sydney (Australia); Hey-Cunningham, A J [Discipline of Medical Radiation Sciences, Faculty of Health Sciences, University of Sydney, PO Box 170, Lidcombe, NSW 1825, Sydney (Australia); Lehnert, W [Discipline of Medical Radiation Sciences, Faculty of Health Sciences, University of Sydney, PO Box 170, Lidcombe, NSW 1825, Sydney (Australia); Kench, P L [Discipline of Medical Radiation Sciences, Faculty of Health Sciences, University of Sydney, PO Box 170, Lidcombe, NSW 1825, Sydney (Australia); Kassiou, M [Discipline of Medical Radiation Sciences, Faculty of Health Sciences, University of Sydney, PO Box 170, Lidcombe, NSW 1825, Sydney (Australia); Banati, R [Discipline of Medical Radiation Sciences, Faculty of Health Sciences, University of Sydney, PO Box 170, Lidcombe, NSW 1825, Sydney (Australia); Meikle, S R [Discipline of Medical Radiation Sciences, Faculty of Health Sciences, University of Sydney, PO Box 170, Lidcombe, NSW 1825, Sydney (Australia)

    2007-11-21

    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 mm{sup 3} FWHM from centre to 4 cm offset) compared to both 3D ordered subsets expectation maximization (OSEM) (5.6-8.3 mm{sup 3}) and 3D reprojection (3DRP) (5.9-9.1 mm{sup 3}). A pilot {sup 18}F-2-fluoro-2-deoxy-d-glucose ([{sup 18}F]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.

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

    Science.gov (United States)

    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.

  19. "Vision for Action" in Young Children Aligning Multi-Featured Objects: Development and Comparison with Nonhuman Primates.

    Science.gov (United States)

    Fragaszy, Dorothy Munkenbeck; Kuroshima, Hika; Stone, Brian W

    2015-01-01

    Effective vision for action and effective management of concurrent spatial relations underlie skillful manipulation of objects, including hand tools, in humans. Children's performance in object insertion tasks (fitting tasks) provides one index of the striking changes in the development of vision for action in early life. Fitting tasks also tap children's ability to work with more than one feature of an object concurrently. We examine young children's performance on fitting tasks in two and three dimensions and compare their performance with the previously reported performance of adult individuals of two species of nonhuman primates on similar tasks. Two, three, and four year-old children routinely aligned a bar-shaped stick and a cross-shaped stick but had difficulty aligning a tomahawk-shaped stick to a matching cut-out. Two year-olds were especially challenged by the tomahawk. Three and four year-olds occasionally held the stick several inches above the surface, comparing the stick to the surface visually, while trying to align it. The findings suggest asynchronous development in the ability to use vision to achieve alignment and to work with two and three spatial features concurrently. Using vision to align objects precisely to other objects and managing more than one spatial relation between an object and a surface are already more elaborated in two year-old humans than in other primates. The human advantage in using hand tools derives in part from this fundamental difference in the relation between vision and action between humans and other primates.

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

    Science.gov (United States)

    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 0.05). Crypt depth was also significantly reduced in all segments on day 4, 7 and 12 after irradiation (P 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 marrow decreased significantly. In summary, TBI in the hematopoietic ARS dose range induces substantial intestinal injury in all segments of the small bowel. These findings underscore the importance of maintaining the

  1. Plasma and cerebrospinal fluid pharmacokinetics of the histone deacetylase inhibitor, belinostat (PXD101), in non-human primates

    DEFF Research Database (Denmark)

    Warren, K.E.; McCully, C.; Dvinge, H.;

    2008-01-01

    is a novel, potent, pan-HDAC inhibitor with antiproliferative activity on a wide variety of tumor cell lines. We studied the cerebrospinal fluid (CSF) penetration of intravenous (IV) belinostat in a non-human primate model as a surrogate for blood:brain barrier penetration. DESIGN: Five adult rhesus monkeys...... received increasing doses of belinostat (10-60 mg/kg) as a 30-min IV infusion. Serial blood and CSF samples were collected over 48 h. Plasma and CSF concentrations of belinostat were quantified with an LC/MS/MS assay. Pharmacokinetic parameters were calculated using non-compartmental methods, and CSF....... CSF drug exposure was drug exposure and drug exposure. CONCLUSION: IV belinostat is rapidly cleared from plasma and has limited penetration into the CSF Udgivelsesdato: 2008/8...

  2. Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail.

    Science.gov (United States)

    Kugelman, Jeffrey R; Kugelman-Tonos, Johanny; Ladner, Jason T; Pettit, James; Keeton, Carolyn M; Nagle, Elyse R; Garcia, Karla Y; Froude, Jeffrey W; Kuehne, Ana I; Kuhn, Jens H; Bavari, Sina; Zeitlin, Larry; Dye, John M; Olinger, Gene G; Sanchez-Lockhart, Mariano; Palacios, Gustavo F

    2015-09-29

    MB-003, a plant-derived monoclonal antibody cocktail used effectively in treatment of Ebola virus infection in non-human primates, was unable to protect two of six animals when initiated 1 or 2 days post-infection. We characterized a mechanism of viral escape in one of the animals, after observation of two clusters of genomic mutations that resulted in five nonsynonymous mutations in the monoclonal antibody target sites. These mutations were linked to a reduction in antibody binding and later confirmed to be present in a viral isolate that was not neutralized in vitro. Retrospective evaluation of a second independent study allowed the identification of a similar case. Four SNPs in previously identified positions were found in this second fatality, suggesting that genetic drift could be a potential cause for treatment failure. These findings highlight the importance selecting different target domains for each component of the cocktail to minimize the potential for viral escape.

  3. Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates.

    Science.gov (United States)

    Bates, John T; Pickens, Jennifer A; Schuster, Jennifer E; Johnson, Monika; Tollefson, Sharon J; Williams, John V; Davis, Nancy L; Johnston, Robert E; Schultz-Darken, Nancy; Slaughter, James C; Smith-House, Frances; Crowe, James E

    2016-02-10

    Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are major causes of illness among children, the elderly, and the immunocompromised. No vaccine has been licensed for protection against either of these viruses. We tested the ability of two Venezuelan equine encephalitis virus-based viral replicon particle (VEE-VRP) vaccines that express the hRSV or hMPV fusion (F) protein to confer protection against hRSV or hMPV in African green monkeys. Animals immunized with VEE-VRP vaccines developed RSV or MPV F-specific antibodies and serum neutralizing activity. Compared to control animals, immunized animals were better able to control viral load in the respiratory mucosa following challenge and had lower levels of viral genome in nasopharyngeal and bronchoalveolar lavage fluids. The high level of immunogenicity and protective efficacy induced by these vaccine candidates in nonhuman primates suggest that they hold promise for further development.

  4. A Kunjin Replicon Virus-like Particle Vaccine Provides Protection Against Ebola Virus Infection in Nonhuman Primates.

    Science.gov (United States)

    Pyankov, Oleg V; Bodnev, Sergey A; Pyankova, Olga G; Solodkyi, Vladislav V; Pyankov, Stepan A; Setoh, Yin Xiang; Volchkova, Valentina A; Suhrbier, Andreas; Volchkov, Viktor V; Agafonov, Alexander A; Khromykh, Alexander A

    2015-10-01

    The current unprecedented outbreak of Ebola virus (EBOV) disease in West Africa has demonstrated the urgent need for a vaccine. Here, we describe the evaluation of an EBOV vaccine candidate based on Kunjin replicon virus-like particles (KUN VLPs) encoding EBOV glycoprotein with a D637L mutation (GP/D637L) in nonhuman primates. Four African green monkeys (Cercopithecus aethiops) were injected subcutaneously with a dose of 10(9) KUN VLPs per animal twice with an interval of 4 weeks, and animals were challenged 3 weeks later intramuscularly with 600 plaque-forming units of Zaire EBOV. Three animals were completely protected against EBOV challenge, while one vaccinated animal and the control animal died from infection. We suggest that KUN VLPs encoding GP/D637L represent a viable EBOV vaccine candidate.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  7. Comparison of ICRP 67 and Other Plutonium Systemic Model Predictions with the Biokinetic Data from Nonhuman Primates.

    Science.gov (United States)

    Poudel, Deepesh; Krage, Eric Stephen; Brey, Richard Ray; Guilmette, Raymond A

    2016-04-01

    Despite the presence of a relatively large amount of human data available on the metabolism of plutonium, the experimental animal data is still important in constructing and parameterizing the biokinetic models. Recognizing this importance, the biokinetic data obtained from studies done by P.W. Durbin in nonhuman primates (NHP) were evaluated against the ICRP 67 systemic model and the two human models developed thereafter. The default transfer rates recommended for adult humans in these models predict the urinary excretion in NHP to a certain extent. However, they were unable to describe the fecal excretion rates several days post intake and the activities in skeleton and liver at the time of the death. These inconsistencies between the human reference models and the NHP biokinetic data are the result of metabolic and physiological differences between the species, as demonstrated by early biokinetic studies.

  8. The rapid and sustained responses of dendritic cells to influenza virus infection in a non-human primate model.

    Science.gov (United States)

    Jie, Zhijun; Sun, Wei; Wang, Shanze; Koster, Frederick; Li, Bilan; Harrod, Kevin S

    2014-01-01

    Dendritic cells (DCs) are readily infected by influenza viruses and play a crucial role in regulating host innate and adaptive immune responses to viral infection. The aims of this study are to characterize the dynamic changes in the numbers and maturation status of dendritic cells present in the lung and lung-associated lymph nodes (LALNs) in the model of a non-human primate (NHP) infected by influenza A virus (IAV). Cynomolgus macaques were infected with influenza A virus (H3N2) via bronchoscopy. Flow cytometry was used to analyze the DC numbers, maturation status and subsets during the time of acute infection (days 1, 2, 3, 4, 7) and the resolution phase (day 30). A dramatic increase in the numbers of influenza A virus-infected CD11c+CD14- myeloid dendritic cells (mDCs) and CD11c-CD123+ plasmacytoid dendritic cells (pDCs) were observed from day 1 to day 4 and peak up from day 7 post-infection. In lung and lung-associated lymph nodes, the numbers and maturation status of myeloid dendritic cells and plasmacytoid dendritic cells increased more slowly than those in the lung tissues. On day 30 post-infection, influenza A virus challenge increased the number of myeloid dendritic cells, but not plasmacytoid dendritic cells, compared with baseline. These findings indicate that dendritic cells are susceptible to influenza A virus infection, with the likely purpose of increasing mature myeloid dendritic cells numbers in the lung and lung and lung-associated lymph nodes, which provides important new insights into the regulation of dendritic cells in a non-human primate model.

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

    Directory of Open Access Journals (Sweden)

    Vadim I Krivokrysenko

    Full Text Available 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.

  10. The role of harmonic resolvability in pitch perception in a vocal nonhuman primate, the common marmoset (Callithrix jacchus).

    Science.gov (United States)

    Osmanski, Michael S; Song, Xindong; Wang, Xiaoqin

    2013-05-22

    Pitch is one of the most fundamental percepts in the auditory system and can be extracted using either spectral or temporal information in an acoustic signal. Although pitch perception has been extensively studied in human subjects, it is far less clear how nonhuman primates perceive pitch. We have addressed this question in a series of behavioral studies in which marmosets, a vocal nonhuman primate species, were trained to discriminate complex harmonic tones differing in either spectral (fundamental frequency [f0]) or temporal envelope (repetition rate) cues. We found that marmosets used temporal envelope information to discriminate pitch for acoustic stimuli with higher-order harmonics and lower f0 values and spectral information for acoustic stimuli with lower-order harmonics and higher f0 values. We further measured frequency resolution in marmosets using a psychophysical task in which pure tone thresholds were measured as a function of notched noise masker bandwidth. Results show that only the first four harmonics are resolved at low f0 values and up to 16 harmonics are resolved at higher f0 values. Resolvability in marmosets is different from that in humans, where the first five to nine harmonics are consistently resolved across most f0 values, and is likely the result of a smaller marmoset cochlea. In sum, these results show that marmosets use two mechanisms to extract pitch (harmonic templates [spectral] for resolved harmonics, and envelope extraction [temporal] for unresolved harmonics) and that species differences in stimulus resolvability need to be taken into account when investigating and comparing mechanisms of pitch perception across animals.

  11. Energy expenditure in chow-fed female non-human primates of various weights

    Directory of Open Access Journals (Sweden)

    Kral John G

    2008-11-01

    Full Text Available Abstract Background Until now no technology has been available to study energy metabolism in monkeys. The objective of this study was to determine daily energy expenditures (EE and respiratory quotients (RQ in female monkeys of various body weights and ages. Methods 16 socially reared Bonnet Macaque female monkeys [5.5 ± 1.4 kg body weight, modified BMI (length measurement from head to base of the tail = 28.8 ± 6.7 kg/crown-rump length, m2 and 11.7 ± 4.6 years] were placed in the primate Enhanced Metabolic Testing Activity Chamber (Model 3000a, EMTAC Inc. Santa Barbara, CA for 22-hour measurements of EE (kcal/kg and RQ (VCO2/VO2. All were fed monkey chow (4.03 kcal/g ad-libitum under a 12/12 hour light/dark cycle. Metabolic data were corrected for differences in body weight. Results were divided into day (8-hours, dark (12 hours and morning (2-hours periods. Data analysis was conducted utilizing SPSS (Version 13. Results Modified BMI negatively correlated with 22-hour energy expenditure in all monkeys (r = -0.80, p 23 kcal/kg. There were reductions (p 30. The obese group had lower EE (p Conclusion The EMTAC proved to be a valuable tool for metabolic measurements in monkeys. The accuracy and sensitivity of the instrument allowed detection of subtle metabolic changes in relation to energy intake. Moreover, there is an association between a reduction of energy expenditure and a gain in body weight.

  12. Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates.

    Directory of Open Access Journals (Sweden)

    John C Lin

    Full Text Available Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity.

  13. 77 FR 6971 - Establishment of User Fees for Filovirus Testing of Nonhuman Primate Liver Samples

    Science.gov (United States)

    2012-02-10

    ... facial edema and jaundice. Severe thrombocytopenia can occur, with hemorrhagic manifestations ranging... instructed how to transfer tissue specimens to HHS/ CDC for testing. After receipt of the specimens, HHS/CDC..., Clarence J. Enzyme immunosorbent assay for Ebola virus antigens in tissues of infected primates. Journal...

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

    Directory of Open Access Journals (Sweden)

    Roqueline A. G. M. F. Aversi-Ferreira

    2014-01-01

    Full Text Available 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.

  15. Molecular identification and characterization of Mycobacterium avium subspecies paratuberculosis in free living non-human primate (Rhesus macaques) from North India.

    Science.gov (United States)

    Singh, S V; Singh, A V; Singh, P K; Kumar, A; Singh, B

    2011-05-01

    In recent years, Mycobacterium avium subspecies paratuberculosis (MAP) has emerged as major animal pathogen with significant zoonotic concerns, worldwide. MAP infection is endemic in domestic and wild ruminant population in India. However, information on MAP infection in free ranging animal species and non human primates is limited. Present study aimed to estimate the status of MAP infection in free living Rhesus macaques suffering with multiple clinical conditions (coughing and loose stool). A total of 25 stool samples were collected from six colonies of Rhesus macaques from Mathura region (North India) and screened for the presence of MAP, using microscopic examination and IS900 PCR, directly from stool samples. PCR positive DNA samples were further genotyped using IS1311 PCR-restriction enzyme analysis. Of the 25 stool samples, 10 (40.0%) and 2 (8.0%) were positive for MAP using microscopic examination and direct IS900 PCR, respectively. IS900 PCR positive DNA samples were genotyped as 'Indian Bison type', which is a major MAP genotype infecting domestic and wild ruminant species and human beings in India. Prevalence of MAP in Rhesus macaques (Indian monkeys) was moderately high and confirmed interspecies sharing of MAP between domestic livestock and non-human primates. Presence of MAP in non-human primates, support the etiological role of MAP in inflammatory bowel disease patients. Indian monkeys may serve as model for understanding the role of non-human primates in sustenance, transmission and pathogenesis of MAP infection.

  16. Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospinal fluid.

    Science.gov (United States)

    Butelman, Eduardo R; Prisinzano, Thomas E; Deng, Haiteng; Rus, Szymon; Kreek, Mary Jeanne

    2009-02-01

    Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high-efficacy kappa-agonist in vitro, with some unique pharmacodynamic properties. Descriptive reports show that salvinorin A-containing products produce robust behavioral effects in humans. However, these effects have not been systematically characterized in human or nonhuman primates to date. Therefore, the present studies focused on the characterization of overt effects of salvinorin A, such as sedation (operationally defined as unresponsiveness to environmental stimuli) and postural relaxation, previously observed with centrally penetrating kappa-agonists in nonhuman primates. Salvinorin A was active in these endpoints (dose range, 0.01-0.1 mg/kg i.v.) in nonhuman primates (n = 3-5), similar to the synthetic kappa-agonist U69,593 [(+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]-dec-8-yl]-benzeneacetamide], used for comparison herein. Salvinorin A effects could be prevented by a clinically available opioid antagonist, nalmefene (0.1 mg/kg), at doses known to block kappa-receptor-mediated effects in nonhuman primates. When injected intravenously, salvinorin A (0.032 mg/kg) could enter the central nervous system (as reflected in cisternal cerebrospinal fluid) within 1 min and reach concentrations that are in the reported range of the affinity (K(i)) of this ligand for brain kappa-receptors. Consistent with this finding, specific translationally viable behavioral effects (e.g., facial relaxation and ptosis) could also be detected within 1 to 2 min of injection of salvinorin A. These are the first studies documenting rapid unconditioned effects of salvinorin A in a primate species, consistent with descriptive reports of rapid and robust effects of this powerful hallucinogen in humans.

  17. Resveratrol metabolism in a non-human primate, the grey mouse lemur (Microcebus murinus, using ultra-high-performance liquid chromatography-quadrupole time of flight.

    Directory of Open Access Journals (Sweden)

    Marie-Claude Menet

    Full Text Available 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.

  18. Reference in human and non-human primate communication: What does it take to refer?

    Science.gov (United States)

    Sievers, Christine; Gruber, Thibaud

    2016-07-01

    The concept of functional reference has been used to isolate potentially referential vocal signals in animal communication. However, its relatedness to the phenomenon of reference in human language has recently been brought into question. While some researchers have suggested abandoning the concept of functional reference altogether, others advocate a revision of its definition to include contextual cues that play a role in signal production and perception. Empirical and theoretical work on functional reference has also put much emphasis on how the receiver understands the referential signal. However, reference, as defined in the linguistic literature, is an action of the producer, and therefore, any definition describing reference in non-human animals must also focus on the producer. To successfully determine whether a signal is used to refer, we suggest an approach from the field of pragmatics, taking a closer look at specific situations of signal production, specifically at the factors that influence the production of a signal by an individual. We define the concept of signaller's reference to identify intentional acts of reference produced by a signaller independently of the communicative modality, and illustrate it with a case study of the hoo vocalizations produced by wild chimpanzees during travel. This novel framework introduces an intentional approach to referentiality. It may therefore permit a closer comparison of human and non-human animal referential behaviour and underlying cognitive processes, allowing us to identify what may have emerged solely in the human lineage.

  19. Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates

    Directory of Open Access Journals (Sweden)

    Unzu Carmen

    2012-06-01

    Full Text Available Abstract Background Adeno-associated vectors (rAAV have been used to attain long-term liver gene expression. In humans, the cellular immune response poses a serious obstacle for transgene persistence while neutralizing humoral immunity curtails re-administration. Porphobilinogen deaminase (PBGD haploinsufficiency (acute intermittent porphyria benefits from liver gene transfer in mouse models and clinical trials are about to begin. In this work, we sought to study in non-human primates the feasibility of repeated gene-transfer with intravenous administration of rAAV5 vectors under the effects of an intensive immunosuppressive regimen and to analyze its ability to circumvent T-cell immunity and thereby prolong transgene expression. Methods Three female Macaca fascicularis were intravenously injected with 1x1013 genome copies/kg of rAAV5 encoding the human PBGD. Mycophenolate mofetil (MMF, anti-thymocyte immunoglobulin, methylprednisolone, tacrolimus and rituximab were given in combination during 12 weeks to block T- and B-cell mediated adaptive immune responses in two macaques. Immunodeficient and immunocompetent mice were intravenously injected with 5x1012 genome copies/kg of rAAV5-encoding luciferase protein. Forty days later MMF, tacrolimus and rituximab were daily administrated to ascertain whether the immunosuppressants or their metabolites could interfere with transgene expression. Results Macaques given a rAAV5 vector encoding human PBGD developed cellular and humoral immunity against viral capsids but not towards the transgene. Anti-AAV humoral responses were attenuated during 12 weeks but intensely rebounded following cessation of the immunosuppressants. Accordingly, subsequent gene transfer with a rAAV5 vector encoding green fluorescent protein was impossible. One macaque showed enhanced PBGD expression 25 weeks after rAAV5-pbgd administration but overexpression had not been detected while the animal was under immunosuppression. As

  20. Teratogenicity studies on late blighted potatoes in nonhuman primates (Macaca mulatta and Saguinus labiatus).

    Science.gov (United States)

    Allen, J R; Marlar, R J; Chesney, C F; Helgeson, J P; Kelman, A; Weckel, G; Traisman, E; White, J W

    1977-02-01

    Female rhesus monkeys and marmosets were fed a diet containing blighted potatoes (Phytophthora infestans) at a level of 10g/kg per day for at least two weeks prior to breeding and six weeks following conception in order to gain additional information on the association of blighted potatoes and the development of anencephaly and spina bifida in primate species. There was an absence of either of these neural-tube defects in 32 rhesus and 14 marmoset infants whose mothers had received a blighted potato diet. In addition there were no cranial osseous defects. There were, however, two rhesus monkey infants with internal hydrocephalus whose mothers had consumed blighted potatoes.

  1. Evolution of invasive placentation with special reference to non-human primates

    DEFF Research Database (Denmark)

    Carter, Anthony Michael; Pijnenborg, Robert

    2011-01-01

    It is now possible to view human placentation in an evolutionary context because advances in molecular phylogenetics provide a reliable scenario for the evolution of mammals. Perhaps the most striking finding is the uniqueness of human placenta. The lower primates have non-invasive placentae...... of decidualization, formation and disintegration of a cytotrophoblastic shell, degree of interstitial trophoblast invasion and depth of trophoblast invasion into spiral arteries. Recently, the occurrence of human-like deep invasion was confirmed in gorillas and chimpanzees. As the still enigmatic disease of pre...

  2. Detection of antibodies to Oropouche virus in non-human primates in Goiânia City, Goiás

    OpenAIRE

    2016-01-01

    Abstract: INTRODUCTION 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. METHODS: Fifty blood samples were analyzed by hemagglutination-inhibition and neutralization assays. RESULTS: Two monkeys (Alouatta caraya) had antibodies to OROV by both techniques. CONCL...

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

    Science.gov (United States)

    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.

  4. Derivation and characterization of novel nonhuman primate embryonic stem cell lines from in vitro-fertilized baboon preimplantation embryos.

    Science.gov (United States)

    Chang, Tien-Cheng; Liu, Ya-Guang; Eddy, Carlton A; Jacoby, Ethan S; Binkley, Peter A; Brzyski, Robert G; Schenken, Robert S

    2011-06-01

    The development of nonhuman primate (NHP) embryonic stem cell (ESC) models holds great promise for cell-mediated treatment of debilitating diseases and to address numerous unanswered questions regarding the therapeutic efficacy of ESCs while supplanting ethical considerations involved with human studies. Here we report successful establishment and characterization of 3 novel baboon (Papio cynocephalus) ESC lines from the inner cell mass of intracytoplasmic sperm injection-derived blastocysts. Embryos were cultured in an improved baboon embryo in vitro culture protocol. The inner cell mass of blastocyst was laser-dissected and plated on mouse embryonic fibroblast feeder cell monolayer in the NHP ESC culture medium. Three cell lines with characteristic ESC morphology have been cultured through an extended period (>14 months), with 2 male cell lines (UT-1 and -2) and 1 female cell line (UT-3) displaying normal baboon karyotypes. Reverse transcription-polymerase chain reaction analysis confirmed that all 3 lines express primate ESC pluripotency markers, including OCT-4, NANOG, SOX-2, TERT, TDGF, LEFTYA, and REX-1. All 3 lines demonstrated positive immunocytochemical staining for OCT-4, stage-specific embryonic antigen-3, stage-specific embryonic antigen-4, TRA-1-60, and TRA-1-81. Baboon ESCs injected into NOD/SCID mice formed teratomas with all 3 germ layers. In addition, embryoid body-like spherical structures were derived and initial outgrowth was observed when embedded into extracellular matrix Matrigel. The ESC lines established in this NHP model have the potential to extend our knowledge in the fields of developmental biology, regenerative medicine, and future applications, including preclinical safety assessment of in vivo stem cell therapy.

  5. On the origins of human handedness and language: a comparative review of hand preferences for bimanual coordinated actions and gestural communication in nonhuman primates.

    Science.gov (United States)

    Meguerditchian, Adrien; Vauclair, Jacques; Hopkins, William D

    2013-09-01

    Within the evolutionary framework about the origin of human handedness and hemispheric specialization for language, the question of expression of population-level manual biases in nonhuman primates and their potential continuities with humans remains controversial. Nevertheless, there is a growing body of evidence showing consistent population-level handedness particularly for complex manual behaviors in both monkeys and apes. In the present article, within a large comparative approach among primates, we will review our contribution to the field and the handedness literature related to two particular sophisticated manual behaviors regarding their potential and specific implications for the origins of hemispheric specialization in humans: bimanual coordinated actions and gestural communication. Whereas bimanual coordinated actions seem to elicit predominance of left-handedness in arboreal primates and of right-handedness in terrestrial primates, all handedness studies that have investigated gestural communication in several primate species have reported stronger degree of population-level right-handedness compared to noncommunicative actions. Communicative gestures and bimanual actions seem to affect differently manual asymmetries in both human and nonhuman primates and to be related to different lateralized brain substrates. We will discuss (1) how the data of hand preferences for bimanual coordinated actions highlight the role of ecological factors in the evolution of handedness and provide additional support the postural origin theory of handedness proposed by MacNeilage [MacNeilage [2007]. Present status of the postural origins theory. In W. D. Hopkins (Ed.), The evolution of hemispheric specialization in primates (pp. 59-91). London: Elsevier/Academic Press] and (2) the hypothesis that the emergence of gestural communication might have affected lateralization in our ancestor and may constitute the precursors of the hemispheric specialization for language.

  6. A Serial Reaction Time (SRT) task with symmetrical joystick responding for nonhuman primates.

    Science.gov (United States)

    Heimbauer, Lisa A; Conway, Christopher M; Christiansen, Morten H; Beran, Michael J; Owren, Michael J

    2012-09-01

    The serial reaction time (SRT) task is a simple procedure in which participants produce differentiated responses to each of a series of stimuli presented at varying locations. Learning about stimulus order is revealed through decreased latencies for structured versus randomized sequences. Although widely used with humans and well suited to nonhumans, this paradigm is little used in comparative research. In the present article, we describe an SRT procedure that uses colored circles as stimuli, a circular layout of locations, and symmetrical joystick deflections as responses. In two experiments, we showed that four rhesus macaques (Macaca mulatta) learned to track sequences up to eight items long, with three animals showing faster responding to repeating sequences than to randomized versions. After extended training, these participants also showed evidence of faster responding at all positions within repeating sequences. This method minimizes response effort, equates effort and travel distance across stimulus locations, and is applicable to any joystick-capable species.

  7. Generalization of category knowledge and dimensional categorization in humans (Homo sapiens) and nonhuman primates (Macaca mulatta).

    Science.gov (United States)

    Smith, J David; Zakrzewski, Alexandria C; Johnston, Jennifer J R; Roeder, Jessica L; Boomer, Joseph; Ashby, F Gregory; Church, Barbara A

    2015-10-01

    A theoretical framework within neuroscience distinguishes humans' implicit and explicit systems for category learning. We used a perceptual-categorization paradigm to ask whether nonhumans share elements of these systems. Participants learned categories that foster implicit or explicit categorization in humans, because they had a multidimensional, information-integration (II) solution or a unidimensional, rule-based (RB) solution. Then humans and macaques generalized their category knowledge to new, untested regions of the stimulus space. II generalization was impaired, suggesting that II category learning is conditioned and constrained by stimulus generalization to its original, trained stimulus contexts. RB generalization was nearly seamless, suggesting that RB category knowledge in humans and monkeys has properties that grant it some independence from the original, trained stimulus contexts. These findings raise the questions of (a) how closely macaques' dimensional categorization verges on humans' explicit/declarative categorization, and (b) how far macaques' dimensional categorization has advanced beyond that in other vertebrate species.

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

    Science.gov (United States)

    Petkov, Christopher I; Wilson, Benjamin

    2012-07-19

    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.

  9. Vesicular stomatitis virus-based vaccines protect nonhuman primates against aerosol challenge with Ebola and Marburg viruses.

    Science.gov (United States)

    Geisbert, Thomas W; Daddario-Dicaprio, Kathleen M; Geisbert, Joan B; Reed, Douglas S; Feldmann, Friederike; Grolla, Allen; Ströher, Ute; Fritz, Elizabeth A; Hensley, Lisa E; Jones, Steven M; Feldmann, Heinz

    2008-12-09

    Considerable progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against Ebola and Marburg viruses. A vaccine based on recombinant vesicular stomatitis virus (VSV) seems to be particularly robust as it can also confer protection when administered as a postexposure treatment. While filoviruses are not thought to be transmitted by aerosol in nature the inhalation route is among the most likely portals of entry in the setting of a bioterrorist event. At present, all candidate filoviral vaccines have been evaluated against parenteral challenges but none have been tested against an aerosol exposure. Here, we evaluated our recombinant VSV-based Zaire ebolavirus (ZEBOV) and Marburg virus (MARV) vaccines against aerosol challenge in cynomolgus macaques. All monkeys vaccinated with a VSV vector expressing the glycoprotein of ZEBOV were completely protected against an aerosol exposure of ZEBOV. Likewise, all monkeys vaccinated with a VSV vector expressing the glycoprotein of MARV were completely protected against an aerosol exposure of MARV. All control animals challenged by the aerosol route with either ZEBOV or MARV succumbed. Interestingly, disease in control animals appeared to progress slower than previously seen in macaques exposed to comparable doses by intramuscular injection.

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

    Science.gov (United States)

    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.

  11. Monkey in the middle: Why nonhuman primates are needed to bridge the gap in resting-state investigations

    Directory of Open Access Journals (Sweden)

    R. Matthew eHutchison

    2012-07-01

    Full Text Available Resting-state investigations based on the evaluation of intrinsic low-frequency fluctuations of the BOLD fMRI signal have been extensively utilized to map the structure and dynamics of large-scale functional network organization in humans. In addition to increasing our knowledge of normal brain connectivity, disruptions of the spontaneous hemodynamic fluctuations have been suggested as possible diagnostic indicators of neurological and psychiatric disease states. Though the non-invasive technique has been received with much acclamation, open questions remain regarding the origin, organization, phylogenesis, as well as the basis of disease-related alterations underlying the signal patterns. Experimental work utilizing animal models, including the use of neurophysiological recordings and pharmacological manipulations, therefore, represents a critical component in the understanding and successful application of resting-state analysis as it affords a range of experimental manipulations not possible in human subjects. In this article, we review recent rodent and nonhuman primate studies and based on the examination of the homologous functional architecture propose the latter to be the best-suited model for exploring these unresolved resting-state concerns. Ongoing work examining the correspondence of functional and structural connectivity, state-dependency and the neuronal correlates of the hemodynamic oscillations are discussed. We then consider the potential experiments that will allow insight into different brain states and disease-related network disruptions that can extend the clinical applications of resting-state fMRI.

  12. Antibody quality and protection from lethal Ebola virus challenge in nonhuman primates immunized with rabies virus based bivalent vaccine.

    Directory of Open Access Journals (Sweden)

    Joseph E Blaney

    Full Text Available We have previously described the generation of a novel Ebola virus (EBOV vaccine platform based on (a replication-competent rabies virus (RABV, (b replication-deficient RABV, or (c chemically inactivated RABV expressing EBOV glycoprotein (GP. Mouse studies demonstrated safety, immunogenicity, and protective efficacy of these live or inactivated RABV/EBOV vaccines. Here, we evaluated these vaccines in nonhuman primates. Our results indicate that all three vaccines do induce potent immune responses against both RABV and EBOV, while the protection of immunized animals against EBOV was largely dependent on the quality of humoral immune response against EBOV GP. We also determined if the induced antibodies against EBOV GP differ in their target, affinity, or the isotype. Our results show that IgG1-biased humoral responses as well as high levels of GP-specific antibodies were beneficial for the control of EBOV infection after immunization. These results further support the concept that a successful EBOV vaccine needs to induce strong antibodies against EBOV. We also showed that a dual vaccine against RABV and filoviruses is achievable; therefore addressing concerns for the marketability of this urgently needed vaccine.

  13. The human GLP-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates.

    Science.gov (United States)

    Gotfredsen, Carsten F; Mølck, Anne-Marie; Thorup, Inger; Nyborg, Niels C Berg; Salanti, Zaki; Knudsen, Lotte Bjerre; Larsen, Marianne O

    2014-07-01

    Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks' duration. No treatment-related histopathological abnormalities were observed in any of the studies. Quantitative histology of the pancreas from the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutide treatment. Semaglutide showed no increase in pancreas weight and no treatment-related histopathological findings in the pancreas after 13 or 52 weeks' dosing. Overall, results in 138 nonhuman primates showed no histopathological changes in the pancreas associated with liraglutide or semaglutide, two structurally different GLP-1 receptor agonists.

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

    Science.gov (United States)

    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.

  15. GSK3β Inhibition Promotes Efficient Myeloid and Lymphoid Hematopoiesis from Non-human Primate-Induced Pluripotent Stem Cells.

    Science.gov (United States)

    D'Souza, Saritha S; Maufort, John; Kumar, Akhilesh; Zhang, Jiuchun; Smuga-Otto, Kimberley; Thomson, James A; Slukvin, Igor I

    2016-02-09

    Advances in the scalable production of blood cells from induced pluripotent stem cells (iPSCs) open prospects for the clinical translation of de novo generated blood products, and evoke the need for preclinical evaluation of their efficacy, safety, and immunogenicity in large animal models. Due to substantial similarities with humans, the outcomes of cellular therapies in non-human primate (NHP) models can be readily extrapolated to a clinical setting. However, the use of this model is hampered by relatively low efficiency of blood generation and lack of lymphoid potential in NHP-iPSC differentiation cultures. Here, we generated transgene-free iPSCs from different NHP species and showed the efficient induction of mesoderm, myeloid, and lymphoid cells from these iPSCs using a GSK3β inhibitor. Overall, our studies enable scalable production of hematopoietic progenitors from NHP-iPSCs, and lay the foundation for preclinical testing of iPSC-based therapies for blood and immune system diseases in an NHP model.

  16. GSK3β Inhibition Promotes Efficient Myeloid and Lymphoid Hematopoiesis from Non-human Primate-Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Saritha S. D'Souza

    2016-02-01

    Full Text Available Advances in the scalable production of blood cells from induced pluripotent stem cells (iPSCs open prospects for the clinical translation of de novo generated blood products, and evoke the need for preclinical evaluation of their efficacy, safety, and immunogenicity in large animal models. Due to substantial similarities with humans, the outcomes of cellular therapies in non-human primate (NHP models can be readily extrapolated to a clinical setting. However, the use of this model is hampered by relatively low efficiency of blood generation and lack of lymphoid potential in NHP-iPSC differentiation cultures. Here, we generated transgene-free iPSCs from different NHP species and showed the efficient induction of mesoderm, myeloid, and lymphoid cells from these iPSCs using a GSK3β inhibitor. Overall, our studies enable scalable production of hematopoietic progenitors from NHP-iPSCs, and lay the foundation for preclinical testing of iPSC-based therapies for blood and immune system diseases in an NHP model.

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

    Institute of Scientific and Technical Information of China (English)

    Madhusudana Girija Sanal

    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 im-plantable bioengineered constructs. Reproducing the complex relations between different cell types, gen-eration of adequate vasculature, and immunological complications are road blocks in generation of bioengi-neered 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 lack-ing 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 ap-proach can be curative in genetic disorders as this of-fers the possibility of gene manipulation and correction of the patient's genome at the iPSC stage before tet-raploid 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 sig-naling 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.

  18. Exploring the Innate Immunological Response of an Alternative Nonhuman Primate Model of Infectious Disease; the Common Marmoset

    Directory of Open Access Journals (Sweden)

    M. Nelson

    2014-01-01

    Full Text Available The common marmoset (Callithrix jacchus is increasingly being utilised as a nonhuman primate model for human disease, ranging from autoimmune to infectious disease. In order to fully exploit these models, meaningful comparison to the human host response is necessary. Commercially available reagents, primarily targeted to human cells, were utilised to assess the phenotype and activation status of key immune cell types and cytokines in naive and infected animals. Single cell suspensions of blood, spleen, and lung were examined. Generally, the phenotype of cells was comparable between humans and marmosets, with approximately 63% of all lymphocytes in the blood of marmosets being T cells, 25% B-cells, and 12% NK cells. The percentage of neutrophils in marmoset blood were more similar to human values than mouse values. Comparison of the activation status of cells following experimental systemic or inhalational infection exhibited different trends in different tissues, most obvious in cell types active in the innate immune response. This work significantly enhances the ability to understand the immune response in these animals and fortifies their use as models of infectious disease.

  19. Use of CTLA4Ig for induction of mixed chimerism and renal allograft tolerance in nonhuman primates.

    Science.gov (United States)

    Yamada, Y; Ochiai, T; Boskovic, S; Nadazdin, O; Oura, T; Schoenfeld, D; Cappetta, K; Smith, R-N; Colvin, R B; Madsen, J C; Sachs, D H; Benichou, G; Cosimi, A B; Kawai, T

    2014-12-01

    We have previously reported successful induction of renal allograft tolerance via a mixed chimerism approach in nonhuman primates. In those studies, we found that costimulatory blockade with anti-CD154 mAb was an effective adjunctive therapy for induction of renal allograft tolerance. However, since anti-CD154 mAb is not clinically available, we have evaluated CTLA4Ig as an alternative agent for effecting costimulation blockade in this treatment protocol. Two CTLA4Igs, abatacept and belatacept, were substituted for anti-CD154 mAb in the conditioning regimen (low dose total body irradiation, thymic irradiation, anti-thymocyte globulin and a 1-month posttransplant course of cyclosporine [CyA]). Three recipients treated with the abatacept regimen failed to develop comparable lymphoid chimerism to that achieved with anti-CD154 mAb treatment and these recipients rejected their kidney allografts early. With the belatacept regimen, four of five recipients developed chimerism and three of these achieved long-term renal allograft survival (>861, >796 and >378 days) without maintenance immunosuppression. Neither chimerism nor long-term allograft survival were achieved in two recipients treated with the belatacept regimen but with a lower, subtherapeutic dose of CyA. This study indicates that CD28/B7 blockade with belatacept can provide a clinically applicable alternative to anti-CD154 mAb for promoting chimerism and renal allograft tolerance.

  20. Correlations between Hippocampal Neurogenesis and Metabolic Indices in Adult Nonhuman Primates

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    Tarique D. Perera

    2011-01-01

    Full Text Available Increased neurogenesis in feeding centers of the murine hypothalamus is associated with weight loss in diet-induced obese rodents (Kokoeva et al., 2005 and Matrisciano et al., 2010, but this relationship has not been examined in other species. Postmortem hippocampal neurogenesis rates and premortem metabolic parameters were statistically analyzed in 8 chow-fed colony-reared adult bonnet macaques. Dentate gyrus neurogenesis, reflected by the immature neuronal marker, doublecortin (DCX, and expression of the antiapoptotic gene factor, B-cell lymphoma 2 (BCL-2, but not the precursor proliferation mitotic marker, Ki67, was inversely correlated with body weight and crown-rump length. DCX and BCL-2 each correlated positively with blood glucose level and lipid ratio (total cholesterol/high-density lipoprotein. This study demonstrates that markers of dentate gyrus neuroplasticity correlate with metabolic parameters in primates.

  1. Utility, limitations and future of non-human primates for dengue research and vaccine development

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    Laura eWhite

    2014-09-01

    Full Text Available Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately there are no licensed dengue vaccines available or specific antiviral drugs. The development of a dengue vaccine faces unique challenges. The 4 serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, Non Human Primates (NHP are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally we propose some guidelines towards a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups.

  2. Temporal and Spatial Categorization in Human and Non-Human Primates

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    Juan Carlos eMendez

    2011-09-01

    Full Text Available It has been proposed that a functional overlap exists in the brain for temporal and spatial information processing. To test this, we designed two relative categorization tasks in which human subjects and a Rhesus monkey had to assign time intervals or distances to a ‘short’ or ‘long’ category according to varying prototypes. The performance of both species was analyzed using psychometric techniques that showed that they may have similar perceptual, memory and/or decision mechanisms, specially for the estimation of time intervals. We also did a correlation analysis with human subjects’ psychometric thresholds and the results imply that indeed, temporal and spatial information categorization share neural substrates. However, not all of the tested distances and intervals correlated with each other, suggesting the existence of sub-circuits that process restricted ranges of distances and intervals. A different analysis was done on the monkey data, in which the influence of the previous categorical prototypes was measured on the task currently being performed. Again, we found a significant interaction between previous and current interval and distance categorization. Overall, the present paper points towards common or at least partially overlapped neural circuits for temporal and spatial categorization in primates.

  3. Temporal and spatial categorization in human and non-human primates.

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    Mendez, Juan Carlos; Prado, Luis; Mendoza, German; Merchant, Hugo

    2011-01-01

    It has been proposed that a functional overlap exists in the brain for temporal and spatial information processing. To test this, we designed two relative categorization tasks in which human subjects and a Rhesus monkey had to assign time intervals or distances to a "short" or "long" category according to varying prototypes. The performance of both species was analyzed using psychometric techniques that showed that they may have similar perceptual, memory, and/or decision mechanisms, specially for the estimation of time intervals. We also did a correlation analysis with human subjects' psychometric thresholds and the results imply that indeed, temporal and spatial information categorization share neural substrates. However, not all of the tested distances and intervals correlated with each other, suggesting the existence of sub-circuits that process restricted ranges of distances and intervals. A different analysis was done on the monkey data, in which the influence of the previous categorical prototypes was measured on the task currently being performed. Again, we found a significant interaction between previous and current interval and distance categorization. Overall, the present paper points toward common or at least partially overlapped neural circuits for temporal and spatial categorization in primates.

  4. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

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    Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  5. Non-human primate model of Kaposi's sarcoma-associated herpesvirus infection.

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    Heesoon Chang

    2009-10-01

    Full Text Available Since Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8 was first identified in Kaposi's sarcoma (KS lesions of HIV-infected individuals with AIDS, the basic biological understanding of KSHV has progressed remarkably. However, the absence of a proper animal model for KSHV continues to impede direct in vivo studies of viral replication, persistence, and pathogenesis. In response to this need for an animal model of KSHV infection, we have explored whether common marmosets can be experimentally infected with human KSHV. Here, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj, a New World primate. Marmosets infected with recombinant KSHV rapidly seroconverted and maintained a vigorous anti-KSHV antibody response. KSHV DNA and latent nuclear antigen (LANA were readily detected in the peripheral blood mononuclear cells (PBMCs and various tissues of infected marmosets. Remarkably, one orally infected marmoset developed a KS-like skin lesion with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These results demonstrate that human KSHV infects common marmosets, establishes an efficient persistent infection, and occasionally leads to a KS-like skin lesion. This is the first animal model to significantly elaborate the important aspects of KSHV infection in humans and will aid in the future design of vaccines against KSHV and anti-viral therapies targeting KSHV coinfected tumor cells.

  6. Myotonin protein-kinase [AGC]n trinucleotide repeat in seven nonhuman primates

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    Novelli, G.; Sineo, L.; Pontieri, E. [Catholic Univ. of Rome (Italy)]|[Univ. of Milan (Italy)]|[Univ. Florence (Italy)] [and others

    1994-09-01

    Myotonic dystrophy (DM) is due to a genomic instability of a trinucleotide [AGC]n motif, located at the 3{prime} UTR region of a protein-kinase gene (myotonin protein kinase, MT-PK). The [AGC] repeat is meiotically and mitotically unstable, and it is directly related to the manifestations of the disorder. Although a gene dosage effect of the MT-PK has been demonstrated n DM muscle, the mechanism(s) by which the intragenic repeat expansion leads to disease is largely unknown. This non-standard mutational event could reflect an evolutionary mechanism widespread among animal genomes. We have isolated and sequenced the complete 3{prime}UTR region of the MT-PK gene in seven primates (macaque, orangutan, gorilla, chimpanzee, gibbon, owl monkey, saimiri), and examined by comparative sequence nucleotide analysis the [AGC]n intragenic repeat and the surrounding nucleotides. The genomic organization, including the [AGC]n repeat structure, was conserved in all examined species, excluding the gibbon (Hylobates agilis), in which the [AGC]n upstream sequence (GGAA) is replaced by a GA dinucleotide. The number of [AGC]n in the examined species ranged between 7 (gorilla) and 13 repeats (owl monkeys), with a polymorphism informative content (PIC) similar to that observed in humans. These results indicate that the 3{prime}UTR [AGC] repeat within the MT-PK gene is evolutionarily conserved, supporting that this region has important regulatory functions.

  7. Multisensory integration in non-human primates during a sensory-motor task

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    Florian eLanz

    2013-11-01

    Full Text Available Daily our central nervous system receives inputs via several sensory modalities, processes them and integrates information in order to produce a suitable behaviour. 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 msec, 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.

  8. 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?

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    Marie Cibot

    Full Text Available 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

  9. Biodistribution of Yttrium-90-Labeled Anti-CD45 Antibody in a Nonhuman Primate Model

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    Nemecek, Eneida; Hamlin, Donald K.; Fisher, Darrell R.; Krohn, Kenneth A.; Pagel, John M.; Applebaum, F. R.; Press, Oliver W.; Matthews, Dana C.

    2005-01-15

    Radioimmunotherapy may improve the outcome of hematopoietic cell transplantation for hematologic malignancies by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the organ localization of yttrium-90-labeled anti-CD45 (90Y-anti-CD45) antibody in macaques, a model that had previously predicted iodine-131-labeled anti-CD-45 (131I-anti-CD45) antibody biodistribution in humans. Experimental Design: Twelve Macaca nemestrina primates received anti-CD45 antibody labeled with 1 to 2 mCi of 90Y followed by serial blood sampling and marrow and lymph node biopsies, and necropsy. The content of 90Y per gram of tissue was determined by liquid scintillation spectrometry. Time-activity curves were constructed using average isotope concentrations in each tissue at measured time points to yield the fractional residence time and estimate radiation absorbed doses for each organ per unit of administered activity. The biodistribution of 90Y-anti-CD45 antibody was then compared with that previously obtained with 131I-anti-CD45 antibody in macaques. Results: The spleen received 2,120, marrow 1,060, and lymph nodes 315 cGy/mCi of 90Y injected. The liver and lungs were the nontarget organs receiving the highest radiation absorbed doses (440 and 285 cGy/mCi, respectively). Ytrrium-90-labeled anti-CD45 antibody delivered 2.5- and 3.7-fold more radiation to marrow than to liver and lungs, respectively. The ratios previously observed with 131I-antiCD45 antibody were 2.5-and 2.2-fold more radiation to marrow than to liver and lungs, respectively. Conclusions: This study shows that 90Y-anti-CD45 antibody can deliver relatively selective radiation to hematopoietic tissues, with similar ratios of radiation delivered to target versus nontarget organs, as compared with the 131I immunoconjugate in the same animal model.

  10. Placental Estrogen Suppresses Cyclin D1 Expression in the Nonhuman Primate Fetal Adrenal Cortex*

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    Dumitrescu, Adina; Aberdeen, Graham W.; Pepe, Gerald J.

    2014-01-01

    We have previously shown that estrogen selectively suppresses growth of the fetal zone of the baboon fetal adrenal cortex, which produces the C19-steroid precursors, eg, dehydroepiandrosterone sulfate, which are aromatized to estrogen within the placenta. In the present study, we determined whether fetal adrenal expression of cell cycle regulators are altered by estrogen and thus provide a mechanism by which estrogen regulates fetal adrenocortical development. Cyclin D1 mRNA levels in the whole fetal adrenal were increased 50% (P < .05), and the number of cells in the fetal adrenal definitive zone expressing cyclin D1 protein was increased 2.5-fold (P < .05), whereas the total number of cells in the fetal zone and fetal serum dehydroepiandrosterone sulfate levels were elevated 2-fold (P < .05) near term in baboons in which fetal serum estradiol levels were decreased by 95% (P < .05) after maternal administration of the aromatase inhibitor letrozole and restored to normal by concomitant administration of letrozole plus estradiol throughout second half of gestation. However, fetal adrenocortical expression of cyclin D2, the cyclin-dependent kinase (Cdk)-2, Cdk4, and Cdk6, and Cdk regulatory proteins p27Kip1 and p57Kip2 were not changed by letrozole or letrozole plus estradiol administration. We suggest that estrogen controls the growth of the fetal zone of the fetal adrenal by down-regulating cyclin D1 expression and thus proliferation of progenitor cells within the definitive zone that migrate to the fetal zone. We propose that estrogen restrains growth and function of the fetal zone via cyclin D1 to maintain estrogen levels in a physiological range during primate pregnancy. PMID:25247468

  11. Placental estrogen suppresses cyclin D1 expression in the nonhuman primate fetal adrenal cortex.

    Science.gov (United States)

    Dumitrescu, Adina; Aberdeen, Graham W; Pepe, Gerald J; Albrecht, Eugene D

    2014-12-01

    We have previously shown that estrogen selectively suppresses growth of the fetal zone of the baboon fetal adrenal cortex, which produces the C19-steroid precursors, eg, dehydroepiandrosterone sulfate, which are aromatized to estrogen within the placenta. In the present study, we determined whether fetal adrenal expression of cell cycle regulators are altered by estrogen and thus provide a mechanism by which estrogen regulates fetal adrenocortical development. Cyclin D1 mRNA levels in the whole fetal adrenal were increased 50% (P < .05), and the number of cells in the fetal adrenal definitive zone expressing cyclin D1 protein was increased 2.5-fold (P < .05), whereas the total number of cells in the fetal zone and fetal serum dehydroepiandrosterone sulfate levels were elevated 2-fold (P < .05) near term in baboons in which fetal serum estradiol levels were decreased by 95% (P < .05) after maternal administration of the aromatase inhibitor letrozole and restored to normal by concomitant administration of letrozole plus estradiol throughout second half of gestation. However, fetal adrenocortical expression of cyclin D2, the cyclin-dependent kinase (Cdk)-2, Cdk4, and Cdk6, and Cdk regulatory proteins p27(Kip1) and p57(Kip2) were not changed by letrozole or letrozole plus estradiol administration. We suggest that estrogen controls the growth of the fetal zone of the fetal adrenal by down-regulating cyclin D1 expression and thus proliferation of progenitor cells within the definitive zone that migrate to the fetal zone. We propose that estrogen restrains growth and function of the fetal zone via cyclin D1 to maintain estrogen levels in a physiological range during primate pregnancy.

  12. New STLV-3 strains and a divergent SIVmus strain identified in non-human primate bushmeat in Gabon

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    Liégeois Florian

    2012-03-01

    Full Text Available Abstract Background Human retroviral infections such as Human Immunodeficiency Virus (HIV or Human T-cell Lymphotropic Virus (HTLV are the result of simian zoonotic transmissions through handling and butchering of Non-Human Primates (NHP or by close contact with pet animals. Recent studies on retroviral infections in NHP bushmeat allowed for the identification of numerous Simian Immunodeficiency Viruses (SIV and Simian T-cell Lymphotropic Viruses (STLV to which humans are exposed. Nevertheless, today, data on simian retroviruses at the primate/hunter interface remain scarce. We conducted a pilot study on 63 blood and/or tissues samples derived from NHP bushmeat seized by the competent authorities in different locations across the country. Results SIV and STLV were detected by antibodies to HIV and HTLV antigens, and PCRs were performed on samples with an HIV or/and HTLV-like or indeterminate profile. Fourteen percent of the samples cross-reacted with HIV antigens and 44% with HTLV antigens. We reported STLV-1 infections in five of the seven species tested. STLV-3 infections, including a new STLV-3 subtype, STLV-1 and -3 co-infections, and triple SIV, STLV-1, STLV-3 infections were observed in red-capped mangabeys (C.torquatus. We confirmed SIV infections by PCR and sequence analyses in mandrills, red-capped mangabeys and showed that mustached monkeys in Gabon are infected with a new SIV strain basal to the SIVgsn/mus/mon lineage that did not fall into the previously described SIVmus lineages reported from the corresponding species in Cameroon. The same monkey (subspecies can thus be carrier of, at least, three distinct SIVs. Overall, the minimal prevalence observed for both STLV and SIV natural infections were 26.9% and 11.1% respectively. Conclusions Overall, these data, obtained from a restricted sampling, highlight the need for further studies on simian retroviruses in sub-Saharan Africa to better understand their evolutionary history and to

  13. Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain.

    Science.gov (United States)

    Mano, Yui; Saito, Ryuta; Haga, Yoichi; Matsunaga, Tadao; Zhang, Rong; Chonan, Masashi; Haryu, Shinya; Shoji, Takuhiro; Sato, Aya; Sonoda, Yukihiko; Tsuruoka, Noriko; Nishiyachi, Keisuke; Sumiyoshi, Akira; Nonaka, Hiroi; Kawashima, Ryuta; Tominaga, Teiji

    2016-05-01

    OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 μl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 μl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way

  14. Rabies in nonhuman primates and potential for transmission to humans: a literature review and examination of selected French national data.

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    Philippe Gautret

    2014-05-01

    Full Text Available BACKGROUND: The nonhuman primate (NHP-related injuries in rabies-enzootic countries is a public health problem of increasing importance. The aims of this work are to collect data concerning rabies transmission from NHPs to humans; to collate medical practices regarding rabies postexposure prophylaxis (PEP in different countries, and to provide an evidence base to support the decision to apply rabies PEP in this context. METHODOLOGY: To retrieve information, we conducted a literature search from 1960 to January 2013. All reports of rabies in NHPs and rabies transmission to humans by infected NHPs were included. Also included were studies of travelers seeking care for rabies PEP in various settings. Data collected by the French National Reference Centre for Rabies concerning NHPs submitted for rabies diagnosis in France and human rabies exposure to NHPs in travelers returning to France were analyzed for the periods 1999-2012 and 1994-2011, respectively. PRINCIPAL FINDINGS: A total of 159 reports of rabies in NHPs have been retrieved from various sources in South America, Africa, and Asia, including 13 cases in animals imported to Europe and the US. 134 were laboratory confirmed cases. 25 cases of human rabies following NHP-related injuries were reported, including 20 from Brazil. Among more than 2000 international travelers from various settings, the proportion of injuries related to NHP exposures was about 31%. NHPs rank second, following dogs in most studies and first in studies conducted in travelers returning from Southeast Asia. In France, 15.6% of 1606 travelers seeking PEP for exposure to any animal were injured by monkeys. CONCLUSIONS/SIGNIFICANCE: Although less frequently reported in published literature than human rabies, confirmed rabies cases in NHPs occur. The occurrence of documented transmission of rabies from NHPs to human suggests that rabies PEP is indicated in patients injured by NHPs in rabies-enzootic countries.

  15. Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates.

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    Fabrice Marquet

    Full Text Available 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.

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

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    Armstrong Dianna

    2004-12-01

    Full Text Available Abstract 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.

  17. Local domains of motor cortical activity revealed by fiber-optic calcium recordings in behaving nonhuman primates

    Science.gov (United States)

    Adelsberger, Helmuth; Zainos, Antonio; Alvarez, Manuel; Romo, Ranulfo; Konnerth, Arthur

    2014-01-01

    Brain mapping experiments involving electrical microstimulation indicate that the primary motor cortex (M1) directly regulates muscle contraction and thereby controls specific movements. Possibly, M1 contains a small circuit “map” of the body that is formed by discrete local networks that code for specific movements. Alternatively, movements may be controlled by distributed, larger-scale overlapping circuits. Because of technical limitations, it remained unclear how movement-determining circuits are organized in M1. Here we introduce a method that allows the functional mapping of small local neuronal circuits in awake behaving nonhuman primates. For this purpose, we combined optic-fiber–based calcium recordings of neuronal activity and cortical microstimulation. The method requires targeted bulk loading of synthetic calcium indicators (e.g., OGB-1 AM) for the staining of neuronal microdomains. The tip of a thin (200 µm) optical fiber can detect the coherent activity of a small cluster of neurons, but is insensitive to the asynchronous activity of individual cells. By combining such optical recordings with microstimulation at two well-separated sites of M1, we demonstrate that local cortical activity was tightly associated with distinct and stereotypical simple movements. Increasing stimulation intensity increased both the amplitude of the movements and the level of neuronal activity. Importantly, the activity remained local, without invading the recording domain of the second optical fiber. Furthermore, there was clear response specificity at the two recording sites in a trained behavioral task. Thus, the results provide support for movement control in M1 by local neuronal clusters that are organized in discrete cortical domains. PMID:24344287

  18. B-Cells and the Use of Non-Human Primates for Evaluation of HIV Vaccine Candidates.

    Science.gov (United States)

    Demberg, Thorsten; Robert-Guroff, Marjorie

    2015-01-01

    The RV144 clinical trial in Thailand associated vaccine-induced antibodies with protective efficacy, leading to a focus in HIV vaccine research on protective antibody induction. This has necessitated greater understanding of B cell biology in humans as well as non-human primates (NHP), the principle animal model for pre-clinical HIV/SIV vaccine research. This review covers development and maturation of NHP B cells within the framework of current knowledge of human and murine B cells. Identification of many NHP B cell subpopulations is now possible, although consensus is lacking in some cases, and better distinction of some populations is still needed. Elucidation of mechanisms that control germinal center maintenance, selection of B cells into the memory cell pool, and differentiation of B cells into long-lived plasma cells remains critical for improving vaccine design. B cell dysfunction occurs during both HIV and SIV infection. Whether the processes leading to this impairment are identical in humans and NHP is not known. Uncovering the mechanisms involved could lead to improved treatment regimens. The SIV/NHP model effectively mimics HIV infection of people, but key differences between NHP and humans in antibody characteristics such as glycosylation and structure may lead to unexpected outcomes in pre-clinical studies. Important new areas for investigation include the role of B cell cytokines in the immune system and the impact of the microbiome on B cell development and maturation. Enhanced knowledge of B cells in NHP as well as humans should enable improved vaccine design, leading to induction of potent, long-lasting protective antibodies.

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

    Science.gov (United States)

    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.

  20. Resveratrol Prevents β-Cell Dedifferentiation in Nonhuman Primates Given a High-Fat/High-Sugar Diet

    Science.gov (United States)

    Fiori, Jennifer L.; Shin, Yu-Kyong; Kim, Wook; Krzysik-Walker, Susan M.; González-Mariscal, Isabel; Carlson, Olga D.; Sanghvi, Mitesh; Moaddel, Ruin; Farhang, Kathleen; Gadkaree, Shekhar K.; Doyle, Maire E.; Pearson, Kevin J.; Mattison, Julie A.; de Cabo, Rafael; Egan, Josephine M.

    2013-01-01

    Eating a “Westernized” diet high in fat and sugar leads to weight gain and numerous health problems, including the development of type 2 diabetes mellitus (T2DM). Rodent studies have shown that resveratrol supplementation reduces blood glucose levels, preserves β-cells in islets of Langerhans, and improves insulin action. Although rodent models are helpful for understanding β-cell biology and certain aspects of T2DM pathology, they fail to reproduce the complexity of the human disease as well as that of nonhuman primates. Rhesus monkeys were fed a standard diet (SD), or a high-fat/high-sugar diet in combination with either placebo (HFS) or resveratrol (HFS+Resv) for 24 months, and pancreata were examined before overt dysglycemia occurred. Increased glucose-stimulated insulin secretion and insulin resistance occurred in both HFS and HFS+Resv diets compared with SD. Although islet size was unaffected, there was a significant decrease in β-cells and an increase in α-cells containing glucagon and glucagon-like peptide 1 with HFS diets. Islets from HFS+Resv monkeys were morphologically similar to SD. HFS diets also resulted in decreased expression of essential β-cell transcription factors forkhead box O1 (FOXO1), NKX6–1, NKX2–2, and PDX1, which did not occur with resveratrol supplementation. Similar changes were observed in human islets where the effects of resveratrol were mediated through Sirtuin 1. These findings have implications for the management of humans with insulin resistance, prediabetes, and diabetes. PMID:23884882

  1. Circulating interleukin-18 as a biomarker of total-body radiation exposure in mice, minipigs, and nonhuman primates (NHP.

    Directory of Open Access Journals (Sweden)

    Cam T Ha

    Full Text Available We aim to develop a rapid, easy-to-use, inexpensive and accurate radiation dose-assessment assay that tests easily obtained samples (e.g., blood to triage and track radiological casualties, and to evaluate the radioprotective and therapeutic effects of radiation countermeasures. In the present study, we evaluated the interleukin (IL-1 family of cytokines, IL-1β, IL-18 and IL-33, as well as their secondary cytokines' expression and secretion in CD2F1 mouse bone marrow (BM, spleen, thymus and serum in response to γ-radiation from sublethal to lethal doses (5, 7, 8, 9, 10, or 12 Gy at different time points using the enzyme-linked immune sorbent assay (ELISA, immunoblotting, and cytokine antibody array. Our data identified increases of IL-1β, IL-18, and/or IL-33 in mouse thymus, spleen and BM cells after total-body irradiation (TBI. However, levels of these cytokines varied in different tissues. Interestingly, IL-18 but not IL-1β or IL-33 increased significantly (2.5-24 fold and stably in mouse serum from day 1 after TBI up to 13 days in a radiation dose-dependent manner. We further confirmed our finding in total-body γ-irradiated nonhuman primates (NHPs and minipigs, and demonstrated that radiation significantly enhanced IL-18 in serum from NHPs 2-4 days post-irradiation and in minipig plasma 1-3 days post-irradiation. Finally, we compared circulating IL-18 with the well known hematological radiation biomarkers lymphocyte and neutrophil counts in blood of mouse, minipigs and NHPs and demonstrated close correlations between these biomarkers in response to radiation. Our results suggest that the elevated levels of circulating IL-18 after radiation proportionally reflect radiation dose and severity of radiation injury and may be used both as a potential biomarker for triage and also to track casualties after radiological accidents as well as for therapeutic radiation exposure.

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

    Science.gov (United States)

    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.

  3. Quantitative serology assays for determination of antibody responses to Ebola virus glycoprotein and matrix protein in nonhuman primates and humans.

    Science.gov (United States)

    Vu, Hong; Shulenin, Sergey; Grolla, Allen; Audet, Jonathan; He, Shihua; Kobinger, Gary; Unfer, Robert C; Warfield, Kelly L; Aman, M Javad; Holtsberg, Frederick W

    2016-02-01

    The West Africa Ebola virus disease (EVD) outbreak has reached unprecedented magnitude and caused worldwide concerns for the spread of this deadly virus. Recent findings in nonhuman primates (NHPs) demonstrate that antibodies can be protective against EVD. However, the role of antibody response in vaccine-mediated protection is not fully understood. To address these questions quantitative serology assays are needed for measurement of the antibody response to key Ebola virus (EBOV) proteins. Serology enzyme-linked immunosorbent assays (ELISA's), using a reference detection antibody, were developed in order to standardize the quantitation of antibody levels in vaccinated NHPs or in humans exposed to EBOV or immunized with an EBOV vaccine. Critical reagents were generated to support the development of the serology ELISAs. Recombinant EBOV matrix protein (VP40) was expressed in Escherichia coli and purified. Two variants of the glycoprotein (GP), the ectodomain lacking the transmembrane domain (GPΔTM), and an engineered GP lacking the mucin-like domain (GPΔmuc) were expressed and purified from mammalian cell systems. Using these proteins, three ELISA methods were developed and optimized for reproducibility and robustness, including stability testing of critical reagents. The assay was used to determine the antibody response against VP40, GPΔTM, and GPΔmuc in a NHP vaccine study using EBOV virus-like particles (VLP) vaccine expressing GP, VP40 and the nucleoprotein. Additionally, these ELISAs were used to successfully detect antibody responses to VP40, GPΔTM and GPΔmuc in human sera from EBOV infected individuals.

  4. SPECT imaging with the serotonin transporter radiotracer [{sup 123}I]p ZIENT in nonhuman primate brain

    Energy Technology Data Exchange (ETDEWEB)

    Cosgrove, Kelly P., E-mail: kelly.cosgrove@yale.ed [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Staley, Julie K.; Baldwin, Ronald M.; Bois, Frederic [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Plisson, Christophe [Emory University School of Medicine, Atlanta, GA 30322 (United States); Al-Tikriti, Mohammed S. [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Seibyl, John P. [Institute for Neurodegenerative Disorders, New Haven, CT 06510 (United States); Goodman, Mark M. [Emory University School of Medicine, Atlanta, GA 30322 (United States); Tamagnan, Gilles D. [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Institute for Neurodegenerative Disorders, New Haven, CT 06510 (United States)

    2010-07-15

    Introduction: Serotonin dysfunction has been linked to a variety of psychiatric diseases; however, an adequate SPECT radioligand to probe the serotonin transporter system has not been successfully developed. The purpose of this study was to characterize and determine the in vivo selectivity of iodine-123-labeled 2{beta}-carbomethoxy-3{beta}-(4'-((Z)-2-iodoethenyl)phenyl)nortropane, [{sup 123}I]p ZIENT, in nonhuman primate brain. Methods: Two ovariohysterectomized female baboons participated in nine studies (one bolus and eight bolus to constant infusion at a ratio of 9.0 h) to evaluate [{sup 123}I]p ZIENT. To evaluate the selectivity of [{sup 123}I]p ZIENT, the serotonin transporter blockers fenfluramine (1.5, 2.5 mg/kg) and citalopram (5 mg/kg), the dopamine transporter blocker methylphenidate (0.5 mg/kg) and the norepinephrine transporter blocker nisoxetine (1 mg/kg) were given at 8 h post-radiotracer injection. Results: In the bolus to constant infusion studies, equilibrium was established by 4-8 h. [{sup 123}I]p ZIENT was 93% and 90% protein bound in the two baboons and there was no detection of lipophilic radiolabeled metabolites entering the brain. In the high-density serotonin transporter regions (diencephalon and brainstem), fenfluramine and citalopram resulted in 35-71% and 129-151% displacement, respectively, whereas methylphenidate and nisoxetine did not produce significant changes (<10%). Conclusion: These findings suggest that [{sup 123}I]p ZIENT is a favorable compound for in vivo SPECT imaging of serotonin transporters with negligible binding to norepinephrine and dopamine transporters.

  5. An analysis approach for high-field fMRI data from awake non-human primates.

    Directory of Open Access Journals (Sweden)

    Steffen Stoewer

    Full Text Available fMRI experiments with awake non-human primates (NHP have seen a surge of applications in recent years. However, the standard fMRI analysis tools designed for human experiments are not optimal for analysis of NHP fMRI data collected at high fields. There are several reasons for this, including the trial-based nature of NHP experiments, with inter-trial periods being of no interest, and segmentation artefacts and distortions that may result from field changes due to movement. We demonstrate an approach that allows us to address some of these issues consisting of the following steps: 1 Trial-based experimental design. 2 Careful control of subject movement. 3 Computer-assisted selection of trials devoid of artefacts and animal motion. 4 Nonrigid between-trial and rigid within-trial realignment of concatenated data from temporally separated trials and sessions. 5 Linear interpolation of inter-trial intervals and high-pass filtering of temporally continuous data 6 Removal of interpolated data and reconcatenation of datasets before statistical analysis with SPM. We have implemented a software toolbox, fMRI Sandbox (http://code.google.com/p/fmri-sandbox/, for semi-automated application of these processing steps that interfaces with SPM software. Here, we demonstrate that our methodology provides significant improvements for the analysis of awake monkey fMRI data acquired at high-field. The method may also be useful for clinical applications with subjects that are unwilling or unable to remain motionless for the whole duration of a functional scan.

  6. Novel Serum Proteomic Signatures in a Non-Human Primate Model of Retinal Injury

    Science.gov (United States)

    2011-01-01

    investigate alterations in the retinal proteome as a result of diabetes, age-related macular degeneration , or glaucoma. Some studies have assessed the...13. Hollyfield JG, Salomon RG, Crabb JW. Proteomic approaches to understanding age-related macular degeneration . Adv Exp Med Biol 2003; 533:83-9...using the C18 reverse phase column (1 µl/min flow rate) in line with the mass spectrometer. Mobile phases consisted of 0.1% formic acid, 5

  7. Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676.

    Science.gov (United States)

    Varnäs, Katarina; Juréus, Anders; Johnström, Peter; Ahlgren, Charlotte; Schött, Pär; Schou, Magnus; Gruber, Susanne; Jerning, Eva; Malmborg, Jonas; Halldin, Christer; Afzelius, Lovisa; Farde, Lars

    2016-09-01

    Positron emission tomography (PET) is widely applied in central nervous system (CNS) drug development for assessment of target engagement in vivo. As the majority of PET investigations have addressed drug interaction at a single binding site, findings of multitarget engagement have been less frequently reported and have often been inconsistent with results obtained in vitro. AZD3676 [N,N-dimethyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl) benzofuran-2-carboxamide] is a novel combined serotonin (5-hydroxytryptamine) 5-HT1A and 5-HT1B receptor antagonist that was developed for the treatment of cognitive impairment in Alzheimer's disease. Here, we evaluated the properties of AZD3676 as a CNS drug by combining in vitro and ex vivo radioligand binding techniques, behavioral pharmacology in rodents, and PET imaging in nonhuman primates. Target engagement in the nonhuman primate brain was assessed in PET studies by determination of drug-induced occupancy using receptor-selective radioligands. AZD3676 showed preclinical properties consistent with CNS drug potential, including nanomolar receptor affinity and efficacy in rodent models of learning and memory. In PET studies of the monkey brain, AZD3676 inhibited radioligand binding in a dose-dependent manner with similar affinity at both receptors. The equally high affinity at 5-HT1A and 5-HT1B receptors as determined in vivo was not predicted from corresponding estimates obtained in vitro, suggesting more than 10-fold selectivity for 5-HT1A versus 5-HT1B receptors. These findings support the further integrated use of PET for confirmation of multitarget occupancy of CNS drugs. Importantly, earlier introduction of PET studies in nonhuman primates may reduce future development costs and the requirement for animal experiments in preclinical CNS drug development programs.

  8. 非人灵长类糖尿病动物模型研究进展%Progress on nonhuman primate models of diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    梁斌; 吴晓云

    2011-01-01

    Diabetes is the third most severely chronic disease after cardiovascular disease and cancer. World Health Organization (WHO) estimated 220 million diabetes patients worldwide in 2009. The rational animal models of diabetes are necessary for understanding the mechanisms of diabetes, diagnosis and prevention of diabetes as well as screen and evaluation of new drugs for diabetes treatment. Compared to other animal models of diabetes, the causes and symptoms of diabetes of nonhuman primates is more like human diabetes. We here reviewed the reported nonhuman primate models of diabetes based on the sources they were generated; especially focused on three models, Macaca mullata, M.fascicularis, Tupaia belangeri. Furthermore, we discussed the perspective development of nonhuman primate models of diabetes mellitus.%糖尿病是继心血管疾病和肿瘤之后的另一种严重危害人类健康的重要慢性疾病,据世界卫生组织(WHO)报道,2009年全世界约有2.2亿糖尿病患者.对糖尿病发病机理的研究、预防和诊断、治疗药物的筛选和评价都需要合适的动物模型.在已报道的糖尿病动物模型中,非人灵长类动物糖尿病病程、病症与人类的糖尿病最为相似.该文从糖尿病动物模型的来源归纳了目前报道的主要的非人灵长类糖尿病模型,重点介绍了猕猴、食蟹猴和树鼩糖尿病模型及其特征,并对该领域的发展提出了一些思考.

  9. Development of Dose-Response Models of Creutzfeldt-Jakob Disease Infection in Nonhuman Primates for Assessing the Risk of Transfusion-Transmitted Variant Creutzfeldt-Jakob Disease

    Science.gov (United States)

    Gregori, Luisa; Anderson, Steven A.; Asher, David M.

    2014-01-01

    ABSTRACT Estimates for the risk of transmitting variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion have relied largely on data from rodent experiments, but the relationship between dose (amount of infected blood) and response (vCJD infection) has never been well quantified. The goal of this study was to develop a dose-response model based on nonhuman primate data to better estimate the likelihood of transfusion-transmitted vCJD (TTvCJD) in humans. Our model used dose-response data from nonhuman primates inoculated intracerebrally (i.c.) with brain tissues of patients with sporadic and familial CJD. We analyzed the data statistically by using a beta-Poisson dose-response model. We further adjusted model parameters to account for the differences in infectivity between blood and brain tissue and in transmission efficiency between intravenous (i.v.) and i.c. routes to estimate dose-dependent TTvCJD infection. The model estimates a mean infection rate of 76% among recipients who receive one unit of whole blood collected from an infected donor near the end of the incubation period. The nonhuman primate model provides estimates that are more consistent with those derived from a risk analysis of transfused nonleukoreduced red blood cells in the United Kingdom than prior estimates based on rodent models. IMPORTANCE TTvCJD was recently identified as one of three emerging infectious diseases posing the greatest immediate threat to the safety of the blood supply. Cases of TTvCJD were reported in recipients of nonleukoreduced red blood cells and coagulation factor VIII manufactured from blood of United Kingdom donors. As the quantity of abnormal prions (the causative agent of TTvCJD) varies significantly in different blood components and products, it is necessary to quantify the dose-response relationship for a wide range of doses for the vCJD agent in transfused blood and plasma derivatives. In this paper, we suggest the first mechanistic dose-response model for

  10. Evaluation of arboviruses of public health interest in free-living non-human primates (Alouatta spp., Callithrix spp., Sapajus spp.) in Brazil

    OpenAIRE

    2015-01-01

    INTRODUCTION: The aim of the present study was to evaluate the presence of arboviruses from the Flavivirus genus in asymptomatic free-living non-human primates (NHPs) living in close contact with humans and vectors in the States of Paraná and Mato Grosso do Sul, Brazil. METHODS: NHP sera samples (total n = 80, Alouatta spp. n = 07, Callithrix spp. n = 29 and Sapajus spp. n = 44) were screened for the presence of viral genomes using reverse transcription polymerase chain reaction and 10% ...

  11. Comparative analysis of protocadherin-11 X-linked expression among postnatal rodents, non-human primates, and songbirds suggests its possible involvement in brain evolution.

    Directory of Open Access Journals (Sweden)

    Eiji Matsunaga

    Full Text Available BACKGROUND: Protocadherin-11 is a cell adhesion molecule of the cadherin superfamily. Since, only in humans, its paralog is found on the Y chromosome, it is expected that protocadherin-11X/Y plays some role in human brain evolution or sex differences. Recently, a genetic mutation of protocadherin-11X/Y was reported to be associated with a language development disorder. Here, we compared the expression of protocadherin-11 X-linked in developing postnatal brains of mouse (rodent and common marmoset (non-human primate to explore its possible involvement in mammalian brain evolution. We also investigated its expression in the Bengalese finch (songbird to explore a possible function in animal vocalization and human language faculties. METHODOLOGY/PRINCIPAL FINDINGS: Protocadherin-11 X-linked was strongly expressed in the cerebral cortex, hippocampus, amygdala and brainstem. Comparative analysis between mice and marmosets revealed that in certain areas of marmoset brain, the expression was clearly enriched. In Bengalese finches, protocadherin-11 X-linked was expressed not only in nuclei of regions of the vocal production pathway and the tracheosyringeal hypoglossal nucleus, but also in areas homologous to the mammalian amygdala and hippocampus. In both marmosets and Bengalese finches, its expression in pallial vocal control areas was developmentally regulated, and no clear expression was seen in the dorsal striatum, indicating a similarity between songbirds and non-human primates. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the enriched expression of protocadherin-11 X-linked is involved in primate brain evolution and that some similarity exists between songbirds and primates regarding the neural basis for vocalization.

  12. Cytokine expression in malaria-infected non-human primate placentas

    Directory of Open Access Journals (Sweden)

    M.M. Gicheru

    2012-06-01

    Full Text Available Malaria parasites are known to mediate the induction of inflammatory immune responses at the maternal-foetal interface during placental malaria (PM leading to adverse consequences like pre-term deliveries and abortions. Immunological events that take place within the malaria-infected placental micro-environment leading to retarded foetal growth and disruption of pregnancies are among the critical parameters that are still in need of further elucidation. The establishment of more animal models for studying placental malaria can provide novel ways of circumventing problems experienced during placental malaria research in humans such as inaccurate estimation of gestational ages. Using the newly established olive baboon (Papio anubis-Plasmodium knowlesi (P. knowlesi H strain model of placental malaria, experiments were carried out to determine placental cytokine profiles underlying the immunopathogenesis of placental malaria. Four pregnant olive baboons were infected with blood stage P. knowlesi H strain parasites on the one fiftieth day of gestation while four other uninfected pregnant olive baboons were maintained as uninfected controls. After nine days of infection, placentas were extracted from all the eight baboons through cesarean surgery and used for the processing of placental plasma and sera samples for cytokine sandwich enzyme linked immunosorbent assays (ELISA. Results indicated that the occurrence of placental malaria was associated with elevated concentrations of tumour necrosis factor alpha (TNF-α and interleukin 12 (IL-12. Increased levels of IL-4, IL-6 and IL-10 and interferon gamma (IFN-γ levels were detected in uninfected placentas. These findings match previous reports regarding immunity during PM thereby demonstrating the reliability of the olive baboon-P. knowlesi model for use in further studies.

  13. Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset.

    Science.gov (United States)

    Tardif, Suzette; Ross, Corinna; Bergman, Phillip; Fernandez, Elizabeth; Javors, Marty; Salmon, Adam; Spross, Jennifer; Strong, Randy; Richardson, Arlan

    2015-05-01

    This report is the first description of dosing procedures, pharmacokinetics, biochemical action, and general tolerability of the antiaging drug rapamycin in the common marmoset, a small and short-lived monkey. Eudragit-encapsulated rapamycin was given orally to trained marmosets in a short-term (3 weeks) and a long-term (14 months) study. Circulating trough rapamycin levels (mean = 5.2 ng/mL; 1.93-10.73 ng/mL) achieved at roughly 1.0 mg/kg/day was comparable to those reported in studies of rodents and within the therapeutic range for humans. Long-term treated animals (6/8) indicated a reduction in mammalian target of rapamycin complex 1 signaling as noted by a decrease in the phospho rpS6 to total rpS6 ratio after 2 weeks of treatment. All long-term treated subjects had detectable concentrations of rapamycin in liver (4.7-19.9 pg/mg) and adipose tissue (2.2-32.8 pg/mg) with reduced mammalian target of rapamycin signaling in these tissues. There was no evidence of clinical anemia, fibrotic lung changes, or mouth ulcers. The observed death rate in the long-term study was as expected given the animals' ages. The ability to rapidly and reliably dose socially housed marmosets with an oral form of rapamycin that is well tolerated and that demonstrates a suppression of the mammalian target of rapamycin pathway leads us to conclude that this species offers a viable model for rapamycin testing to establish safety and efficacy for long-term antiaging intervention.

  14. Differences in type I interferon signaling antagonism by dengue viruses in human and non-human primate cell lines.

    Directory of Open Access Journals (Sweden)

    Freddy A Medina

    2015-03-01

    Full Text Available BACKGROUND/OBJECTIVES: In vitro studies have shown that dengue virus (DENV can thwart the actions of interferon (IFN-α/β and prevent the development of an antiviral state in infected cells. Clinical studies looking at gene expression in patients with severe dengue show a reduced expression of interferon stimulated genes compared to patients with dengue fever. Interestingly, there are conflicting reports as to the ability of DENV or other flaviviruses to inhibit IFN-α/β signaling. METHODOLOGY/PRINCIPAL FINDINGS: In order to determine the relative inhibition of IFN-α/β signaling by DENVs, a method combining flow cytometry and a four-parameter logistic regression model was established. A representative isolate from DENV-1, -3 and -4 and seventeen representative isolates encompassing all DENV-2 genotypes were evaluated. All of the DENVs evaluated in this study were capable of inhibiting IFN-α/β signaling. Most of the strains were able to inhibit IFN-α/β to a degree similar to DENV strain 16681; however, DENV-2 sylvatic strains demonstrated an increased inhibition of phosphorylated signal transducer and activator of transcription (pSTAT1. Surprisingly, we were unable to observe inhibition of pSTAT1 by DENV-2 sylvatic strains or the Asian strain 16681 in non-human primate (NHP cell lines. Analysis in primary Rhesus macaque dendritic cells suggests that DENVs are capable of inhibiting IFN signaling in these cells. However, contrary to human dendritic cells, production of IFN-α was detected in the supernatant of DENV-infected Rhesus macaque dendritic cells. CONCLUSIONS: The ability of DENVs to inhibit IFN-α/β signaling is conserved. Although some variation in the inhibition was observed, the moderate differences may be difficult to correlate with clinical outcomes. DENVs were unable to inhibit pSTAT1 in NHP cell lines, but their ability to inhibit pSTAT1 in primary Rhesus macaque dendritic cells suggests that this may be a cell specific

  15. An in vivo comparison of cis- and trans-[{sup 18}F]mefway in the nonhuman primate

    Energy Technology Data Exchange (ETDEWEB)

    Wooten, Dustin, E-mail: dwooten@wisc.edu [Department of Medical Physics, Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI 53705 (United States); Hillmer, Ansel; Murali, Dhanabalan; Barnhart, Todd [Department of Medical Physics, Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI 53705 (United States); Schneider, Mary L. [Department of Kinesiology, University of Wisconsin-Madison, Madison, WI 53706 (United States); Mukherjee, Jogeshwar [Preclinical Imaging Center, Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine 92697 (United States); Christian, Bradley T. [Department of Medical Physics, Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI 53705 (United States)

    2011-10-15

    Introduction: [{sup 18}F]Mefway is a serotonin 5-HT{sub 1A} PET radiotracer with high specificity and favorable in vivo imaging properties. The chemical structure of [{sup 18}F]mefway permits {sup 18}F labeling in either the cis or trans positions at the 4-cyclohexyl site. We have previously reported on the in vivo kinetics of trans-[{sup 18}F]mefway in the nonhuman primate. In this work, we compare the in vivo binding of cis-[{sup 18}F]mefway and trans-[{sup 18}F]mefway to evaluate the properties of cis-[{sup 18}F]mefway for 5-HT{sub 1A} PET imaging. Methods: The cis- and trans-[{sup 18}F]mefway tracers were synthesized via nucleophilic substitution with their respective tosyl precursors. Two monkeys (one male, one female) were given bolus injections of both cis- and trans-labeled [{sup 18}F]mefway in separate experiments. Dynamic scans were acquired for 90 min with a microPET P4 scanner. Time-activity curves were extracted in the areas of the mesial temporal cortex (MTC), anterior cingulate gyrus (aCG), insular cortex (IC), raphe nuclei (RN) and cerebellum (CB). The in vivo behavior of the radiotracers was compared based upon the nondisplaceable binding potential (BP{sub ND}) using the CB as a reference region. Results: Averaged over the two subjects, BP{sub ND} values were as follows: MTC: 7.7, 0.58; aCG: 4.95, 0.32; IC: 3.27, 0.2; and RN: 3.05, 0.13, for trans-[{sup 18}F]mefway and cis-[{sup 18}F]mefway, respectively. Conclusion: The cis-labeled [{sup 18}F]mefway tracer has low specific binding throughout the 5-HT{sub 1A} regions of the brain compared to trans-[{sup 18}F]mefway, suggesting that the target-to-background binding of cis-[{sup 18}F]mefway may limit its use for in vivo assessment of 5-HT{sub 1A} binding.

  16. Learning at a distance II. Statistical learning of non-adjacent dependencies in a non-human primate.

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    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.

  17. Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study.

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    Stephanie Seah

    Full Text Available BACKGROUND: Pharmacological MRI (phMRI is a neuroimaging technique where drug-induced hemodynamic responses can represent a pharmacodynamic biomarker to delineate underlying biological consequences of drug actions. In most preclinical studies, animals are anesthetized during image acquisition to minimize movement. However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns. Significant efforts have been made to establish awake imaging in rodents and nonhuman primates (NHP. Whilst various platforms have been developed for imaging awake NHP, comparison and validation of phMRI data as translational biomarkers across species remain to be explored. METHODOLOGY: We have established an awake NHP imaging model that encompasses comprehensive acclimation procedures with a dedicated animal restrainer. Using a cerebral blood volume (CBV-based phMRI approach, we have determined differential responses of brain activation elicited by the systemic administration of buprenorphine (0.03 mg/kg i.v., a partial µ-opioid receptor agonist, in the same animal under awake and anesthetized conditions. Additionally, region-of-interest analyses were performed to determine regional drug-induced CBV time-course data and corresponding area-under-curve (AUC values from brain areas with high density of µ-opioid receptors. PRINCIPAL FINDINGS: In awake NHPs, group-level analyses revealed buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n = 4. This observation is strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[(11C]methyl]buprenorphine ([(11C]BPN positron emission tomography imaging study in baboons. Furthermore, our findings are consistent with previous buprenorphine phMRI studies in humans and conscious rats which collectively

  18. Memory impairment in aged primates is associated with region-specific network dysfunction

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    Thomé, Alexander; Gray, Daniel T.; Erickson, Cynthia A.; Lipa, Peter; Barnes, Carol A.

    2015-01-01

    Age-related deficits in episodic memory result, in part, from declines in the integrity of medial temporal lobe structures, such as the hippocampus, but are not thought to be due to widespread loss of principal neurons. Studies in rodents suggest, however, that inhibitory interneurons may be particularly vulnerable in advanced age. Optimal encoding and retrieval of information depend on a balance of excitatory and inhibitory transmission. It is not known whether a disruption of this balance is observed in aging nonhuman primates, and whether such changes affect network function and behavior. To examine this question we combine large scale electrophysiological recordings with cell type-specific imaging in the medial temporal lobe of cognitively-assessed, aged rhesus macaques. We found that neuron excitability in hippocampal region CA3 is negatively correlated with the density of the somatostatin-expressing inhibitory interneurons in the vicinity of the recording electrodes in stratum oriens. By contrast, no hyperexcitability or interneuron loss was observed in the perirhinal cortex of these aged, memory-impaired monkeys. These data provide a link, for the first time, between selective increases in principal cell excitability and declines in a molecularly-defined population of interneurons that regulate network inhibition. PMID:26503764

  19. Of mice and monkeys: using non-human primate models to bridge mouse- and human-based investigations of autism spectrum disorders

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    Watson Karli K

    2012-07-01

    Full Text Available Abstract 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.

  20. Of mice and monkeys: using non-human primate models to bridge mouse- and human-based investigations of autism spectrum disorders.

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    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.

  1. Development of the first marmoset-specific DNA microarray (EUMAMA: a new genetic tool for large-scale expression profiling in a non-human primate

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    Waegele Brigitte

    2007-06-01

    Full Text Available Abstract 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.

  2. LES of Laminar-to-Turbulent Particle-Fluid Dynamics in Human and Nonhuman Primate Airways: Applications to Aerosolized Drug Delivery Animal Testing

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    Geisler, Taylor; Padhy, Sourav; Shaqfeh, Eric; Iaccarino, Gianluca

    2016-11-01

    Both the human health benefit and risk from the inhalation of aerosolized medications is often predicted by extrapolating experimental data taken using nonhuman primates to human inhalation. In this study, we employ Large Eddy Simulation to simulate particle-fluid dynamics in realistic upper airway models of both humans and rhesus monkeys. We report laminar-to-turbulent flow transitions triggered by constrictions in the upper trachea and the persistence of unsteadiness into the low Reynolds number bifurcating lower airway. Micro-particle deposition fraction and locations are shown to depend significantly on particle size. In particular, particle filtration in the nasal airways is shown to approach unity for large aerosols (8 microns) or high-rate breathing. We validate the accuracy of LES mean flow predictions using MRV imaging results. Additionally, particle deposition fractions are validated against experiments in 3 model airways.

  3. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease

    DEFF Research Database (Denmark)

    Hallett, Penelope J; Deleidi, Michela; Astradsson, Arnar;

    2015-01-01

    Autologous transplantation of patient-specific induced pluripotent stem cell (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. Postmortem analyses demonstrated robust survival of midbrain-like dopaminergic...

  4. Detection of antibodies to Oropouche virus in non-human primates in Goiânia City, Goiás

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    Marize Moreira Gibrail

    2016-06-01

    Full Text Available Abstract: INTRODUCTION 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. METHODS: Fifty blood samples were analyzed by hemagglutination-inhibition and neutralization assays. RESULTS: Two monkeys (Alouatta caraya had antibodies to OROV by both techniques. CONCLUSIONS 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.

  5. Evaluation of arboviruses of public health interest in free-living non-human primates (Alouatta spp., Callithrix spp., Sapajus spp. in Brazil

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    Tatiana Carneiro da Rocha

    2015-04-01

    Full Text Available INTRODUCTION: The aim of the present study was to evaluate the presence of arboviruses from the Flavivirus genus in asymptomatic free-living non-human primates (NHPs living in close contact with humans and vectors in the States of Paraná and Mato Grosso do Sul, Brazil. METHODS: NHP sera samples (total n = 80, Alouatta spp. n = 07, Callithrix spp. n = 29 and Sapajus spp. n = 44 were screened for the presence of viral genomes using reverse transcription polymerase chain reaction and 10% polyacrylamide gel electrophoresis techniques. RESULTS: All of the samples were negative for the Flavivirus genome following the 10% polyacrylamide gel electrophoresis analysis. CONCLUSIONS: These negative results indicate that the analyzed animals were not infected with arboviruses from the Flavivirus genus and did not represent a risk for viral transmission through vectors during the period in which the samples were collected.

  6. A high density of human communication-associated genes in chromosome 7q31-q36: differential expression in human and non-human primate cortices.

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    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.

  7. Fully human monoclonal antibody inhibitors of the neonatal Fc receptor (FcRn reduce circulating IgG in nonhuman primates

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    Andrew E Nixon

    2015-04-01

    Full Text Available The therapeutic management of antibody mediated autoimmune disease typically involves immunosuppressant and immunomodulatory strategies. However, perturbing the fundamental role of the neonatal Fc receptor (FcRn in salvaging IgG from lysosomal degradation provides a novel approach – depleting the body of pathogenic immunoglobulin by preventing IgG binding to FcRn and thereby increasing the rate of IgG catabolism. Herein, we describe the discovery and preclinical evaluation of fully human monoclonal IgG antibody inhibitors of FcRn. Using phage display, we identified several potent inhibitors of human FcRn in which binding to FcRn is pH independent, with over 1000-fold higher affinity for human FcRn than human IgG-Fc at pH 7.4. FcRn antagonism in vivo using a human-FcRn knock-in transgenic mouse model caused enhanced catabolism of exogenously administered human IgG. In non-human primates we observed reductions in endogenous circulating IgG of > 60% with no changes in albumin, IgM, or IgA. FcRn antagonism did not disrupt the ability of non-human primates to mount IgM/IgG primary and secondary immune responses. Interestingly, the therapeutic anti-FcRn antibodies had a short serum half-life but caused a prolonged reduction in IgG levels. This may be explained by the high affinity of the antibodies to FcRn at both acidic and neutral pH. These results provide important preclinical proof of concept data in support of FcRn antagonism as a novel approach to the treatment of antibody mediated autoimmune diseases.

  8. Activation of TrkB with TAM-163 results in opposite effects on body weight in rodents and non-human primates.

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    Mylène Perreault

    Full Text Available 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.

  9. Atypical BSE (BASE transmitted from asymptomatic aging cattle to a primate.

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    Emmanuel E Comoy

    Full Text Available BACKGROUND: Human variant Creutzfeldt-Jakob Disease (vCJD results from foodborne transmission of prions from slaughtered cattle with classical Bovine Spongiform Encephalopathy (cBSE. Atypical forms of BSE, which remain mostly asymptomatic in aging cattle, were recently identified at slaughterhouses throughout Europe and North America, raising a question about human susceptibility to these new prion strains. METHODOLOGY/PRINCIPAL FINDINGS: Brain homogenates from cattle with classical BSE and atypical (BASE infections were inoculated intracerebrally into cynomolgus monkeys (Macacca fascicularis, a non-human primate model previously demonstrated to be susceptible to the original strain of cBSE. The resulting diseases were compared in terms of clinical signs, histology and biochemistry of the abnormal prion protein (PrPres. The single monkey infected with BASE had a shorter survival, and a different clinical evolution, histopathology, and prion protein (PrPres pattern than was observed for either classical BSE or vCJD-inoculated animals. Also, the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine. CONCLUSION/SIGNIFICANCE: Our results point to a possibly higher degree of pathogenicity of BASE than classical BSE in primates and also raise a question about a possible link to one uncommon subset of cases of apparently sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of atypical strains should temper the urge to relax measures currently in place to protect public health from accidental contamination by BSE-contaminated products.

  10. Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

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    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

  11. Regularly scheduled, day-time, slow-onset 60 Hz electric and magnetic field exposure does not depress serum melatonin concentration in nonhuman primates

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    Rogers, W.R.; Smith, H.D.; Orr, J.L. [Southwest Research Inst., San Antonio, TX (United States); Reiter, R.J.; Barlow-Walden, L. [Univ. of Texas Health Science Center, San Antonio, TX (United States)

    1995-12-31

    Experiments conducted with laboratory rodents indicate that exposure to 60 Hz electric fields or magnetic fields can suppress nocturnal melatonin concentrations in pineal gland and blood. In three experiments employing three field-exposed and three sham-exposed nonhuman primates, each implanted with an indwelling venous cannula to allow repeated blood sampling, the authors studied the effects of either 6 kV/m and 50 {micro}T (0.5 G) or 30 kV/m and 100 {micro}T (1.0 G) on serum melatonin patterns. The fields were ramped on and off slowly, so that no transients occurred. Extensive quality control for the melatonin assay, computerized control and monitoring of field intensities, and consistent exposure protocols were used. No changes in nocturnal serum melatonin concentration resulted from 6 weeks of day-time exposure with slow field onset/offset and a highly regular exposure protocol. These results indicate that, under the conditions tested, day-time exposure to 60 Hz electric and magnetic fields in combination does not result in melatonin suppression in primates.

  12. Systems biology discoveries using non-human primate pluripotent stem and germ cells: novel gene and genomic imprinting interactions as well as unique expression patterns.

    Science.gov (United States)

    Ben-Yehudah, Ahmi; Easley, Charles A; Hermann, Brian P; Castro, Carlos; Simerly, Calvin; Orwig, Kyle E; Mitalipov, Shoukhrat; Schatten, Gerald

    2010-08-05

    The study of pluripotent stem cells has generated much interest in both biology and medicine. Understanding the fundamentals of biological decisions, including what permits a cell to maintain pluripotency, that is, its ability to self-renew and thereby remain immortal, or to differentiate into multiple types of cells, is of profound importance. For clinical applications, pluripotent cells, including both embryonic stem cells and adult stem cells, have been proposed for cell replacement therapy for a number of human diseases and disorders, including Alzheimer's, Parkinson's, spinal cord injury and diabetes. One challenge in their usage for such therapies is understanding the mechanisms that allow the maintenance of pluripotency and controlling the specific differentiation into required functional target cells. Because of regulatory restrictions and biological feasibilities, there are many crucial investigations that are just impossible to perform using pluripotent stem cells (PSCs) from humans (for example, direct comparisons among panels of inbred embryonic stem cells from prime embryos obtained from pedigreed and fertile donors; genomic analysis of parent versus progeny PSCs and their identical differentiated tissues; intraspecific chimera analyses for pluripotency testing; and so on). However, PSCs from nonhuman primates are being investigated to bridge these knowledge gaps between discoveries in mice and vital information necessary for appropriate clinical evaluations. In this review, we consider the mRNAs and novel genes with unique expression and imprinting patterns that were discovered using systems biology approaches with primate pluripotent stem and germ cells.

  13. Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate.

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    Vinot, Nina; Jouin, Mélanie; Lhomme-Duchadeuil, Adrien; Guesnet, Philippe; Alessandri, Jean-Marc; Aujard, Fabienne; Pifferi, Fabien

    2011-01-01

    Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are major components of brain cells membranes. ω3 PUFA-deficient rodents exhibit severe cognitive impairments (learning, memory) that have been linked to alteration of brain glucose utilization or to changes in neurotransmission processes. ω3 PUFA supplementation has been shown to lower anxiety and to improve several cognitive parameters in rodents, while very few data are available in primates. In humans, little is known about the association between anxiety and ω3 fatty acids supplementation and data are divergent about their impact on cognitive functions. Therefore, the development of nutritional studies in non-human primates is needed to disclose whether a long-term supplementation with long-chain ω3 PUFA has an impact on behavioural and cognitive parameters, differently or not from rodents. We address the hypothesis that ω3 PUFA supplementation could lower anxiety and improve cognitive performances of the Grey Mouse Lemur (Microcebus murinus), a nocturnal Malagasy prosimian primate. Adult male mouse lemurs were fed for 5 months on a control diet or on a diet supplemented with long-chain ω3 PUFA (n = 6 per group). Behavioural, cognitive and motor performances were measured using an open field test to evaluate anxiety, a circular platform test to evaluate reference spatial memory, a spontaneous locomotor activity monitoring and a sensory-motor test. ω3-supplemented animals exhibited lower anxiety level compared to control animals, what was accompanied by better performances in a reference spatial memory task (80% of successful trials vs 35% in controls, pfatty acids may represent a valuable dietary strategy to improve behavioural and cognitive functions.

  14. Establishing 'quality of life' parameters using behavioural guidelines for humane euthanasia of captive non-human primates.

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    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.

  15. Aging in the natural world: comparative data reveal similar mortality patterns across primates.

    Science.gov (United States)

    Bronikowski, Anne M; Altmann, Jeanne; Brockman, Diane K; Cords, Marina; Fedigan, Linda M; Pusey, Anne; Stoinski, Tara; Morris, William F; Strier, Karen B; Alberts, Susan C

    2011-03-11

    Human senescence patterns-late onset of mortality increase, slow mortality acceleration, and exceptional longevity-are often described as unique in the animal world. Using an individual-based data set from longitudinal studies of wild populations of seven primate species, we show that contrary to assumptions of human uniqueness, human senescence falls within the primate continuum of aging; the tendency for males to have shorter life spans and higher age-specific mortality than females throughout much of adulthood is a common feature in many, but not all, primates; and the aging profiles of primate species do not reflect phylogenetic position. These findings suggest that mortality patterns in primates are shaped by local selective forces rather than phylogenetic history.

  16. Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline.

    Science.gov (United States)

    Kupsch, A; Sautter, J; Götz, M E; Breithaupt, W; Schwarz, J; Youdim, M B; Riederer, P; Gerlach, M; Oertel, W H

    2001-01-01

    The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (-)-methamphetamine and (-)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly

  17. Effect of palm olein oil in a moderate-fat diet on plasma lipoprotein profile and aortic atherosclerosis in non-human primates.

    Science.gov (United States)

    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

  18. Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans.

    Science.gov (United States)

    Butelman, Eduardo R; Mandau, Marek; Tidgewell, Kevin; Prisinzano, Thomas E; Yuferov, Vadim; Kreek, Mary Jeanne

    2007-01-01

    This study focused on the in vivo effects of the kappa-opioid hallucinogen salvinorin A, derived from the plant Salvia divinorum. The effects of salvinorin A (0.0032-0.056 mg/kg i.v.) were studied in a neuroendocrine biomarker assay of the anterior pituitary hormone prolactin in gonadally intact, adult male and female rhesus monkeys (n = 4 each). Salvinorin A produced dose- and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy kappa-agonist U69,593 ((+)-(5alpha,7 alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiniyl)-1-oxaspiro[4.5]dec-8yl]-benzeneacetamide), but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED50, 0.015 mg/kg; U69,593 ED(50), 0.0098 mg/kg). The effects of i.v. salvinorin A were not prevented by a small dose of the opioid antagonist nalmefene (0.01 mg/kg s.c.) but were prevented by a larger dose of nalmefene (0.1 mg/kg); the latter nalmefene dose is sufficient to produce kappa-antagonist effects in this species. In contrast, the 5HT2 receptor antagonist ketanserin (0.1 mg/kg i.m.) did not prevent the effects of salvinorin A. As expected, the neuroendocrine effects of salvinorin A (0.0032 mg/kg i.v.) were more robust in female than in male subjects. Related studies focused on full-length cloning of the coding region of the rhesus monkey kappa-opioid receptor (OPRK1) gene and revealed a high homology of the nonhuman primate OPRK1 gene compared with the human OPRK1 gene, including particular C-terminal residues thought to be involved in receptor desensitization and internalization. The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy kappa-agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.

  19. Comparing adjuvanted H28 and modified vaccinia virus ankara expressingH28 in a mouse and a non-human primate tuberculosis model.

    Directory of Open Access Journals (Sweden)

    Rolf Billeskov

    Full Text Available 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.

  20. Distinct BOLD fMRI Responses of Capsaicin-Induced Thermal Sensation Reveal Pain-Related Brain Activation in Nonhuman Primates.

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    Abu Bakar Ali Asad

    Full Text Available Approximately 20% of the adult population suffer from chronic pain that is not adequately treated by current therapies, highlighting a great need for improved treatment options. To develop effective analgesics, experimental human and animal models of pain are critical. Topically/intra-dermally applied capsaicin induces hyperalgesia and allodynia to thermal and tactile stimuli that mimics chronic pain and is a useful translation from preclinical research to clinical investigation. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored.Here we establish an aversive capsaicin-induced fMRI model using non-noxious heat stimuli in Cynomolgus monkeys (n = 8. BOLD fMRI data were collected during thermal challenge (ON:20 s/42°C; OFF:40 s/35°C, 4-cycle at baseline and 30 min post-capsaicin (0.1 mg, topical, forearm application. Tail withdrawal behavioral studies were also conducted in the same animals using 42°C or 48°C water bath pre- and post- capsaicin application (0.1 mg, subcutaneous, tail.Group comparisons between pre- and post-capsaicin application revealed significant BOLD signal increases in brain regions associated with the 'pain matrix', including somatosensory, frontal, and cingulate cortices, as well as the cerebellum (paired t-test, p<0.02, n = 8, while no significant change was found after the vehicle application. The tail withdrawal behavioral study demonstrated a significant main effect of temperature and a trend towards capsaicin induced reduction of latency at both temperatures.These findings provide insights into the specific brain regions involved with aversive, 'pain-like', responses in a nonhuman primate model. Future studies may employ both behavioral and fMRI measures as translational biomarkers to gain deeper understanding of pain processing and evaluate

  1. Informing the Historical Record of Experimental Nonhuman Primate Infections with Ebola Virus: Genomic Characterization of USAMRIID Ebola Virus/H.sapiens-tc/COD/1995/Kikwit-9510621 Challenge Stock R4368 and Its Replacement R4415

    Science.gov (United States)

    2016-03-20

    Lefkowitz EJ, editors. Virus Taxonomy - 8 Ninth Report of the International Committee on Taxonomy of Viruses . London, UK: 9 Elsevier/Academic Press...Ebola virus variants that emerged in Guinea and the 16 Democratic Republic of the Congo in 2014. Viruses . 2014;6(11):4760-99. doi: 17 10.3390/v6114760...1 Informing the historical record of experimental nonhuman primate 1 infections with Ebola virus : genomic characterization of 2 USAMRIID Ebola

  2. Diverse captive non-human primates with phytanic acid-deficient diets rich in plant products have substantial phytanic acid levels in their red blood cells

    Directory of Open Access Journals (Sweden)

    Moser Ann B

    2013-02-01

    Full Text Available Abstract Background Humans and rodents with impaired phytanic acid (PA metabolism can accumulate toxic stores of PA that have deleterious effects on multiple organ systems. Ruminants and certain fish obtain PA from the microbial degradation of dietary chlorophyll and/or through chlorophyll-derived precursors. In contrast, humans cannot derive PA from chlorophyll and instead normally obtain it only from meat, dairy, and fish products. Results Captive apes and Old world monkeys had significantly higher red blood cell (RBC PA levels relative to humans when all subjects were fed PA-deficient diets. Given the adverse health effects resulting from PA over accumulation, we investigated the molecular evolution of thirteen PA metabolism genes in apes, Old world monkeys, and New world monkeys. All non-human primate (NHP orthologs are predicted to encode full-length proteins with the marmoset Phyh gene containing a rare, but functional, GA splice donor dinucleotide. Acox2, Scp2, and Pecr sequences had amino acid positions with accelerated substitution rates while Amacr had significant variation in evolutionary rates in apes relative to other primates. Conclusions Unlike humans, diverse captive NHPs with PA-deficient diets rich in plant products have substantial RBC PA levels. The favored hypothesis is that NHPs can derive significant amounts of PA from the degradation of ingested chlorophyll through gut fermentation. If correct, this raises the possibility that RBC PA levels could serve as a biomarker for evaluating the digestive health of captive NHPs. Furthermore, the evolutionary rates of the several genes relevant to PA metabolism provide candidate genetic adaptations to NHP diets.

  3. Teeth, sex, and testosterone: aging in the world's smallest primate.

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    Sarah Zohdy

    Full Text Available Mouse lemurs (Microcebus spp. are an exciting new primate model for understanding human aging and disease. In captivity, Microcebus murinus develops human-like ailments of old age after five years (e.g., neurodegeneration analogous to Alzheimer's disease but can live beyond 12 years. It is believed that wild Microcebus follow a similar pattern of senescence observed in captive animals, but that predation limits their lifespan to four years, thus preventing observance of these diseases in the wild. Testing whether this assumption is true is informative about both Microcebus natural history and environmental influences on senescence, leading to interpretation of findings for models of human aging. Additionally, the study of Microcebus longevity provides an opportunity to better understand mechanisms of sex-biased longevity. Longevity is often shorter in males of species with high male-male competition, such as Microcebus, but mouse lemurs are sexually monomorphic, suggesting similar lifespans. We collected individual-based observations of wild brown mouse lemurs (Microcebus rufus from 2003-2010 to investigate sex-differences in survival and longevity. Fecal testosterone was measured as a potential mechanism of sex-based differences in survival. We used a combination of high-resolution tooth wear techniques, mark-recapture, and hormone enzyme immunoassays. We found no dental or physical signs of senescence in M. rufus as old as eight years (N = 189, ages 1-8, mean = 2.59 ± 1.63 SE, three years older than captive, senescent congeners (M. murinus. Unlike other polygynandrous vertebrates, we found no sex difference in age-dependent survival, nor sex or age differences in testosterone levels. While elevated male testosterone levels have been implicated in shorter lifespans in several species, this is one of the first studies to show equivalent testosterone levels accompanying equivalent lifespans. Future research on captive aged individuals can

  4. Injection parameters and virus dependent choice of promoters to improve neuron targeting in the nonhuman primate brain.

    Science.gov (United States)

    Lerchner, W; Corgiat, B; Der Minassian, V; Saunders, R C; Richmond, B J

    2014-03-01

    We, like many others, wish to use modern molecular methods to alter neuronal functionality in primates. For us, this requires expression in a large proportion of the targeted cell population. Long generation times make germline modification of limited use. The size and intricate primate brain anatomy poses additional challenges. We surved methods using lentiviruses and serotypes of adeno-associated viruses (AAVs) to introduce active molecular material into cortical and subcortical regions of old-world monkey brains. Slow injections of AAV2 give well-defined expression of neurons in the cortex surrounding the injection site. Somewhat surprisingly we find that in the monkey the use of cytomegalovirus promoter in lentivirus primarily targets glial cells but few neurons. In contrast, with a synapsin promoter fragment the lentivirus expression is neuron specific at high transduction levels in all cortical layers. We also achieve specific targeting of tyrosine hydroxlase (TH)- rich neurons in the locus coeruleus and substantia nigra with a lentvirus carrying a fragment of the TH promoter. Lentiviruses carrying neuron specific promoters are suitable for both cortical and subcortical injections even when injected quickly.

  5. Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate.

    Directory of Open Access Journals (Sweden)

    Nina Vinot

    Full Text Available Omega-3 (ω3 polyunsaturated fatty acids (PUFA are major components of brain cells membranes. ω3 PUFA-deficient rodents exhibit severe cognitive impairments (learning, memory that have been linked to alteration of brain glucose utilization or to changes in neurotransmission processes. ω3 PUFA supplementation has been shown to lower anxiety and to improve several cognitive parameters in rodents, while very few data are available in primates. In humans, little is known about the association between anxiety and ω3 fatty acids supplementation and data are divergent about their impact on cognitive functions. Therefore, the development of nutritional studies in non-human primates is needed to disclose whether a long-term supplementation with long-chain ω3 PUFA has an impact on behavioural and cognitive parameters, differently or not from rodents. We address the hypothesis that ω3 PUFA supplementation could lower anxiety and improve cognitive performances of the Grey Mouse Lemur (Microcebus murinus, a nocturnal Malagasy prosimian primate. Adult male mouse lemurs were fed for 5 months on a control diet or on a diet supplemented with long-chain ω3 PUFA (n = 6 per group. Behavioural, cognitive and motor performances were measured using an open field test to evaluate anxiety, a circular platform test to evaluate reference spatial memory, a spontaneous locomotor activity monitoring and a sensory-motor test. ω3-supplemented animals exhibited lower anxiety level compared to control animals, what was accompanied by better performances in a reference spatial memory task (80% of successful trials vs 35% in controls, p<0.05, while the spontaneous locomotor activity was reduced by 31% in ω3-supplemented animals (p<0.001, a parameter that can be linked with lowered anxiety. The long-term dietary ω3 PUFA supplementation positively impacts on anxiety and cognitive performances in the adult mouse lemur. The supplementation of human food with ω3 fatty

  6. Ebola virus genome plasticity as a marker of its passaging history: a comparison of in vitro passaging to non-human primate infection.

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    Jeffrey R Kugelman

    Full Text Available 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.

  7. Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose-Response Model for Inhalational Anthrax in Nonhuman Primate, Rabbit, and Guinea Pig.

    Science.gov (United States)

    Gutting, Bradford W; Rukhin, Andrey; Mackie, Ryan S; Marchette, David; Thran, Brandolyn

    2015-05-01

    The application of the exponential model is extended by the inclusion of new nonhuman primate (NHP), rabbit, and guinea pig dose-lethality data for inhalation anthrax. Because deposition is a critical step in the initiation of inhalation anthrax, inhaled doses may not provide the most accurate cross-species comparison. For this reason, species-specific deposition factors were derived to translate inhaled dose to deposited dose. Four NHP, three rabbit, and two guinea pig data sets were utilized. Results from species-specific pooling analysis suggested all four NHP data sets could be pooled into a single NHP data set, which was also true for the rabbit and guinea pig data sets. The three species-specific pooled data sets could not be combined into a single generic mammalian data set. For inhaled dose, NHPs were the most sensitive (relative lowest LD50) species and rabbits the least. Improved inhaled LD50 s proposed for use in risk assessment are 50,600, 102,600, and 70,800 inhaled spores for NHP, rabbit, and guinea pig, respectively. Lung deposition factors were estimated for each species using published deposition data from Bacillus spore exposures, particle deposition studies, and computer modeling. Deposition was estimated at 22%, 9%, and 30% of the inhaled dose for NHP, rabbit, and guinea pig, respectively. When the inhaled dose was adjusted to reflect deposited dose, the rabbit animal model appears the most sensitive with the guinea pig the least sensitive species.

  8. Ebola Virus Infections in Nonhuman Primates Are Temporally Influenced by Glycoprotein Poly-U Editing Site Populations in the Exposure Material.

    Science.gov (United States)

    Trefry, John C; Wollen, Suzanne E; Nasar, Farooq; Shamblin, Joshua D; Kern, Steven J; Bearss, Jeremy J; Jefferson, Michelle A; Chance, Taylor B; Kugelman, Jeffery R; Ladner, Jason T; Honko, Anna N; Kobs, Dean J; Wending, Morgan Q S; Sabourin, Carol L; Pratt, William D; Palacios, Gustavo F; Pitt, M Louise M

    2015-12-19

    Recent experimentation with the variants of the Ebola virus that differ in the glycoprotein's poly-uridine site, which dictates the form of glycoprotein produced through a transcriptional stutter, has resulted in questions regarding the pathogenicity and lethality of the stocks used to develop products currently undergoing human clinical trials to combat the disease. In order to address these concerns and prevent the delay of these critical research programs, we designed an experiment that permitted us to intramuscularly challenge statistically significant numbers of naïve and vaccinated cynomolgus macaques with either a 7U or 8U variant of the Ebola virus, Kikwit isolate. In naïve animals, no difference in survivorship was observed; however, there was a significant delay in the disease course between the two groups. Significant differences were also observed in time-of-fever, serum chemistry, and hematology. In vaccinated animals, there was no statistical difference in survivorship between either challenge groups, with two succumbing in the 7U group compared to 1 in the 8U challenge group. In summary, survivorship was not affected, but the Ebola virus disease course in nonhuman primates is temporally influenced by glycoprotein poly-U editing site populations.

  9. Functional connectivity between Layer 2/3 and Layer 5 neurons in prefrontal cortex of nonhuman primates during a delayed match-to-sample task.

    Science.gov (United States)

    Song, Dong; Opris, Ioan; Chan, Rosa H M; Marmarelis, Vasilis Z; Hampson, Robert E; Deadwyler, Sam A; Berger, Theodore W

    2012-01-01

    The prefrontal cortex (PFC) has been postulated to play critical roles in cognitive control and the formation of long-term memories. To gain insights into the neurobiological mechanism of such high-order cognitive functions, it is important to understand the input-output transformational properties of the PFC micro-circuitry. In this study, we identify the functional connectivity between the Layer 2/3 (input) neurons and the Layer 5 (output) neurons using a previously developed generalized Volterra model (GVM). Input-output spike trains are recorded from the PFCs of nonhuman primates performing a memory-dependent delayed match-to-sample task with a customized conformal ceramic multi-electrode array. The GVM describes how the input spike trains are transformed into the output spike trains by the PFC micro-circuitry and represents the transformation in the form of Volterra kernels. Results show that Layer 2/3 neurons have strong and transient facilitatory effects on the firings of Layer 5 neurons. The magnitude and temporal range of the input-output nonlinear dynamics are strikingly different from those of the hippocampal CA3-CA1. This form of functional connectivity may have important implications to understanding the computational principle of the PFC.

  10. Contact to Non-human Primates and Risk Factors for Zoonotic Disease Emergence in the Taï Region, Côte d'Ivoire.

    Science.gov (United States)

    Mossoun, Arsène; Pauly, Maude; Akoua-Koffi, Chantal; Couacy-Hymann, Emmanuel; Leendertz, Siv Aina J; Anoh, Augustin E; Gnoukpoho, Ange H; Leendertz, Fabian H; Schubert, Grit

    2015-12-01

    Elevated exposure levels to non-human primates (NHP) and NHP bushmeat represent major risk factors for zoonotic disease transmission in sub-Saharan Africa. Demography can affect personal nutritional behavior, and thus rates of contact to NHP bushmeat. Here, we analyzed demographic and NHP contact data from 504 participants of differing demographic backgrounds living in proximity to the Taï National Park in Western Côte d'Ivoire (CI) to identify factors impacting the risk of NHP exposure. Overall, participants' contact rates to NHP were high, and increased along a gradient of bushmeat processing (e.g., 7.7% hunted, but 61.9% consumed monkeys). Contact to monkeys was significantly more frequent than to chimpanzees, most likely a reflection of meat availability and hunting effort. 17.2% of participants reported previous interaction with NHP pets. Generalized linear mixed model analysis revealed significant effects of sex, country of birth or ethnicity on rates of NHP bushmeat contact, with male participants from CI being at particular risk of exposure to NHP. The presence of zoonotic pathogens in humans and NHP in Taï further highlights the risk for zoonotic disease emergence in this region. Our results are relevant for formulating prevention strategies to reduce zoonotic pathogen burden in tropical Africa.

  11. Follow-up of cortical activity and structure after lesion with laser speckle imaging and magnetic resonance imaging in nonhuman primates

    Science.gov (United States)

    Peuser, Jörn; Belhaj-Saif, Abderraouf; Hamadjida, Adjia; Schmidlin, Eric; Gindrat, Anne-Dominique; Völker, Andreas Charles; Zakharov, Pavel; Hoogewoud, Henri-Marcel; Rouiller, Eric M.; Scheffold, Frank

    2011-09-01

    The nonhuman primate model is suitable to study mechanisms of functional recovery following lesion of the cerebral cortex (motor cortex), on which therapeutic strategies can be tested. To interpret behavioral data (time course and extent of functional recovery), it is crucial to monitor the properties of the experimental cortical lesion, induced by infusion of the excitotoxin ibotenic acid. In two adult macaque monkeys, ibotenic acid infusions produced a restricted, permanent lesion of the motor cortex. In one monkey, the lesion was monitored over 3.5 weeks, combining laser speckle imaging (LSI) as metabolic readout (cerebral blood flow) and anatomical assessment with magnetic resonance imaging (T2-weighted MRI). The cerebral blood flow, measured online during subsequent injections of the ibotenic acid in the motor cortex, exhibited a dramatic increase, still present after one week, in parallel to a MRI hypersignal. After 3.5 weeks, the cerebral blood flow was strongly reduced (below reference level) and the hypersignal disappeared from the MRI scan, although the lesion was permanent as histologically assessed post-mortem. The MRI data were similar in the second monkey. Our experiments suggest that LSI and MRI, although they reflect different features, vary in parallel during a few weeks following an excitotoxic cortical lesion.

  12. Rapid-onset/offset, variably scheduled 60 Hz electric and magnetic field exposure reduces nocturnal serum melatonin concentration in nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Rogers, W.R.; Smith, H.D. [Southwest Research Inst., San Antonio, TX (United States). Dept. of Biosciences and Bioengineering; Reiter, R.J.; Barlow-Walden, L. [Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Cellular and Structural Biology

    1995-12-31

    Experiments with rodents indicate that power-frequency electric field (EF) or magnetic field (MF) exposure can suppress the normal nocturnal increase in melatonin concentration in pineal gland and blood. In a separate set of three experiments conducted with nonhuman primates, the authors did not observe melatonin suppression as a result of 6 weeks of day-time exposure to combined 60 Hz electric and magnetic fields (E/MF) with regularly schedule ``slow`` E/MF onsets/offsets. The study described here used a different exposure paradigm in which two baboons were exposed to E/MF with ``rapid`` E/MF onsets/offsets accompanied by EF transients not found with slowly ramped E/MF onset/offset; profound reductions in nocturnal serum melatonin concentration were observed in this experiment. If replicated in a more extensive experiment, the observation of melatonin suppression only in the presence of E/MF transients would suggest that very specific exposure parameters determine the effects of 60 Hz E/MF on melatonin.

  13. Hemoglobin A1C Percentage in Nonhuman Primates: A Useful Tool to Monitor Diabetes before and after Porcine Pancreatic Islet Xenotransplantation

    Directory of Open Access Journals (Sweden)

    Marco Marigliano

    2011-01-01

    Full Text Available Non-human primates (NHPs are a very valuable experimental model for diabetes research studies including experimental pancreatic islet transplantation. In particular NHPs are the recipients of choice to validate pigs as possible source of pancreatic islets. The aim of this study was to quantify glycated hemoglobin percentage in NHPs and to assess whether changes in values reflect the metabolic trends after diabetes induction and islet transplantation. Sera from 15 NHPs were analyzed. 9 NHPs were rendered diabetic with streptozotocin (STZ, and 3 of them received porcine islet transplants. Hemoglobin A1c (HbA1c percentage was measured with an assay based on a latex immunoagglutination inhibition methodology. Whereas diabetes and its duration were associated with increasing HbA1c levels, postislet transplantation blood glucose normalization was paralleled by a decrease in the HbA1c percentage. Our data provide evidence that HbA1c is a useful tool to monitor glucose metabolism in NHPs.

  14. Ebola Virus Infections in Nonhuman Primates Are Temporally Influenced by Glycoprotein Poly-U Editing Site Populations in the Exposure Material

    Directory of Open Access Journals (Sweden)

    John C. Trefry

    2015-12-01

    Full Text Available Recent experimentation with the variants of the Ebola virus that differ in the glycoprotein’s poly-uridine site, which dictates the form of glycoprotein produced through a transcriptional stutter, has resulted in questions regarding the pathogenicity and lethality of the stocks used to develop products currently undergoing human clinical trials to combat the disease. In order to address these concerns and prevent the delay of these critical research programs, we designed an experiment that permitted us to intramuscularly challenge statistically significant numbers of naïve and vaccinated cynomolgus macaques with either a 7U or 8U variant of the Ebola virus, Kikwit isolate. In naïve animals, no difference in survivorship was observed; however, there was a significant delay in the disease course between the two groups. Significant differences were also observed in time-of-fever, serum chemistry, and hematology. In vaccinated animals, there was no statistical difference in survivorship between either challenge groups, with two succumbing in the 7U group compared to 1 in the 8U challenge group. In summary, survivorship was not affected, but the Ebola virus disease course in nonhuman primates is temporally influenced by glycoprotein poly-U editing site populations.

  15. Surveillance for yellow Fever virus in non-human primates in southern Brazil, 2001-2011: a tool for prioritizing human populations for vaccination.

    Directory of Open Access Journals (Sweden)

    Marco A B Almeida

    2014-03-01

    Full Text Available 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.

  16. Surveillance for yellow Fever virus in non-human primates in southern Brazil, 2001-2011: a tool for prioritizing human populations for vaccination.

    Science.gov (United States)

    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.

  17. A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion.

    Science.gov (United States)

    Cordoba, F; Wieczorek, G; Audet, M; Roth, L; Schneider, M A; Kunkler, A; Stuber, N; Erard, M; Ceci, M; Baumgartner, R; Apolloni, R; Cattini, A; Robert, G; Ristig, D; Munz, J; Haeberli, L; Grau, R; Sickert, D; Heusser, C; Espie, P; Bruns, C; Patel, D; Rush, J S

    2015-11-01

    CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC-mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well-tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.

  18. Path to the Clinic: Assessment of iPSC-Based Cell Therapies In Vivo in a Nonhuman Primate Model

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    So Gun Hong

    2014-05-01

    Full Text Available Induced pluripotent stem cell (iPSC-based cell therapies have great potential for regenerative medicine but are also potentially associated with tumorigenic risks. Current rodent models are not optimal predictors of efficiency and safety for clinical application. Therefore, we developed a clinically relevant nonhuman primate model to assess the tumorigenic potential and in vivo efficacy of both undifferentiated and differentiated iPSCs in autologous settings without immunosuppression. Undifferentiated autologous iPSCs indeed form mature teratomas in a dose-dependent manner. However, tumor formation is accompanied by an inflammatory reaction. On the other hand, iPSC-derived mesodermal stromal-like cells form new bone in vivo without any evidence of teratoma formation. We therefore show 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.

  19. Touchscreen-based cognitive tasks reveal age-related impairment in a primate aging model, the grey mouse lemur (Microcebus murinus.

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    Marine Joly

    Full Text Available Mouse lemurs are suggested to represent promising novel non-human primate models for aging research. However, standardized and cross-taxa cognitive testing methods are still lacking. Touchscreen-based testing procedures have proven high stimulus control and reliability in humans and rodents. The aim of this study was to adapt these procedures to mouse lemurs, thereby exploring the effect of age. We measured appetitive learning and cognitive flexibility of two age groups by applying pairwise visual discrimination (PD and reversal learning (PDR tasks. On average, mouse lemurs needed 24 days of training before starting with the PD task. Individual performances in PD and PDR tasks correlate significantly, suggesting that individual learning performance is unrelated to the respective task. Compared to the young, aged mouse lemurs showed impairments in both PD and PDR tasks. They needed significantly more trials to reach the task criteria. A much higher inter-individual variation in old than in young adults was revealed. Furthermore, in the PDR task, we found a significantly higher perseverance in aged compared to young adults, indicating an age-related deficit in cognitive flexibility. This study presents the first touchscreen-based data on the cognitive skills and age-related dysfunction in mouse lemurs and provides a unique basis to study mechanisms of inter-individual variation. It furthermore opens exciting perspectives for comparative approaches in aging, personality, and evolutionary research.

  20. Touchscreen-based cognitive tasks reveal age-related impairment in a primate aging model, the grey mouse lemur (Microcebus murinus).

    Science.gov (United States)

    Joly, Marine; Ammersdörfer, Sandra; Schmidtke, Daniel; Zimmermann, Elke

    2014-01-01

    Mouse lemurs are suggested to represent promising novel non-human primate models for aging research. However, standardized and cross-taxa cognitive testing methods are still lacking. Touchscreen-based testing procedures have proven high stimulus control and reliability in humans and rodents. The aim of this study was to adapt these procedures to mouse lemurs, thereby exploring the effect of age. We measured appetitive learning and cognitive flexibility of two age groups by applying pairwise visual discrimination (PD) and reversal learning (PDR) tasks. On average, mouse lemurs needed 24 days of training before starting with the PD task. Individual performances in PD and PDR tasks correlate significantly, suggesting that individual learning performance is unrelated to the respective task. Compared to the young, aged mouse lemurs showed impairments in both PD and PDR tasks. They needed significantly more trials to reach the task criteria. A much higher inter-individual variation in old than in young adults was revealed. Furthermore, in the PDR task, we found a significantly higher perseverance in aged compared to young adults, indicating an age-related deficit in cognitive flexibility. This study presents the first touchscreen-based data on the cognitive skills and age-related dysfunction in mouse lemurs and provides a unique basis to study mechanisms of inter-individual variation. It furthermore opens exciting perspectives for comparative approaches in aging, personality, and evolutionary research.

  1. Alefacept promotes immunosuppression-free renal allograft survival in nonhuman primates via depletion of recipient memory T cells.

    Science.gov (United States)

    Lee, S; Yamada, Y; Tonsho, M; Boskovic, S; Nadazdin, O; Schoenfeld, D; Cappetta, K; Atif, M; Smith, R-N; Cosimi, A B; Benichou, G; Kawai, T

    2013-12-01

    Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow transplantation (DBMT). To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel-conditioning regimen, the "delayed protocol" in which donor bone marrow (DBM) is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8(+) memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2(high) CD8(+) effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2(high) cells including CD8(+) TEM while sparing naïve CD8(+) T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2(high) T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach.

  2. Visual recognition of age class and preference for infantile features: implications for species-specific vs universal cognitive traits in primates.

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    Anna Sato

    Full Text Available Despite not knowing the exact age of individuals, humans can estimate their rough age using age-related physical features. Nonhuman primates show some age-related physical features; however, the cognitive traits underlying their recognition of age class have not been revealed. Here, we tested the ability of two species of Old World monkey, Japanese macaques (JM and Campbell's monkeys (CM, to spontaneously discriminate age classes using visual paired comparison (VPC tasks based on the two distinct categories of infant and adult images. First, VPCs were conducted in JM subjects using conspecific JM stimuli. When analyzing the side of the first look, JM subjects significantly looked more often at novel images. Based on analyses of total looking durations, JM subjects looked at a novel infant image longer than they looked at a familiar adult image, suggesting the ability to spontaneously discriminate between the two age classes and a preference for infant over adult images. Next, VPCs were tested in CM subjects using heterospecific JM stimuli. CM subjects showed no difference in the side of their first look, but looked at infant JM images longer than they looked at adult images; the fact that CMs were totally naïve to JMs suggested that the attractiveness of infant images transcends species differences. This is the first report of visual age class recognition and a preference for infant over adult images in nonhuman primates. Our results suggest not only species-specific processing for age class recognition but also the evolutionary origins of the instinctive human perception of baby cuteness schema, proposed by the ethologist Konrad Lorenz.

  3. Social and emotional values of sounds influence human (Homo sapiens and non-human primate (Cercopithecus campbelli auditory laterality.

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    Muriel Basile

    Full Text Available The last decades evidenced auditory laterality in vertebrates, offering new important insights for the understanding of the origin of human language. Factors such as the social (e.g. specificity, familiarity and emotional value of sounds have been proved to influence hemispheric specialization. However, little is known about the crossed effect of these two factors in animals. In addition, human-animal comparative studies, using the same methodology, are rare. In our study, we adapted the head turn paradigm, a widely used non invasive method, on 8-9-year-old schoolgirls and on adult female Campbell's monkeys, by focusing on head and/or eye orientations in response to sound playbacks. We broadcast communicative signals (monkeys: calls, humans: speech emitted by familiar individuals presenting distinct degrees of social value (female monkeys: conspecific group members vs heterospecific neighbours, human girls: from the same vs different classroom and emotional value (monkeys: contact vs threat calls; humans: friendly vs aggressive intonation. We evidenced a crossed-categorical effect of social and emotional values in both species since only "negative" voices from same class/group members elicited a significant auditory laterality (Wilcoxon tests: monkeys, T = 0 p = 0.03; girls: T = 4.5 p = 0.03. Moreover, we found differences between species as a left and right hemisphere preference was found respectively in humans and monkeys. Furthermore while monkeys almost exclusively responded by turning their head, girls sometimes also just moved their eyes. This study supports theories defending differential roles played by the two hemispheres in primates' auditory laterality and evidenced that more systematic species comparisons are needed before raising evolutionary scenario. Moreover, the choice of sound stimuli and behavioural measures in such studies should be the focus of careful attention.

  4. Social and emotional values of sounds influence human (Homo sapiens) and non-human primate (Cercopithecus campbelli) auditory laterality.

    Science.gov (United States)

    Basile, Muriel; Lemasson, Alban; Blois-Heulin, Catherine

    2009-07-17

    The last decades evidenced auditory laterality in vertebrates, offering new important insights for the understanding of the origin of human language. Factors such as the social (e.g. specificity, familiarity) and emotional value of sounds have been proved to influence hemispheric specialization. However, little is known about the crossed effect of these two factors in animals. In addition, human-animal comparative studies, using the same methodology, are rare. In our study, we adapted the head turn paradigm, a widely used non invasive method, on 8-9-year-old schoolgirls and on adult female Campbell's monkeys, by focusing on head and/or eye orientations in response to sound playbacks. We broadcast communicative signals (monkeys: calls, humans: speech) emitted by familiar individuals presenting distinct degrees of social value (female monkeys: conspecific group members vs heterospecific neighbours, human girls: from the same vs different classroom) and emotional value (monkeys: contact vs threat calls; humans: friendly vs aggressive intonation). We evidenced a crossed-categorical effect of social and emotional values in both species since only "negative" voices from same class/group members elicited a significant auditory laterality (Wilcoxon tests: monkeys, T = 0 p = 0.03; girls: T = 4.5 p = 0.03). Moreover, we found differences between species as a left and right hemisphere preference was found respectively in humans and monkeys. Furthermore while monkeys almost exclusively responded by turning their head, girls sometimes also just moved their eyes. This study supports theories defending differential roles played by the two hemispheres in primates' auditory laterality and evidenced that more systematic species comparisons are needed before raising evolutionary scenario. Moreover, the choice of sound stimuli and behavioural measures in such studies should be the focus of careful attention.

  5. 非人灵长类雌性等级的研究方法%The Methods of Research on the Dominance of Female in Non-human Primates

    Institute of Scientific and Technical Information of China (English)

    赵海涛; 张剑; 朱紫瑞; 李保国; 王晓卫

    2011-01-01

    Socio-ecological theory suggests a link between the rates of agonism, strength of competition for food or safety, reproduction, and structure of dominance hierarchies among group-living females. With research on non-human primates, it is critical to select the method of determining and describing dominance relationships. In the past, research on the Old World monkeys mainly focused on males, with little emphasis on the role of females. However recently, studies focusing on female dominance relationships have attracted more scientific attention. In primatology, the methods to determine dominance hierarchies are very important. Plenty of behavioral standards (such as aggressive-submissive, feeding, carrying infant, grooming etc. ) were used in researching female relationships with results showing varied strategies among different species. Primate social structures are divided into two types: linear hierarchy and partial hierarchy, which can be described using different methods. We followed the " dominance-directed tree" methodology, which is able to detect both types of hierarchy. By summarizing a number of different research studies on dominance, this article presents a methodological standard for determining and describing female dominance relationships.%在非人灵长类动物等级研究中,有关判定与描述优势等级方法的选择至关重要.早期对旧大陆灵长类的等级研究主要关注雄性,对雌性涉猎较少.目前主要应用攻击—屈服、取食、携婴、相互理毛等行为标准来研究灵长类的雌性等级,也发现不同的物种往往有不同的雌性等级模式.依据社群结构的完整性将其分为线性等级与非线性等级,并采用不同的方式进行描述.本文通过查阅文献资料,对雌性等级的研究内容、判定标准以及描述方式进行论述,以便抛砖引玉提高非人灵长类雌性等级的研究水平.

  6. Predomination and New Genotypes of Enterocytozoon bieneusi in Captive Nonhuman Primates in Zoos in China: High Genetic Diversity and Zoonotic Significance

    Science.gov (United States)

    Karim, Md Robiul; Dong, Haiju; Li, Tongyi; Yu, Fuchang; Li, Dezhong; Zhang, Longxian; Li, Junqiang; Wang, Rongjun; Li, Shouyi; Li, Xiaofeng; Rume, Farzana Islam; Ning, Changshen

    2015-01-01

    To appreciate the genetic diversity and zoonotic implications of Enterocytozoon bieneusi in nonhuman primates (NHPs) in zoos, we genotyped E. bieneusi in captive NHPs in seven zoos located at six major cities in China, using ribosomal internal transcribed spacer (ITS)-based PCR and sequence analyses. A total of 496 fecal specimens from 36 NHP species under nine families were analyzed and E. bieneusi was detected in 148 (29.8%) specimens of 25 NHP species from six families, including Cercopithecidae (28.7%), Cebidae (38.0%), Aotidae (75.0%), Lemuridae (26.0%), Hylobatidae (50.0%) and Hominidae (16.2%) (P = 0.0605). The infection rates were 29.0%, 15.2%, 18.2%, 37.3%, 29.2%, 37.7% and 44.8% in Shijiazhuang Zoo, Wuhan Zoo, Taiyuan Zoo, Changsha Wild Animal Zoo, Beijing Zoo, Shanghai Zoo and Shanghai Wild Animal Park, respectively (P = 0.0146). A total of 25 ITS genotypes were found: 14 known (D, O, EbpC, EbpA, Type IV, Henan-IV, BEB6, BEB4, Peru8, PigEBITS5, EbpD, CM1, CM4 and CS-1) and 11 new (CM8 to CM18). Genotype D was the most prevalent one (40/148), followed by CM4 (20/148), CM1 (15/148), O (13/148), CM16 (13/148), EbpC (11/148). Of them, genotypes D, EbpC, CM4 and O were widely distributed in NHPs (seen in 9 to 12 species) whereas genotypes CM1 and CM16 were restricted to one to three NHP species. In phylogenetic analysis, 20 genotypes (121/148, 81.8%), excluding genotypes BEB4, BEB6, CM9, CM4 and CM18, belonged to group 1 with zoonotic potential. New genotype CM9 clustered in group 2 with BEB4 and BEB6. The remaining two genotypes CM4 and CM18 formed new cluster (group 9) in between two other genotypic clusters found in primates. The findings of high diversity in E. bieneusi genotypes and their zoonotic potentiality concluded the importance of captive NHPs as reservoir hosts for human microsporidiosis. PMID:25705879

  7. Predomination and new genotypes of Enterocytozoon bieneusi in captive nonhuman primates in zoos in China: high genetic diversity and zoonotic significance.

    Directory of Open Access Journals (Sweden)

    Md Robiul Karim

    Full Text Available To appreciate the genetic diversity and zoonotic implications of Enterocytozoon bieneusi in nonhuman primates (NHPs in zoos, we genotyped E. bieneusi in captive NHPs in seven zoos located at six major cities in China, using ribosomal internal transcribed spacer (ITS-based PCR and sequence analyses. A total of 496 fecal specimens from 36 NHP species under nine families were analyzed and E. bieneusi was detected in 148 (29.8% specimens of 25 NHP species from six families, including Cercopithecidae (28.7%, Cebidae (38.0%, Aotidae (75.0%, Lemuridae (26.0%, Hylobatidae (50.0% and Hominidae (16.2% (P = 0.0605. The infection rates were 29.0%, 15.2%, 18.2%, 37.3%, 29.2%, 37.7% and 44.8% in Shijiazhuang Zoo, Wuhan Zoo, Taiyuan Zoo, Changsha Wild Animal Zoo, Beijing Zoo, Shanghai Zoo and Shanghai Wild Animal Park, respectively (P = 0.0146. A total of 25 ITS genotypes were found: 14 known (D, O, EbpC, EbpA, Type IV, Henan-IV, BEB6, BEB4, Peru8, PigEBITS5, EbpD, CM1, CM4 and CS-1 and 11 new (CM8 to CM18. Genotype D was the most prevalent one (40/148, followed by CM4 (20/148, CM1 (15/148, O (13/148, CM16 (13/148, EbpC (11/148. Of them, genotypes D, EbpC, CM4 and O were widely distributed in NHPs (seen in 9 to 12 species whereas genotypes CM1 and CM16 were restricted to one to three NHP species. In phylogenetic analysis, 20 genotypes (121/148, 81.8%, excluding genotypes BEB4, BEB6, CM9, CM4 and CM18, belonged to group 1 with zoonotic potential. New genotype CM9 clustered in group 2 with BEB4 and BEB6. The remaining two genotypes CM4 and CM18 formed new cluster (group 9 in between two other genotypic clusters found in primates. The findings of high diversity in E. bieneusi genotypes and their zoonotic potentiality concluded the importance of captive NHPs as reservoir hosts for human microsporidiosis.

  8. PET imaging evaluation of [{sup 18}F]DBT-10, a novel radioligand specific to α{sub 7} nicotinic acetylcholine receptors, in nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Hillmer, Ansel T.; Zheng, Ming-Qiang; Li, Songye; Lin, Shu-fei; Holden, Daniel; Labaree, David; Ropchan, Jim; Carson, Richard E.; Huang, Yiyun [Yale University, PET Center, 801 Howard Ave, PO Box 208048, New Haven, CT (United States); Scheunemann, Matthias; Teodoro, Rodrigo; Deuther-Conrad, Winnie; Brust, Peter [Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig (Germany)

    2016-03-15

    Positron emission tomography (PET) radioligands specific to α{sub 7} nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an α{sub 7}-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[{sup 18}F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([{sup 18}F]DBT-10), in nonhuman primates. [{sup 18}F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [{sup 18}F]DBT-10 PET, with measurement of [{sup 18}F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the α{sub 7}-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [{sup 18}F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V{sub T}/f{sub P}). [{sup 18}F]DBT-10 was produced within 90 min at high specific activities of 428 ± 436 GBq/μmol at end of synthesis. Metabolism of [{sup 18}F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55 %. Uptake of [{sup 18}F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8 ± 3.4 %. No evidence for radiolabeled [{sup 18}F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V{sub T}/f{sub P} values were 193-376 ml/cm{sup 3} across regions, with regional rank order of thalamus > frontal cortex > striatum

  9. Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.

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    Matthew E Downs

    Full Text Available 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 (500 kHz, 200-400 kPa, 4-5 μm 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.

  10. Characterization of Enteroviruses from non-human primates in cameroon revealed virus types widespread in humans along with candidate new types and species.

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    Serge Alain Sadeuh-Mba

    Full Text Available 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.

  11. Poxvirus antigen staining of immune cells as a biomarker to predict disease outcome in monkeypox and cowpox virus infection in non-human primates.

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    Haifeng Song

    Full Text Available 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.

  12. Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.

    Science.gov (United States)

    Mueller, Melanie; Yuan, Jie; McCann, Una D; Hatzidimitriou, George; Ricaurte, George A

    2013-05-01

    Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated. The aim of the present study was to assess the neurotoxic potential of a range of clinically relevant single oral doses of MDMA in a non-human primate species that metabolizes MDMA in a manner similar to humans, the squirrel monkey. A secondary objective was to explore the relationship between plasma MDMA and metabolite concentrations and lasting serotonergic deficits. Single oral doses of MDMA produced lasting dose-related serotonergic neurochemical deficits in the brains of squirrel monkeys. Notably, even the lowest dose of MDMA tested (5.7 mg/kg, estimated to be equivalent to 1.6 mg/kg in humans) produced significant effects in some brain regions. Plasma levels of MDMA engendered by neurotoxic doses of MDMA were on the order of those found in humans. Serotonergic neurochemical markers were inversely correlated with plasma concentrations of MDMA, but not with those of its major metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. These results suggest that single oral doses of MDMA in the range of those used by humans pose a neurotoxic risk and implicate the parent compound (MDMA), rather than one of its metabolites, in MDMA-induced 5-HT neural injury.

  13. Coordinated Defects in Hepatic Long Chain Fatty Acid Metabolism and Triglyceride Accumulation Contribute to Insulin Resistance in Non-Human Primates

    Science.gov (United States)

    Gastaldelli, Amalia; Casiraghi, Francesca; Halff, Glenn A.; Abrahamian, Gregory A.; Davalli, Alberto M.; Bastarrachea, Raul A.; Comuzzie, Anthony G.; Guardado-Mendoza, Rodolfo; Jimenez-Ceja, Lilia M.; Mattern, Vicki; Paez, Ana Maria; Ricotti, Andrea; Tejero, Mary E.; Higgins, Paul B.; Rodriguez-Sanchez, Iram Pablo; Tripathy, Devjit; DeFronzo, Ralph A.; Dick, Edward J.; Cline, Gary W.; Folli, Franco

    2011-01-01

    Non-Alcoholic fatty liver disease (NAFLD) is characterized by accumulation of triglycerides (TG) in hepatocytes, which may also trigger cirrhosis. The mechanisms of NAFLD are not fully understood, but insulin resistance has been proposed as a key determinant. Aims To determine the TG content and long chain fatty acyl CoA composition profile in liver from obese non-diabetic insulin resistant (IR) and lean insulin sensitive (IS) baboons in relation with hepatic and peripheral insulin sensitivity. Methods Twenty baboons with varying grades of adiposity were studied. Hepatic (liver) and peripheral (mainly muscle) insulin sensitivity was measured with a euglycemic clamp and QUICKI. Liver biopsies were performed at baseline for TG content and LCFA profile by mass spectrometry, and histological analysis. Findings were correlated with clinical and biochemical markers of adiposity and insulin resistance. Results Obese IR baboons had elevated liver TG content compared to IS. Furthermore, the concentration of unsaturated (LC-UFA) was greater than saturated (LC-SFA) fatty acyl CoA in the liver. Interestingly, LC-FA UFA and SFA correlated with waist, BMI, insulin, NEFA, TG, QUICKI, but not M/I. Histological findings of NAFLD ranging from focal to diffuse hepatic steatosis were found in obese IR baboons. Conclusion Liver TG content is closely related with both hepatic and peripheral IR, whereas liver LC-UFA and LC-SFA are closely related only with hepatic IR in non-human primates. Mechanisms leading to the accumulation of TG, LC-UFA and an altered UFA: LC-SFA ratio may play an important role in the pathophysiology of fatty liver disease in humans. PMID:22125617

  14. Coordinated defects in hepatic long chain fatty acid metabolism and triglyceride accumulation contribute to insulin resistance in non-human primates.

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    Subhash Kamath

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is characterized by accumulation of triglycerides (TG in hepatocytes, which may also trigger cirrhosis. The mechanisms of NAFLD are not fully understood, but insulin resistance has been proposed as a key determinant.To determine the TG content and long chain fatty acyl CoA composition profile in liver from obese non-diabetic insulin resistant (IR and lean insulin sensitive (IS baboons in relation with hepatic and peripheral insulin sensitivity.Twenty baboons with varying grades of adiposity were studied. Hepatic (liver and peripheral (mainly muscle insulin sensitivity was measured with a euglycemic clamp and QUICKI. Liver biopsies were performed at baseline for TG content and LCFA profile by mass spectrometry, and histological analysis. Findings were correlated with clinical and biochemical markers of adiposity and insulin resistance.Obese IR baboons had elevated liver TG content compared to IS. Furthermore, the concentration of unsaturated (LC-UFA was greater than saturated (LC-SFA fatty acyl CoA in the liver. Interestingly, LC-FA UFA and SFA correlated with waist, BMI, insulin, NEFA, TG, QUICKI, but not M/I. Histological findings of NAFLD ranging from focal to diffuse hepatic steatosis were found in obese IR baboons.Liver TG content is closely related with both hepatic and peripheral IR, whereas liver LC-UFA and LC-SFA are closely related only with hepatic IR in non-human primates. Mechanisms leading to the accumulation of TG, LC-UFA and an altered UFA: LC-SFA ratio may play an important role in the pathophysiology of fatty liver disease in humans.

  15. Reversible femtosecond laser-assisted myopia correction: a non-human primate study of lenticule re-implantation after refractive lenticule extraction.

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    Andri K Riau

    Full Text Available LASIK (laser-assisted in situ keratomileusis is a common laser refractive procedure for myopia and astigmatism, involving permanent removal of anterior corneal stromal tissue by excimer ablation beneath a hinged flap. Correction of refractive error is achieved by the resulting change in the curvature of the cornea and is limited by central corneal thickness, as a thin residual stromal bed may result in biomechanical instability of the cornea. A recently developed alternative to LASIK called Refractive Lenticule Extraction (ReLEx utilizes solely a femtosecond laser (FSL to incise an intrastromal refractive lenticule (RL, which results in reshaping the corneal curvature and correcting the myopia and/or astigmatism. As the RL is extracted intact in the ReLEx, we hypothesized that it could be cryopreserved and re-implanted at a later date to restore corneal stromal volume, in the event of keratectasia, making ReLEx a potentially reversible procedure, unlike LASIK. In this study, we re-implanted cryopreserved RLs in a non-human primate model of ReLEx. Mild intrastromal haze, noted during the first 2 weeks after re-implantation, subsided after 8 weeks. Refractive parameters including corneal thickness, anterior curvature and refractive error indices were restored to near pre-operative values after the re-implantation. Immunohistochemistry revealed no myofibroblast formation or abnormal collagen type I expression after 8 weeks, and a significant attenuation of fibronectin and tenascin expression from week 8 to 16 after re-implantation. In addition, keratocyte re-population could be found along the implanted RL interfaces. Our findings suggest that RL cryopreservation and re-implantation after ReLEx appears feasible, suggesting the possibility of potential reversibility of the procedure, and possible future uses of RLs in treating other corneal disorders and refractive errors.

  16. Do variations in mast cell hyperplasia account for differences in radiation-induced lung injury among different mouse strains, rats and nonhuman primates?

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    Down, Julian D; Medhora, Meetha; Jackson, Isabel L; Cline, J Mark; Vujaskovic, Zeljko

    2013-08-01

    The role of mast cell infiltrates in the pathology of radiation damage to the lung has been a subject of continuing investigation over the past four decades. This has been accompanied by a number of proposals as to how mast cells and the secretory products thereof participate in the generation of acute inflammation (pneumonitis) and the chronic process of collagen deposition (fibrosis). An additional pathophysiology examines the possible connection between mast cell hyperplasia and pulmonary hypertension through the release of vasoactive mediators. The timing and magnitude of pneumonitis and fibrosis are known to vary tremendously among different genetic mouse strains and animal species. Therefore, we have systematically compared mast cell numbers in lung sections from nine mouse strains, two rat strains and nonhuman primates (NHP) after whole thorax irradiation (WTI) at doses ranging from 10-15 Gy and at the time of entering respiratory distress. Mice of the BALB/c strain had a dramatic increase in interstitial mast cell numbers, similar to WAG/Rij and August rats, while relatively low levels of mast cell infiltrate were observed in other mouse strains (CBA, C3H, B6, C57L, WHT and TO mice). Enumeration of mast cell number in five NHPs (rhesus macaque), exhibiting severe pneumonitis at 17 weeks after 10 Gy WTI, also indicated a low response shared by the majority of mouse strains. There appeared to be no relationship between the mast cell response and the strain-dependent susceptibility towards pneumonitis or fibrosis. Further investigations are required to explore the possible participation of mast cells in mediating specific vascular responses and whether a genetically diverse mast cell response occurs in humans.

  17. Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine.

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    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.

  18. A rapid immunization strategy with a live attenuated tetravalent dengue vaccine elicits protective neutralizing antibody responses in non-human primates

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    Yuping eAmbuel

    2014-06-01

    Full Text Available Dengue viruses (DENVs cause approximately 390 million cases of DENV infections annually and over 3 billion people worldwide are at risk of infection. No dengue vaccine is currently available nor is there an antiviral therapy for DENV infections. We have developed a tetravalent live-attenuated DENV vaccine (TDV that consists of a molecularly characterized attenuated DENV-2 strain (TDV-2 and three chimeric viruses containing the pre-membrane and envelope genes of DENV-1, -3 and -4 expressed in the context of the TDV-2 genome. To impact dengue vaccine delivery in endemic areas and immunize travelers, a simple and rapid immunization strategy (RIS is preferred. We investigated RIS consisting of two full vaccine doses being administered subcutaneously or intradermally on the initial vaccination visit (day 0 at two different anatomical locations with a needle-free disposable syringe jet injection (DSJI delivery devices (PharmaJet in non-human primates (NHP. This vaccination strategy resulted in efficient priming and induction of neutralizing antibody responses to all four DENV serotypes comparable to those elicited by the traditional prime and boost (two months later vaccination schedule. In addition, the vaccine induced CD4+ and CD8+ T cells producing IFN-γ, IL-2, and TNF-α, and targeting the DENV-2 NS1, NS3 and NS5 proteins. Moreover, vaccine-specific T cells were cross-reactive with the non-structural NS3 and NS5 proteins of DENV-4. When animals were challenged with DENV-2 they were protected with no detectable viremia, and exhibited sterilizing immunity (no increase of neutralizing titers post- challenge. RIS could decrease vaccination visits and provide quick immune response to all four DENV serotypes. This strategy could increase vaccination compliance and would be especially advantageous for travelers into endemic areas.

  19. Citrulline as a Biomarker in the Non-human Primate Total- and Partial-body Irradiation Models: Correlation of Circulating Citrulline to Acute and Prolonged Gastrointestinal Injury.

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    Jones, Jace W; Bennett, Alexander; Carter, Claire L; Tudor, Gregory; Hankey, Kim G; Farese, Ann M; Booth, Catherine; MacVittie, Thomas J; Kane, Maureen A

    2015-11-01

    The use of plasma citrulline as a biomarker for acute and prolonged gastrointestinal injury via exposure to total- and partial-body irradiation (6 MV LINAC-derived photons; 0.80 Gy min) in nonhuman primate models was investigated. The irradiation exposure covered gastrointestinal injuries spanning lethal, mid-lethal, and sub-lethal doses. The acute gastrointestinal injury was assessed via measurement of plasma citrulline and small intestinal histopathology over the first 15 d following radiation exposure and included total-body irradiation at 13.0 Gy, 10.5 Gy, and 7.5 Gy and partial-body irradiation at 11.0 Gy with 5% bone marrow sparing. The dosing schemes of 7.5 Gy total-body irradiation and 11.0 Gy partial-body irradiation included time points out to day 60 and day 180, respectively, which allowed for correlation of plasma citrulline to prolonged gastrointestinal injury and survival. Plasma citrulline values were radiation-dependent for all radiation doses under consideration, with nadir values ranging from 63-80% lower than radiation-naïve NHP plasma. The nadir values were observed at day 5 to 7 post irradiation. Longitudinal plasma citrulline profiles demonstrated prolonged gastrointestinal injury resulting from acute high-dose irradiation had long lasting effects on enterocyte function. Moreover, plasma citrulline did not discriminate between total-body or partial-body irradiation over the first 15 d following irradiation and was not predictive of survival based on the radiation models considered herein.

  20. Anti-nicotine vaccines: Comparison of adjuvanted CRM197 and Qb-VLP conjugate formulations for immunogenicity and function in non-human primates.

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    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.

  1. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation.

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    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.

  2. Rapid and High-Throughput Detection and Quantitation of Radiation Biomarkers in Human and Nonhuman Primates by Differential Mobility Spectrometry-Mass Spectrometry

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    Chen, Zhidan; Coy, Stephen L.; Pannkuk, Evan L.; Laiakis, Evagelia C.; Hall, Adam B.; Fornace, Albert J.; Vouros, Paul

    2016-10-01

    Radiation exposure is an important public health issue due to a range of accidental and intentional threats. Prompt and effective large-scale screening and appropriate use of medical countermeasures (MCM) to mitigate radiation injury requires rapid methods for determining the radiation dose. In a number of studies, metabolomics has identified small-molecule biomarkers responding to the radiation dose. Differential mobility spectrometry-mass spectrometry (DMS-MS) has been used for similar compounds for high-throughput small-molecule detection and quantitation. In this study, we show that DMS-MS can detect and quantify two radiation biomarkers, trimethyl-L-lysine (TML) and hypoxanthine. Hypoxanthine is a human and nonhuman primate (NHP) radiation biomarker and metabolic intermediate, whereas TML is a radiation biomarker in humans but not in NHP, which is involved in carnitine synthesis. They have been analyzed by DMS-MS from urine samples after a simple strong cation exchange-solid phase extraction (SCX-SPE). The dramatic suppression of background and chemical noise provided by DMS-MS results in an approximately 10-fold reduction in time, including sample pretreatment time, compared with liquid chromatography-mass spectrometry (LC-MS). DMS-MS quantitation accuracy has been verified by validation testing for each biomarker. Human samples are not yet available, but for hypoxanthine, selected NHP urine samples (pre- and 7-d-post 10 Gy exposure) were analyzed, resulting in a mean change in concentration essentially identical to that obtained by LC-MS (fold-change 2.76 versus 2.59). These results confirm the potential of DMS-MS for field or clinical first-level rapid screening for radiation exposure.

  3. Genome-wide DNA methylation analyses in the brain reveal four differentially methylated regions between humans and non-human primates

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    Wang Jinkai

    2012-08-01

    Full Text Available Abstract Background The highly improved cognitive function is the most significant change in human evolutionary history. Recently, several large-scale studies reported the evolutionary roles of DNA methylation; however, the role of DNA methylation on brain evolution is largely unknown. Results To test if DNA methylation has contributed to the evolution of human brain, with the use of MeDIP-Chip and SEQUENOM MassARRAY, we conducted a genome-wide analysis to identify differentially methylated regions (DMRs in the brain between humans and rhesus macaques. We first identified a total of 150 candidate DMRs by the MeDIP-Chip method, among which 4 DMRs were confirmed by the MassARRAY analysis. All 4 DMRs are within or close to the CpG islands, and a MIR3 repeat element was identified in one DMR, but no repeat sequence was observed in the other 3 DMRs. For the 4 DMR genes, their proteins tend to be conserved and two genes have neural related functions. Bisulfite sequencing and phylogenetic comparison among human, chimpanzee, rhesus macaque and rat suggested several regions of lineage specific DNA methylation, including a human specific hypomethylated region in the promoter of K6IRS2 gene. Conclusions Our study provides a new angle of studying human brain evolution and understanding the evolutionary role of DNA methylation in the central nervous system. The results suggest that the patterns of DNA methylation in the brain are in general similar between humans and non-human primates, and only a few DMRs were identified.

  4. Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe-affected non-human primates by intracerebral lentiviral gene therapy.

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    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

    2016-05-02

    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.

  5. Characterization of regional left ventricular function in nonhuman primates using magnetic resonance imaging biomarkers: a test-retest repeatability and inter-subject variability study.

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    Smita Sampath

    Full Text Available Pre-clinical animal models are important to study the fundamental biological and functional mechanisms involved in the longitudinal evolution of heart failure (HF. Particularly, large animal models, like nonhuman primates (NHPs, that possess greater physiological, biochemical, and phylogenetic similarity to humans are gaining interest. To assess the translatability of these models into human diseases, imaging biomarkers play a significant role in non-invasive phenotyping, prediction of downstream remodeling, and evaluation of novel experimental therapeutics. This paper sheds insight into NHP cardiac function through the quantification of magnetic resonance (MR imaging biomarkers that comprehensively characterize the spatiotemporal dynamics of left ventricular (LV systolic pumping and LV diastolic relaxation. MR tagging and phase contrast (PC imaging were used to quantify NHP cardiac strain and flow. Temporal inter-relationships between rotational mechanics, myocardial strain and LV chamber flow are presented, and functional biomarkers are evaluated through test-retest repeatability and inter subject variability analyses. The temporal trends observed in strain and flow was similar to published data in humans. Our results indicate a dominant dimension based pumping during early systole, followed by a torsion dominant pumping action during late systole. Early diastole is characterized by close to 65% of untwist, the remainder of which likely contributes to efficient filling during atrial kick. Our data reveal that moderate to good intra-subject repeatability was observed for peak strain, strain-rates, E/circumferential strain-rate (CSR ratio, E/longitudinal strain-rate (LSR ratio, and deceleration time. The inter-subject variability was high for strain dyssynchrony, diastolic strain-rates, peak torsion and peak untwist rate. We have successfully characterized cardiac function in NHPs using MR imaging. Peak strain, average systolic strain

  6. First detection of Echinococcus multilocularis infection in two species of nonhuman primates raised in a zoo: a fatal case in Cercopithecus diana and a strongly suspected case of spontaneous recovery in Macaca nigra.

    Science.gov (United States)

    Yamano, Kimiaki; Kouguchi, Hirokazu; Uraguchi, Kohji; Mukai, Takeshi; Shibata, Chikako; Yamamoto, Hideaki; Takaesu, Noboru; Ito, Masaki; Makino, Yoshinori; Takiguchi, Mitsuyoshi; Yagi, Kinpei

    2014-08-01

    The causative parasite of alveolar echinococcosis, Echinococcus multilocularis, maintains its life cycle between red foxes (Vulpes vulples, the definitive hosts) and voles (the intermediate hosts) in Hokkaido, Japan. Primates, including humans, and some other mammal species can be infected by the accidental ingestion of eggs in the feces of red foxes. In August 2011, a 6-year-old zoo-raised female Diana monkey (Cercopithecus diana) died from alveolar echinococcosis. E. multilocularis infection was confirmed by histopathological examination and detection of the E. multilocularis DNA by polymerase chain reaction (PCR). A field survey in the zoo showed that fox intrusion was common, and serodiagnosis of various nonhuman primates using western blotting detected a case of a 14-year-old female Celebes crested macaque (Macaca nigra) that was weakly positive for E. multilocularis. Computed tomography revealed only one small calcified lesion (approximately 8mm) in the macaque's liver, and both western blotting and enzyme-linked immunosorbent assay (ELISA) showed a gradual decline of antibody titer. These findings strongly suggest that the animal had recovered spontaneously. Until this study, spontaneous recovery from E. multilocularis infection in a nonhuman primate had never been reported.

  7. An Overview on Selection and Usage of Sleeping Sites in Non-Human Primates%非人灵长类动物睡眠地点的选择与利用

    Institute of Scientific and Technical Information of China (English)

    王铭; 赵大鹏; 张剑; 李保国

    2009-01-01

    睡眠行为在非人灵长类动物的生活史中占有十分重要地位.关于非人灵长类睡眠地点选择与利用的研究是灵长类行为生态学领域的核心课题之一.本文回顾以往的研究,总结了非人灵长类动物睡眠地点选择的三个主要影响因素,即捕食压力引起的安全因素,睡眠地点的舒适因素和卫生因素;分别对非人灵长类睡眠地点选择的三种主要形式进行了初步的成因讨论,对未来的研究方向进行探索性地展望.%Sleeping behavior is a necessary life-sustaining activity for non-human primates, but is especially important in the life history of these animals because they spend approximately half of their lifetime sleeping. After a retrospective literature overview, we found that security (imposed by predation pressure) , comfort and sanitation are the main factors affecting the selection and utilization of sleeping site by non-human primates. Non-human primates generally display three different choices of sleep site selection, which include arboreal, ground and nesting. By way of conclusion we discuss the differences between species and related environmental effects. The present paper also provides several promising directions for further research .

  8. Micro-MRI study of cerebral aging: ex vivo detection of hippocampal subfield reorganization, microhemorrhages and amyloid plaques in mouse lemur primates.

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    Anne Bertrand

    Full Text Available Mouse lemurs are non-human primate models of cerebral aging and neurodegeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 µm in-plane resolution. First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon's horn. We show that both dentate gyrus and Ammon's horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon's horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral microhemorrhages.

  9. The MPTP marmoset model of parkinsonism: a multi-purpose non-human primate model for neurodegenerative diseases.

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    Philippens, Ingrid H C H M; 't Hart, Bert A; Torres, German

    2010-12-01

    Aging societies face an increasing prevalence of neurodegenerative disorders for which no cure exists. The paucity of relevant animal models that faithfully reproduce clinical and pathogenic features of neurodegenerative diseases is a major cause for the lack of effective therapies. Clinically distinct disorders, such as Alzheimer's and Parkinson's disease, are driven by overlapping pathogenic mechanisms that converge onto vulnerable neurons to ultimately cause abnormal clinical outcomes. These similarities, particularly in the early phases of neurodegeneration, might help identify appropriate animal model systems for studying of cell pathology. While reviewing some of the cellular mechanisms of disease progression, we discuss the MPTP-induced model of Parkinsonism in marmoset monkeys as a model system for construct, face and predictive validity in neurodegenerative studies.

  10. Foodborne transmission of bovine spongiform encephalopathy to non-human primates results in preclinical rapid-onset obesity.

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    Alexander Strom

    Full Text Available Obesity has become one of the largest public health challenges worldwide. Recently, certain bacterial and viral pathogens have been implicated in the pathogenesis of obesity. In the present study, we retrospectively analyzed clinical data, plasma samples and post-mortem tissue specimens derived from a risk assessment study in bovine spongiform encephalopathy (BSE-infected female cynomolgus monkeys (Macaca fascicularis. The original study design aimed to determine minimal infectious doses after oral or intracerebral (i.c. infection of macaques to assess the risk for humans. High-dose exposures resulted in 100% attack rates and a median incubation time of 4.7 years as described previously. Retrospective analyses of clinical data from high-dosed macaques revealed that foodborne BSE transmission caused rapid weight gain within 1.5 years post infection (β = 0.915; P<0.0001 which was not seen in age- and sex-matched control animals or i.c. infected animals. The rapid-onset obesity was not associated with impaired pancreatic islet function or glucose metabolism. In the early preclinical phase of oral transmission associated with body weight gain, prion accumulation was confined to the gastrointestinal tract. Intriguingly, immunohistochemical findings suggest that foodborne BSE transmission has a pathophysiological impact on gut endocrine cells which may explain rapid weight gain. To our knowledge, this is the first experimental model which clearly demonstrates that foodborne pathogens can induce obesity.

  11. Foodborne transmission of bovine spongiform encephalopathy to non-human primates results in preclinical rapid-onset obesity.

    Science.gov (United States)

    Strom, Alexander; Yutzy, Barbara; Kruip, Carina; Ooms, Mark; Schloot, Nanette C; Roden, Michael; Scott, Fraser W; Loewer, Johannes; Holznagel, Edgar

    2014-01-01

    Obesity has become one of the largest public health challenges worldwide. Recently, certain bacterial and viral pathogens have been implicated in the pathogenesis of obesity. In the present study, we retrospectively analyzed clinical data, plasma samples and post-mortem tissue specimens derived from a risk assessment study in bovine spongiform encephalopathy (BSE)-infected female cynomolgus monkeys (Macaca fascicularis). The original study design aimed to determine minimal infectious doses after oral or intracerebral (i.c.) infection of macaques to assess the risk for humans. High-dose exposures resulted in 100% attack rates and a median incubation time of 4.7 years as described previously. Retrospective analyses of clinical data from high-dosed macaques revealed that foodborne BSE transmission caused rapid weight gain within 1.5 years post infection (β = 0.915; P<0.0001) which was not seen in age- and sex-matched control animals or i.c. infected animals. The rapid-onset obesity was not associated with impaired pancreatic islet function or glucose metabolism. In the early preclinical phase of oral transmission associated with body weight gain, prion accumulation was confined to the gastrointestinal tract. Intriguingly, immunohistochemical findings suggest that foodborne BSE transmission has a pathophysiological impact on gut endocrine cells which may explain rapid weight gain. To our knowledge, this is the first experimental model which clearly demonstrates that foodborne pathogens can induce obesity.

  12. Variability of bio-clinical parameters in Chinese-origin Rhesus macaques infected with simian immunodeficiency virus: a nonhuman primate AIDS model.

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    Song Chen

    Full Text Available BACKGROUND: Although Chinese-origin Rhesus macaques (Ch RhMs infected with simian immunodeficiency virus (SIV have been used for many years to evaluate the efficacy of AIDS vaccines and therapeutics, the bio-clinical variability of such a nonhuman primate AIDS model was so far not established. METHODOLOGY/PRINCIPAL FINDINGS: By randomizing 150 (78 male and 72 female Ch RhMs with diverse MHC class I alleles into 3 groups (50 animals per group challenged with intrarectal (i.r. SIVmac239, intravenous (i.v. SIVmac239, or i.v. SIVmac251, we evaluated variability in bio-clinical endpoints for 118 weeks. All SIV-challenged Ch RhMs became seropositive for SIV during 1-2 weeks. Plasma viral load (VL peaked at weeks 1-2 and then declined to set-point levels as from week 5. The set-point VL was 30 fold higher in SIVmac239 (i.r. or i.v.-infected than in SIVmac251 (i.v.-infected animals. This difference in plasma VL increased overtime (>100 fold as from week 68. The rates of progression to AIDS or death were more rapid in SIVmac239 (i.r. or i.v.-infected than in SIVmac251 (i.v.-infected animals. No significant difference in bio-clinical endpoints was observed in animals challenged with i.r. or i.v. SIVmac239. The variability (standard deviation in peak/set-point VL was nearly one-half lower in animals infected with SIVmac239 (i.r. or i.v. than in those infected with SIVmac251 (i.v., allowing that the same treatment-related difference can be detected with one-half fewer animals using SIVmac239 than using SIVmac251. CONCLUSION/SIGNIFICANCE: These results provide solid estimates of variability in bio-clinical endpoints needed when designing studies using the Ch RhM SIV model and contribute to the improving quality and standardization of preclinical studies.

  13. HemaMax™, a recombinant human interleukin-12, is a potent mitigator of acute radiation injury in mice and non-human primates.

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    Lena A Basile

    Full Text Available 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/LD(50/30 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. Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells.

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    Yu Cong

    2016-05-01

    Full Text Available 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.

  15. Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells.

    Science.gov (United States)

    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.

  16. Aging and Gene Expression in the Primate Brain

    Energy Technology Data Exchange (ETDEWEB)

    Fraser, Hunter B.; Khaitovich, Philipp; Plotkin, Joshua B.; Paabo, Svante; Eisen, Michael B.

    2005-02-18

    It is well established that gene expression levels in many organisms change during the aging process, and the advent of DNA microarrays has allowed genome-wide patterns of transcriptional changes associated with aging to be studied in both model organisms and various human tissues. Understanding the effects of aging on gene expression in the human brain is of particular interest, because of its relation to both normal and pathological neurodegeneration. Here we show that human cerebral cortex, human cerebellum, and chimpanzee cortex each undergo different patterns of age-related gene expression alterations. In humans, many more genes undergo consistent expression changes in the cortex than in the cerebellum; in chimpanzees, many genes change expression with age in cortex, but the pattern of changes in expression bears almost no resemblance to that of human cortex. These results demonstrate the diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species; they may also have implications for the oxidative free radical theory of aging, and help to improve our understanding of human neurodegenerative diseases.

  17. [Caloric restriction in primates: how efficient as an anti-aging approach?].

    Science.gov (United States)

    Marchal, Julia; Perret, Martine; Aujard, Fabienne

    2012-12-01

    Caloric restriction (CR) is the only non-genetic intervention known to date to slow the onset of age-related diseases and increase average and maximum lifespan in several species. Its interest is continually growing, particularly for the identification of mechanisms involved in increasing longevity. Unlike studies in invertebrate and rodent models have provided some indication about the mechanisms of the CR, the efficacy of CR as an anti-aging protocol in primates has not yet been fully established. In this review we present the advantages of using non human primates as relevant models to the study of human aging in general and specifically in the context of therapeutic interventions applicable to humans, such as CR. Through the longitudinal findings in the Grey Mouse Lemur (Microcebus murinus), we stress the importance of primate studies in the context of research on aging and their potential to advance the development of molecules which can mimic the beneficial effects of CR, already observed in some species, without imposing a reduced calorie diet.

  18. The active metabolite of prasugrel, R-138727, improves cerebral blood flow and reduces cerebral infarction and neurologic deficits in a non-human primate model of acute ischaemic stroke.

    Science.gov (United States)

    Sugidachi, Atsuhiro; Mizuno, Makoto; Ohno, Kousaku; Jakubowski, Joseph A; Tomizawa, Atsuyuki

    2016-10-05

    Previously, we showed preventive effects of prasugrel, a P2Y12 antagonist, in a non-human primate model of thrombotic middle cerebral artery occlusion (MCAO); however, it remains unclear if P2Y12 inhibition after MCAO reduces cerebral injury and dysfunction. Here we investigated the effects of R-138727, the major active metabolite of prasugrel, on ex vivo platelet aggregation at 5min, 15min, 60min, and 24h after administration to non-human primates (n=3). A single intravenous dose of R-138727 (0.03-0.3mg/kg) resulted in significant and sustained dose-related effects on platelets for up to 24h. R-138727 was administered 1h after MCAO induction, and its effects on thrombosis, cerebral infarction, and neurological deficits were determined (n=8-10). R-138727 (0.3mg/kg) significantly increased total patency rate of the MCA (P=0.0211). Although there was no effect on the patency rate before R-138727 dosing (P=0.3975), it increased 1h after dosing (P=0.0114). R-138727 significantly reduced total ischaemic infarction volumes (P=0.0147), including those of basal ganglia (P=0.0028), white matter (P=0.0393), and haemorrhagic infarction (P=0.0235). Additionally, treatment with R-138727 reduced overall neurological deficits (P=0.0019), including the subcategories of consciousness (P=0.0042), sensory system (P=0.0045), motor system (P=0.0079) and musculoskeletal coordination (P=0.0082). These findings support the possible utility of P2Y12 inhibition during early-onset MCAO to limit the progression and degree of cerebral ischaemia and infarction and also associated neurological deficits.

  19. Energy expenditure evaluation in humans and non-human primates by SenseWear Armband. Validation of energy expenditure evaluation by SenseWear Armband by direct comparison with indirect calorimetry.

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    Francesca Casiraghi

    Full Text Available INTRODUCTION: The purpose of this study was to compare and validate the use of SenseWear Armband (SWA placed on the arm (SWA ARM and on the back (SWA BACK in healthy humans during resting and a cycle-ergometer exercise and to evaluate the SWA to estimate Resting Energy Expenditure (REE and Total Energy Expenditure (TEE in healthy baboons. METHODS: We studied 26 (15F/11M human subjects wearing SWA in two different anatomical sites (arm and back during resting and a cycle-ergometer test and directly compared these results with indirect calorimetry evaluation (IC, performed at the same time. We then inserted the SWA in a metabolic jacket for baboons and evaluated the TEE and REE in free living condition for 6 days in 21 (8F/13M non-human primates. RESULTS: In humans we found a good correlation between SWA place on the ARM and on the BACK with IC during the resting experiment (1.1±0.3 SWAs, 1±0.2 IC kcal/min and a slight underestimation in the SWAs data compared with IC during the cycle-ergometer exercise (5±1.9 SWA ARM, 4.5±1.5 SWA BACK and 5.4±2.1 IC kcal/min. In the non-human primate (baboons experiment SWA estimated a TEE of 0.54±0.009 kcal/min during free living and a REE of 0.82±0.06 kcal/min. CONCLUSION: SWA, an extremely simple and inexpensive apparatus, provides quite accurate measurements of energy expenditure in humans and in baboons. Energy expenditure data obtained with SWA are highly correlated with the data obtained with "gold standard", IC, in humans.

  20. Apports nutritionnels, dépense et bilan énergétiques chez l’homme et les primates non-humains : aspects méthodologiques Nutritional intakes, energy expenditure and energy balance in human and non-human primates: methodological aspects

    Directory of Open Access Journals (Sweden)

    Laurent Tarnaud

    2011-02-01

    intègrent des approches quantitatives dont la précision dépend des populations étudiées et des conditions de terrain. L'approche comportementale est le plus souvent complétée par des analyses réalisées en laboratoire et pouvant nécessiter des équipements lourds et des personnels qualifiés. La présente revue a donc pour objectif d'orienter le(s choix du chercheur en fonction de sa thématique de recherche et des conditions de son étude. Le choix de la ou des techniques sera nécessairement le fruit d’un compromis entre la précision, la faisabilité et le coût des études.This paper presents field methods and laboratory techniques used to evaluate food intake, energy and nutrient input, activity patterns, energy expenditure, and body energy storage in human and non-human primates. The aim is to review both traditional techniques and recent advances in the methods designed to investigate energetic parameters in an anthropobiological perspective. Although most of human habits and behaviours are regarded as culturally determined, Homo as a species share with non-human primates a number of psycho-physiological features originating from biological adaptations and close phylogenetic relationships. Therefore, determining the mechanisms involved in the energetic dynamics in non-human primates may contribute to identify some of these shared biological bases. In this respect, several methods in the field of energetics are applicable to both humans and non-human primates bringing out the similarities of approaches. Besides interspecific comparisons that provide a background to assess the evolution of energy strategies among primates, contrasting the energy fluxes at the population or group level highlights the range of bio-cultural adjustments of humans and non-human primate species to their social and natural environment.The present review distinguishes methods according to the energetic parameters the researcher wishes to describe and quantify: food intake

  1. Estudo anatômico do osso temporal de um primata não-humano (Callithrix sp Anatomical study of a temporal bone from a non-human primate (Callithrix sp

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    Andrei Borin

    2008-06-01

    Full Text Available A busca por modelos experimentais constitui passo fundamental para o avanço da medicina. OBJETIVO: Demonstrar, através da dissecção com técnicas microcirúrgicas, as estruturas anatômicas do osso temporal do primata Callithrix sp. FORMA DE ESTUDO: Experimental. MÉTODO: Dissecção de ossos temporais de Callithrix sp e documentação fotográfica. RESULTADOS: Identificamos as principais estruturas do osso temporal (orelhas externa, média e interna, e nervo facial. CONCLUSÃO: O primata não-humano Callithrix sp representa aparentemente um modelo viável para o estudo do osso temporal uma vez que apresenta alta similaridade anatômica com humanos.The search for experimental (animal models is essential to the development of clinical studies. AIM: To demonstrate, by means of micro dissection techniques, the anatomical structures of temporal bones from the primate Callithrix sp. STUDY DESIGN: Experimental. METHODS: Dissection of temporal bone structures of Callithrix sp and photographic documentation. RESULTS: We identified the main constituents of the temporal bone (external, medium and inner ear and facial nerve. CONCLUSION: The non-human primate Callithrix sp. is an adequate experimental model for the studies of temporal bone structures given its close anatomical similarities to that found in humans.

  2. Jumping Stand Apparatus Reveals Rapidly Specific Age-Related Cognitive Impairments in Mouse Lemur Primates.

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    Jean-Luc Picq

    Full Text Available The mouse lemur (Microcebus murinus is a promising primate model for investigating normal and pathological cerebral aging. The locomotor behavior of this arboreal primate is characterized by jumps to and from trunks and branches. Many reports indicate insufficient adaptation of the mouse lemur to experimental devices used to evaluate its cognition, which is an impediment to the efficient use of this animal in research. In order to develop cognitive testing methods appropriate to the behavioral and biological traits of this species, we adapted the Lashley jumping stand apparatus, initially designed for rats, to the mouse lemur. We used this jumping stand apparatus to compare performances of young (n = 12 and aged (n = 8 adults in acquisition and long-term retention of visual discriminations. All mouse lemurs completed the tasks and only 25 trials, on average, were needed to master the first discrimination problem with no age-related differences. A month later, all mouse lemurs made progress for acquiring the second discrimination problem but only the young group reached immediately the criterion in the retention test of the first discrimination problem. This study shows that the jumping stand apparatus allows rapid and efficient evaluation of cognition in mouse lemurs and demonstrates that about half of the old mouse lemurs display a specific deficit in long-term retention but not in acquisition of visual discrimination.

  3. Synthesis and PET evaluation of the translocator protein (18 kDa) (T.S.P.O.) ligand [{sup 11}C]D.P.A.-715 in rat and non-human primate

    Energy Technology Data Exchange (ETDEWEB)

    Creelman, A.; Mcgregor, I.; Kassiou, M. [Sydney Univ., NSW (Australia); Thominiaux, C.; Chauveau, F.; Kuhnast, B.; Boutin, H.; Hantraye, P.; Tavitian, B.; Dolle, F. [Service Hospitalier Frederic Joliot 91 - Orsay (France); Fulton, R.; Henderson, D. [RPAH, NSW (Australia); Selleri, S. [Firenze Univ. (Italy)

    2008-02-15

    The translocator protein (18 kDa) (T.S.P.O.), formerly known as the peripheral benzodiazepine receptor (P.B.R.), is over expressed upon micro-glial activation. This study involved the evaluation of the pyrazolo-pyrimidine D.P.A.-715 (T.S.P.O. Ki = 16.4 nM) in behavioural studies and the radiolabelled form, [{sup 11}C]D.P.A.-715, in healthy non-human primate and A.M.P.A.-lesioned rats as a model of activated micro-glia using PET. The in vivo anxiolytic effects of D.P.A.-715 were assessed using the social interaction test which represents social anxiety in humans. [{sup 11}C]D.P.A.-715 was prepared using [{sup 11}C]CH{sub 3}I as the labelling intermediate from the phenolic precursor of D.P.A.-715 using T.B.A.H. and D.M.F. followed by H.P.L.C.. The non-human primate distribution studies were performed using a clinical PET scanner, and A.M.P.A.-lesioned rats using micro PET. Blocking studies were conducted using P.K.11195 (5 mg/kg).In the social interaction test a significant overall effect for the duration of time spent in general investigation, adjacent lying and rearing was observed. Post hoc analysis revealed a significantly greater time spent in general investigation and adjacent lying in the 20 mg/kg D.P.A.-715 treatment group compared to vehicle treated rats. The average non-decay corrected radiochemical yield of [{sup 11}C]D.P.A.-715 was 0.27 {+-} 0.05% with an average specific activity of 16.32 {+-} 4.01 GBq/mmol. The PET distribution studies revealed poor brain uptake. Pre-treatment with P.K.1195 resulted in no change of in the uptake of the radioligand, which suggests that brain uptake is representative of non-specific binding. In agreement with these results, the brain uptake in the A.M.P.A. lesioned model, depicted no significant differences between the lesioned striatum and the non-lesioned contralateral striatum. Although D.P.A.-715 does possess anxiolytic properties in vivo, [{sup 11}C]D.P.A.-715 does not possess the required properties for further

  4. Expression and Distribution of Glucagon-Like Peptide-1 Receptor mRNA, Protein and Binding in the Male Nonhuman Primate (Macaca mulatta) Brain

    OpenAIRE

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract, where it acts as an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been...

  5. Comparative analysis of A-to-I editing in human and non-human primate brains reveals conserved patterns and context-dependent regulation of RNA editing.

    Science.gov (United States)

    O'Neil, Richard T; Wang, Xiaojing; Morabito, Michael V; Emeson, Ronald B

    2017-04-06

    A-to-I RNA editing is an important process for generating molecular diversity in the brain through modification of transcripts encoding several proteins important for neuronal signaling. We investigated the relationships between the extent of editing at multiple substrate transcripts (5HT2C, MGLUR4, CADPS, GLUR2, GLUR4, and GABRA3) in brain tissue obtained from adult humans and rhesus macaques. Several patterns emerged from these studies revealing conservation of editing across primate species. Additionally, variability in the human population allows us to make novel inferences about the co-regulation of editing at different editing sites and even across different brain regions.

  6. Epigenetic status of H19/IGF2 and SNRPN imprinted genes in aborted and successfully derived embryonic stem cell lines in non-human primates

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    Florence Wianny

    2016-05-01

    Full Text Available The imprinted genes of primate embryonic stem cells (ESCs often show altered DNA methylation. It is unknown whether these alterations emerge while deriving the ESCs. Here we studied the methylation patterns of two differentially methylated regions (DMRs, SNRPN and H19/IGF2 DMRs, during the derivation of monkey ESCs. We show that the SNRPN DMR is characteristically methylated at maternal alleles, whereas the H19/IGF2 DMR is globally highly methylated, with unusual methylation on the maternal alleles. These methylation patterns remain stable from the early stages of ESC derivation to late passages of monkey ESCs and following differentiation. Importantly, the methylation status of H19/IGF2 DMR and the expression levels of IGF2, H19, and DNMT3B mRNAs in early embryo-derived cells were correlated with their capacity to generate genuine ESC lines. Thus, we propose that these markers could be useful to predict the outcomes of establishing an ESC line in primates.

  7. Informing the Historical Record of Experimental Nonhuman Primate Infections with Ebola Virus: Genomic Characterization of USAMRIID Ebola Virus/H.sapiens-tc/COD/1995/Kikwit-9510621 Challenge Stock "R4368" and Its Replacement "R4415".

    Directory of Open Access Journals (Sweden)

    Jeffrey R Kugelman

    Full Text Available The creation of licensed medical countermeasures against Select Agents such as Ebola virus (EBOV is critically dependent on the use of standardized reagents, assays, and animal models. We performed full genome reconstruction, population genomics, contaminant analysis, and characterization of the glycoprotein gene editing site of historical United States Army Medical Research Institute of Infectious Diseases (USAMRIID nonhuman-primate challenge stock Ebola virus Kikwit "R4368" and its 2014 replacement "R4415." We also provide characterization of the master stock used to create "R4415." The obtained data are essential to understanding the quality of the seed stock reagents used in pivotal animal studies that have been used to inform medical countermeasure development. Furthermore, these data might add to the understanding of the influence of EBOV variant populations on pathogenesis and disease outcome and inform attempts to avoid the evolution of EBOV escape mutants in response to current therapeutics. Finally, as the primary challenge stocks have changed over time, these data will provide a baseline for understanding and correlating past and future animal study results.

  8. Quantification of Temozolomide in Nonhuman Primate Fluids by Isocratic Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry to Study Brain Tissue Penetration Following Intranasal or Intravenous Delivery

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    Cody J. Peer

    2016-02-01

    Full Text Available A sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometric method was developed for the quantification of temozolomide (TMZ in nonhuman primate (NHP plasma, cerebrospinal fluid (CSF, and brain extracellular fluid (ECF following microdialysis. Ethyl acetate was used to extract the plasma and CSF samples, using theophylline as the internal standard (IS. ECF samples were diluted with acetonitrile prior to analysis. TMZ was separated on a Waters UPLC® BEH C18 column with an isocratic mobile phase of ammonium acetate (10 mM-0.1% formic acid/acetonitrile (30:70, v/v in a positive-ion multiple reaction monitoring mode (m/z 195.5→137.6 for TMZ; m/z 181.5→124.2 for IS. The retention time of TMZ and theophylline was 0.45 min with a total run time of 2.5 min. The method was validated over the range from 5–2000 ng/mL in NHP plasma, CSF, and ECF with respect to linearity, accuracy, precision, selectivity, and stability. This method was successfully applied toward the measurement of pharmacokinetic samples following various routes of drug administration.

  9. Informing the Historical Record of Experimental Nonhuman Primate Infections with Ebola Virus: Genomic Characterization of USAMRIID Ebola Virus/H.sapiens-tc/COD/1995/Kikwit-9510621 Challenge Stock "R4368" and Its Replacement "R4415".

    Science.gov (United States)

    Kugelman, Jeffrey R; Rossi, Cynthia A; Wiley, Michael R; Ladner, Jason T; Nagle, Elyse R; Pfeffer, Bradley P; Garcia, Karla; Prieto, Karla; Wada, Jiro; Kuhn, Jens H; Palacios, Gustavo

    2016-01-01

    The creation of licensed medical countermeasures against Select Agents such as Ebola virus (EBOV) is critically dependent on the use of standardized reagents, assays, and animal models. We performed full genome reconstruction, population genomics, contaminant analysis, and characterization of the glycoprotein gene editing site of historical United States Army Medical Research Institute of Infectious Diseases (USAMRIID) nonhuman-primate challenge stock Ebola virus Kikwit "R4368" and its 2014 replacement "R4415." We also provide characterization of the master stock used to create "R4415." The obtained data are essential to understanding the quality of the seed stock reagents used in pivotal animal studies that have been used to inform medical countermeasure development. Furthermore, these data might add to the understanding of the influence of EBOV variant populations on pathogenesis and disease outcome and inform attempts to avoid the evolution of EBOV escape mutants in response to current therapeutics. Finally, as the primary challenge stocks have changed over time, these data will provide a baseline for understanding and correlating past and future animal study results.

  10. HIV treatments reduce malaria liver stage burden in a non-human primate model of malaria infection at clinically relevant concentrations in vivo.

    Directory of Open Access Journals (Sweden)

    Charlotte V Hobbs

    Full Text Available 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.

  11. Diversity and prevalence of gastrointestinal parasites in seven non-human primates of the Taï National Park, Côte d’Ivoire

    Directory of Open Access Journals (Sweden)

    Kouassi Roland Yao Wa

    2015-01-01

    Full Text Available Parasites and infectious diseases are well-known threats to primate populations. The main objective of this study was to provide baseline data on fecal parasites in the cercopithecid monkeys inhabiting Côte d’Ivoire’s Taï National Park. Seven of eight cercopithecid species present in the park were sampled: Cercopithecus diana, Cercopithecus campbelli, Cercopithecus petaurista, Procolobus badius, Procolobus verus, Colobus polykomos, and Cercocebus atys. We collected 3142 monkey stool samples between November 2009 and December 2010. Stool samples were processed by direct wet mount examination, formalin-ethyl acetate concentration, and MIF (merthiolate, iodine, formalin concentration methods. Slides were examined under microscope and parasite identification was based on the morphology of cysts, eggs, and adult worms. A total of 23 species of parasites was recovered including 9 protozoa (Entamoeba coli, Entamoeba histolytica/dispar, Entamoeba hartmanni, Endolimax nana, Iodamoeba butschlii, Chilomastix mesnili, Giardia sp., Balantidium coli, and Blastocystis sp., 13 nematodes (Oesophagostomum sp., Ancylostoma sp., Anatrichosoma sp., Capillariidae Gen. sp. 1, Capillariidae Gen. sp. 2, Chitwoodspirura sp., Subulura sp., spirurids [cf Protospirura muricola], Ternidens sp., Strongyloides sp., Trichostrongylus sp., and Trichuris sp., and 1 trematode (Dicrocoelium sp.. Diversity indices and parasite richness were high for all monkey taxa, but C. diana, C. petaurista, C. atys, and C. campbelli exhibited a greater diversity of parasite species and a more equitable distribution. The parasitological data reported are the first available for these cercopithecid species within Taï National Park.

  12. [{sup 18}F]DPA-714 PET imaging of translocator protein TSPO (18 kDa) in the normal and excitotoxically-lesioned nonhuman primate brain

    Energy Technology Data Exchange (ETDEWEB)

    Lavisse, S.; Inoue, K.; Jan, C.; Petit, F.; Dauguet, J.; Guillermier, M.; Rbah-Vidal, L.; Van Camp, N.; Aron-Badin, R.; Hantraye, P. [CEA, I2BM, MIRCen, Fontenay-aux-Roses (France); CEA, CNRS, URA2210, Fontenay-aux-Roses (France); Peyronneau, M.A.; Goutal, S.; Dolle, F. [CEA, I2BM, Service Hospitalier Frederic Joliot, Orsay (France); Remy, P. [CEA, I2BM, MIRCen, Fontenay-aux-Roses (France); CEA, CNRS, URA2210, Fontenay-aux-Roses (France); Service de Neurologie, CHU Henri Mondor, Creteil (France)

    2014-12-09

    We aimed to characterize pharmacologically the TSPO- radioligand [{sup 18}F]DPA-714 in the brain of healthy cynomolgus monkeys and evaluate the cellular origin of its binding in a model of neurodegeneration induced by intrastriatal injection of quinolinic acid (QA). [{sup 18}F]DPA-714 PET images were acquired before and at 2, 7, 14, 21, 49, 70, 91 days after putaminal lesioning. Blocking and displacement studies were carried out (PK11195). Different modelling approaches estimated rate constants and V{sub T} (total distribution volume) which was used to measure longitudinal changes in the lesioned putamen. Sections for immunohistochemical labelling were prepared at the same time-points to evaluate correlations between in vivo [{sup 18}F]DPA-714 binding and microglial/astrocytic activation. [{sup 18}F]DPA-714 showed a widespread distribution with a higher signal in the thalamus and occipital cortex and lower binding in the cerebellum. TSPO was expressed throughout the whole brain and about 73 % of [{sup 18}F]DPA-714 binding was specific for TSPO in vivo. The one-tissue compartment model (1-TCM) provided good and reproducible estimates of V{sub T} and rate constants, and V{sub T} values from the 1-TCM and the Logan approach were highly correlated (r {sup 2} = 0.85). QA lesioning induced an increase in V{sub T}, which was +17 %, +54 %, +157 % and +39 % higher than baseline on days 7, 14, 21 and 91 after QA injection, respectively. Immunohistochemistry revealed an early microglial and a delayed astrocytic activation after QA injection. [{sup 18}F]DPA-714 binding matched TSPO immunopositive areas and showed a stronger colocalization with CD68 microglia than with GFAP-activated astrocytes. [{sup 18}F]DPA-714 binds to TSPO with high specificity in the primate brain under normal conditions and in the QA model. This tracer provides a sensitive tool for assessing neuroinflammation in the human brain. (orig.)

  13. Absence of intestinal colonization by vancomycin-resistant enterococci in nonhuman primates Ausência de enterococos resistentes à vancomicina na microbiota intestinal de primatas não-humanos

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    Diego Batista Xavier

    2010-06-01

    Full Text Available The animal reservoirs of vancomycin-resistant enterococci (VRE have important role in the epidemiology of the bacteria and resistant genes. The present work searched fecal samples taken off nonhuman primates for the presence of VRE. Resistance profiles, virulence traits, and genetic variability among enterococci isolates were also analyzed. The samples included Capuchin monkeys (Cebus apella, n=28 and Common marmoset (Callithrix penicillata, n=37 housed in the Primate Center of the University of Brasília, Brazil. Most individuals were captive monkeys from the Central-West and South-East regions of Brazil (n=48. We collected rectal swabs and carried out selective isolation followed by multiplex Polymerase Chain Reaction (PCR to identify species and resistance genes. No vanA or vanB-containing enterococci were found. The carriage rates ranged from 1.5% for the VanC-type E. casseliflavus and E. gallinarum until 12.3% (n=8 for Enterococcus faecalis. All E. faecalis isolates showed susceptibility to vancomycin, teicoplanin, ampicillin, gentamicin, and streptomycin. The virulence genes ace and esp were prevalent (100.0%, 87.5%. Multilocus variable number of tandem repeats (MLVA revealed diversity in the number of repeats among E. faecalis isolates and targets, which was higher for espC, efa5, and efa6. We identified six different MLVA genotypes that were divergent from those described in human beings. Also, they were clustered into two genogroups that showed host-specificity for the species Cebus apella or Callithrix penicillata. In conclusion, no vanA- or vanB-containing enterococci were found colonizing those primate individuals. This finding suggested that the primate individuals investigated in our study are not directly involved in the epidemiological chain of high-level vancomycin-resistant genes vanA or vanB in Brazil. Our study also showed that E. faecalis isolated from nonhuman primates carry virulence traits and have ability to spread their

  14. Quantitative Expression Analysis of APP Pathway and Tau Phosphorylation-Related Genes in the ICV STZ-Induced Non-Human Primate Model of Sporadic Alzheimer’s Disease

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    Sang-Je Park

    2015-01-01

    Full Text Available The accumulation and aggregation of misfolded proteins in the brain, such as amyloid-β (Aβ and hyperphosphorylated tau, is a neuropathological hallmark of Alzheimer’s disease (AD. Previously, we developed and validated a novel non-human primate model for sporadic AD (sAD research using intracerebroventricular administration of streptozotocin (icv STZ. To date, no characterization of AD-related genes in different brain regions has been performed. Therefore, in the current study, the expression of seven amyloid precursor protein (APP pathway-related and five tau phosphorylation-related genes was investigated by quantitative real-time PCR experiments, using two matched-pair brain samples from control and icv STZ-treated cynomolgus monkeys. The genes showed similar expression patterns within the control and icv STZ-treated groups; however, marked differences in gene expression patterns were observed between the control and icv STZ-treated groups. Remarkably, other than β-secretase (BACE1 and cyclin-dependent kinase 5 (CDK5, all the genes tested showed similar expression patterns in AD models compared to controls, with increased levels in the precuneus and occipital cortex. However, significant changes in gene expression patterns were not detected in the frontal cortex, hippocampus, or posterior cingulate. Based on these results, we conclude that APP may be cleaved via the general metabolic mechanisms of increased α- and γ-secretase levels, and that hyperphosphorylation of tau could be mediated by elevated levels of tau protein kinase, specifically in the precuneus and occipital cortex.

  15. Cell enrichment-free massive ex-vivo expansion of peripheral CD20⁺ B cells via CD40-CD40L signals in non-human primates.

    Science.gov (United States)

    Kim, Jung-Sik; Byun, Nari; Chung, Hyunwoo; Kim, Hyun-Je; Kim, Jong-Min; Chun, Taehoon; Lee, Won-Woo; Park, Chung-Gyu

    2016-04-22

    Non-human primates (NHPs) are valuable as preclinical resources that bridge the gap between basic science and clinical application. B cells from NHPs have been utilized for the development of B-cell targeted drugs and cell-based therapeutic modalities; however, few studies on the ex-vivo expansion of monkey B cells have been reported. In this study, we developed a highly efficient ex-vivo expansion protocol for monkey B cells resulting in 99% purity without the requirement for prior cell-enrichment procedures. To this end, monkey peripheral blood mononuclear cells (PBMCs) were stimulated for 12 days with cells constitutively expressing monkey CD40L in expansion medium optimized for specific and massive expansion of B cells. The B cells expansion rates obtained were 2-5 times higher than those previously reported in humans, with rates ranging from 7.9 to 16.6 fold increase. Moreover, expanded B cells sustained high expression of co-stimulatory molecules including CD83 and CD86 until day 12 of culture, and the simple application of a brief centrifugation resulted in a CD20(+) B cell purity rate of greater than 99%. Furthermore, small amounts of CD3(+)CD20(+)BT-like cells were generated and CD16 was expressed at moderate levels on expanded B cells. Thus, the establishment of this protocol provides a method to produce quantities of homogeneous, mature B cells in numbers sufficient for the in vitro study of B cell immunity as well as for the development of B cell-diagnostic tools and cell-based therapeutic modalities.

  16. Strontium-90 Biokinetics from Simulated Wound Intakes in Non-human Primates Compared with Combined Model Predictions from National Council on Radiation Protection and Measurements Report 156 and International Commission on Radiological Protection Publication 67.

    Science.gov (United States)

    Allen, Mark B; Brey, Richard R; Gesell, Thomas; Derryberry, Dewayne; Poudel, Deepesh

    2016-01-01

    This study had a goal to evaluate the predictive capabilities of the National Council on Radiation Protection and Measurements (NCRP) wound model coupled to the International Commission on Radiological Protection (ICRP) systemic model for 90Sr-contaminated wounds using non-human primate data. Studies were conducted on 13 macaque (Macaca mulatta) monkeys, each receiving one-time intramuscular injections of 90Sr solution. Urine and feces samples were collected up to 28 d post-injection and analyzed for 90Sr activity. Integrated Modules for Bioassay Analysis (IMBA) software was configured with default NCRP and ICRP model transfer coefficients to calculate predicted 90Sr intake via the wound based on the radioactivity measured in bioassay samples. The default parameters of the combined models produced adequate fits of the bioassay data, but maximum likelihood predictions of intake were overestimated by a factor of 1.0 to 2.9 when bioassay data were used as predictors. Skeletal retention was also over-predicted, suggesting an underestimation of the excretion fraction. Bayesian statistics and Monte Carlo sampling were applied using IMBA to vary the default parameters, producing updated transfer coefficients for individual monkeys that improved model fit and predicted intake and skeletal retention. The geometric means of the optimized transfer rates for the 11 cases were computed, and these optimized sample population parameters were tested on two independent monkey cases and on the 11 monkeys from which the optimized parameters were derived. The optimized model parameters did not improve the model fit in most cases, and the predicted skeletal activity produced improvements in three of the 11 cases. The optimized parameters improved the predicted intake in all cases but still over-predicted the intake by an average of 50%. The results suggest that the modified transfer rates were not always an improvement over the default NCRP and ICRP model values.

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

    NARCIS (Netherlands)

    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 decr

  18. Cardiac safety profile of etamicastat, a novel peripheral selective dopamine-β-hydroxylase inhibitor in non-human primates, human young and elderly healthy volunteers and hypertensive patients

    Directory of Open Access Journals (Sweden)

    Manuel Vaz-da-Silva

    2015-06-01

    Full Text Available The aim of this work was to evaluate the cardiac risk for etamicastat, a peripheral reversible dopamine-β-hydroxylase inhibitor. Etamicastat blocked the hERG current amplitude with an IC50 value of 44 μg/ml. Etamicastat had no substantial effects on arterial blood pressure, heart rate and the PR interval in male Cynomolgus monkeys when administered orally up to 90 mg/kg. Administered orally at 15 and 45 mg/kg/day in female and male Cynomolgus monkey for 91 days, etamicastat had no effect on heart rate and the waveform or intervals of the electrocardiogram. At the highest dose level of 45 mg/kg, mean plasma concentrations of etamicastat ranged from 1875 to 3145 ng/ml on Day 1 and Day 91 of treatment, respectively. The effect of age on the tolerability and pharmacokinetics of etamicastat in elderly (≥65 years and young adult (18–45 years subjects showed that supine systolic (SBP and diastolic (DBP blood pressure, ECG heart rate, PR interval, QRS duration and QTcF interval were not affected following once-daily administration of 100 mg/day etamicastat for 7 days. In hypertensive patients the decrease of blood pressure tended to be more important in subjects who had received etamicastat (50, 100 and 200 mg than in subjects who had received placebo. No clinically significant out-of-range values in vital signs or ECG parameters, ECG heart rate, PR interval, QRS duration and QTcF interval were observed in hypertensive subjects following once-daily administration of etamicastat for 10 days. In conclusion, etamicastat is not likely to prolong the QT interval at therapeutic doses.

  19. Preservation of hippocampal neuron numbers in aged rhesus monkeys

    NARCIS (Netherlands)

    Keuker, J.I.H.; Luiten, P.G.M.; Fuchs, E.

    2003-01-01

    To investigate whether or not aging of nonhuman primates is accompanied by a region-specific neuron loss in the hippocampal formation, we used the optical fractionator technique to obtain stereological estimates of unilateral neuron numbers of the hippocampi of eight young (0-4 years) and five aged

  20. Impending extinction crisis of the world's primates: Why primates matter.

    Science.gov (United States)

    Estrada, Alejandro; Garber, Paul A; Rylands, Anthony B; Roos, Christian; Fernandez-Duque, Eduardo; Di Fiore, Anthony; Nekaris, K Anne-Isola; Nijman, Vincent; Heymann, Eckhard W; Lambert, Joanna E; Rovero, Francesco; Barelli, Claudia; Setchell, Joanna M; Gillespie, Thomas R; Mittermeier, Russell A; Arregoitia, Luis Verde; de Guinea, Miguel; Gouveia, Sidney; Dobrovolski, Ricardo; Shanee, Sam; Shanee, Noga; Boyle, Sarah A; Fuentes, Agustin; MacKinnon, Katherine C; Amato, Katherine R; Meyer, Andreas L S; Wich, Serge; Sussman, Robert W; Pan, Ruliang; Kone, Inza; Li, Baoguo

    2017-01-01

    Nonhuman primates, our closest biological relatives, play important roles in the livelihoods, cultures, and religions of many societies and offer unique insights into human evolution, biology, behavior, and the threat of emerging diseases. They are an essential component of tropical biodiversity, contributing to forest regeneration and ecosystem health. Current information shows the existence of 504 species in 79 genera distributed in the Neotropics, mainland Africa, Madagascar, and Asia. Alarmingly, ~60% of primate species are now threatened with extinction and ~75% have declining populations. This situation is the result of escalating anthropogenic pressures on primates and their habitats-mainly global and local market demands, leading to extensive habitat loss through the expansion of industrial agriculture, large-scale cattle ranching, logging, oil and gas drilling, mining, dam building, and the construction of new road networks in primate range regions. Other important drivers are increased bushmeat hunting and the illegal trade of primates as pets and primate body parts, along with emerging threats, such as climate change and anthroponotic diseases. Often, these pressures act in synergy, exacerbating primate population declines. Given that primate range regions overlap extensively with a large, and rapidly growing, human population characterized by high levels of poverty, global attention is needed immediately to reverse the looming risk of primate extinctions and to attend to local human needs in sustainable ways. Raising global scientific and public awareness of the plight of the world's primates and the costs of their loss to ecosystem health and human society is imperative.

  1. Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. In vitro effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on lymphocytes of venous blood from man and a non-human primate (Callithrix jacchus)

    Energy Technology Data Exchange (ETDEWEB)

    Neubert, R.; Helge, H. (Freie Univ. Berlin (Germany, F.R.). Kinderklinik und Poliklinik); Jacob-Mueller, U.; Stahlmann, R.; Neubert, D. (Freie Univ. Berlin (Germany, F.R.). Inst. fuer Toxikologie und Embryonalpharmakologie)

    1991-04-01

    The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on poke weed mitogen-stimulated proliferation and differentiation of peripheral lymphocytes was studied in vitro with cells from a non-human primate (marmoset monkey, Callithrix jacchus) and from man. Monoclonal antibodies and flow cytometry (FACScan) were used for analysis. The extent of the overall mitogen-stimulated proliferation of isolated lymphocytes in vitro from marmoset blood was only slightly reduced in the presence of TCDD compared to the solvent control (0.01% DMSO). However, incubation with TCDD in the culture medium together with the mitogen led to a pronounced decrease in the percentage of the lymphocyte subset with the surface marker CD4, and a concomitant increase in the percentage of CD8{sup +} cells. The lowest concentration found to be effective in vitro was 1x10{sup -13} M TCDD (25 fg TCDD/ml). When culturing lymphocytes from human blood of different donors under indentical conditions in the presence of TCDD and the mitogen, corresponding effects were observed to those seen with marmoset cells. A closer analysis of the T lymphocyte subsets affected revealed the CD4{sup +}CDw29{sup +} (helper-inducer cells) to be the main target for the action of TCDD. A clear-cut change in the percentage of this subpopulation was induced at concentrations as low as 1x10{sup -13} M TCDD. The development of the IL-2-marker in culture was only slightly affected by TCDD, and concentrations of 1x10{sup -12} M were required to slightly reduce the number of CD2{sup +}CD25{sup +} cells. Special B cells, namely CD20{sup +} (i.e. B{sub 1}) cells, were found to be especially susceptible to the action of TCDD, and clear-cut effects were seen in several experimental series at 1x10{sup -14} M TCDD. The formation of B cells with IgG lambda or kappa chains was also depressed in culture in the presence of TCDD. (orig./MG).

  2. Capillary changes in hippocampal CA1 and CA3 areas of the aging rhesus monkey

    NARCIS (Netherlands)

    Keuker, JIH; Luiten, PGM; Fuchs, E

    2000-01-01

    The rhesus monkey is considered a useful animal model for studying human aging, because non-human primates show many of the neurobiological alterations that have been reported in aging humans. Cognitive impairment that accompanies normal aging may, at least partially, originate from capillary change

  3. Age and sex-specific mortality of wild and captive populations of a monogamous pair-bonded primate (Aotus azarae)

    DEFF Research Database (Denmark)

    Larson, Sam; Colchero, Fernando; Jones, Owen

    2016-01-01

    In polygynous primates, a greater reproductive variance in males has been linked to their reduced life expectancy relative to females. The mortality patterns of monogamous pair-bonded primates, however, are less clear. We analyzed the sex differences in mortality within wild (NMales = 70, NFemales...... were best fit by the logistic and Gompertz models respectively, implying greater heterogeneity in the wild environment likely due to harsher conditions. We found that age patterns of mortality were similar between the sexes in both populations. We calculated life expectancy and disparity, the latter...... a measure of the steepness of senescence, for both sexes in each population. Males and females had similar life expectancies in both populations; the wild population overall having a shorter life expectancy than the captive one. Furthermore, captive females had a reduced life-disparity relative to captive...

  4. Ocular toxoplasmosis in immunosuppressed nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Holland, G.N.; O' Connor, G.R.; Diaz, R.F.; Minasi, P.; Wara, W.M.

    1988-06-01

    To investigate the role of cellular immunodeficiency in recurrent toxoplasmic retinochoroiditis, six Cynomolgus monkeys (Macaca fascicularis) with healed toxoplasmic lesions of the retina were immunosuppressed by total lymphoid irradiation. Three months prior to irradiation 30,000 Toxoplasma gondii organisms of the Beverley strain had been inoculated onto the macula of eye in each monkey via a pars plana approach. Toxoplasmic retinochoroiditis developed in each animal, and lesions were allowed to heal without treatment. During total lymphoid irradiation animals received 2000 centigrays (cGy) over a 7-week period. Irradiation resulted in an immediate drop in total lymphocyte counts and decreased ability to stimulate lymphocytes by phytohemagglutinin. Weekly ophthalmoscopic examinations following irradiation failed to show evidence of recurrent ocular disease despite persistent immunodeficiency. Four months after irradiation live organisms were reinoculated onto the nasal retina of the same eye in each animal. Retinochoroidal lesions identical to those seen in primary disease developed in five of six animals. Toxoplasma organisms therefore were able to proliferate in ocular tissue following the administration of immunosuppressive therapy. This study fails to support the hypothesis that cellular immunodeficiency alone will initiate recurrent toxoplasmic retinochoroiditis. Results suggest that reactivation of disease from encysted organisms involves factors other than suppression of Toxoplasma proliferation. If reactivation occurs by other mechanisms, however, cellular immunodeficiency then may allow development of extensive disease.

  5. Primates in 21st century ecosystems: does primate conservation promote ecosystem conservation?

    Science.gov (United States)

    Norconk, Marilyn A; Boinski, Sue; Forget, Pierre-Michel

    2011-01-01

    Contributors to this issue of the American Journal of Primatology were among the participants in an invited symposium at the 2008 Association for Tropical Biology and Conservation meeting in Paramaribo, Suriname. They were asked to assess how essential primates are to tropical ecosystems and, given their research interests, discuss how primate research contributes to the broader understanding about how ecosystems function. This introduction to the issue is divided into three parts: a review of the roles that nonhuman primates play in tropical ecosystems; the implementation of large-scale landscape methods used to identify primate densities; and concerns about the increasingly porous boundaries between humans, nonhuman primates, and pathogens. Although 20th century primate research created a rich database on individual species, including both theoretical and descriptive approaches, the dual effects of high human population densities and widespread habitat destruction should warn us that creative, interdisciplinary and human-related research is needed to solve 21st century problems.

  6. Yellow fever epizootics in non-human primates, São Paulo state, Brazil, 2008-2009 Epizootias de febre amarela em primatas não humanos no estado de São Paulo, Brasil, 2008-2009

    Directory of Open Access Journals (Sweden)

    Eduardo Stramandinoli Moreno

    2013-02-01

    Full Text Available Since 2000, the expansion of Sylvatic Yellow Fever (YF has been observed in the southeast of Brazil, being detected in areas considered silent for decades. Epizootics in non-human primates (NHPs are considered sentinel events for the detection of human cases. It is important to report epizootic events that could have impact on the conservation status of susceptible species. We describe the epizootics in NHPs, notified in state of São Paulo, Brazil, between September 2008 to August 2009. Ninety-one epizootic events, involving 147 animals, were reported in 36 counties. Samples were obtained from 65 animals (44.2%. Most of the epizootics (46.6% were reported between March and April, the same period during which human cases of YF occurred in the state. Biological samples were collected from animals found dead and were sent to Instituto Adolfo Lutz, in São Paulo. Two samples, collected in two counties without an indication for YF vaccination, were positive for the virus. Another 48 animals were associated with YF by clinical-epidemiological linkage with laboratory confirmed cases. Because the disease in human and NHPs occurred in the same period, the detection of the virus in NHPs did not work as sentinel, but aided in the delineation of new areas of risk.Desde 2000, vem sendo observada a expansão da febre amarela (FA no Sudeste do Brasil, sendo detectados casos em áreas consideradas silenciosas por décadas. Epizootias em primatas não humanos (NHPs são considerados eventos sentinela para a detecção de casos humanos. É importante relatar eventos epizoóticos que podem ter impacto sobre o estado de conservação de espécies sensíveis. Descrevemos as epizootias, notificadas em NHPs no estado de São Paulo, Brasil, entre setembro de 2008 a agosto de 2009. Noventa e um eventos epizoóticos, envolvendo 147 animais, foram notificados em 36 municípios. As amostras foram obtidas a partir de 65 animais (44,2%. A maioria das epizootias (46,6% foram

  7. Organizing Principles of Human Cortical Development--Thickness and Area from 4 to 30 Years: Insights from Comparative Primate Neuroanatomy.

    Science.gov (United States)

    Amlien, Inge K; Fjell, Anders M; Tamnes, Christian K; Grydeland, Håkon; Krogsrud, Stine K; Chaplin, Tristan A; Rosa, Marcello G P; Walhovd, Kristine B

    2016-01-01

    The human cerebral cortex undergoes a protracted, regionally heterogeneous development well into young adulthood. Cortical areas that expand the most during human development correspond to those that differ most markedly when the brains of macaque monkeys and humans are compared. However, it remains unclear to what extent this relationship derives from allometric scaling laws that apply to primate brains in general, or represents unique evolutionary adaptations. Furthermore, it is unknown whether the relationship only applies to surface area (SA), or also holds for cortical thickness (CT). In 331 participants aged 4 to 30, we calculated age functions of SA and CT, and examined the correspondence of human cortical development with macaque to human expansion, and with expansion across nonhuman primates. CT followed a linear negative age function from 4 to 30 years, while SA showed positive age functions until 12 years with little further development. Differential cortical expansion across primates was related to regional maturation of SA and CT, with age trajectories differing between high- and low-expanding cortical regions. This relationship adhered to allometric scaling laws rather than representing uniquely macaque-human differences: regional correspondence with human development was as large for expansion across nonhuman primates as between humans and macaque.

  8. A simpler primate brain: the visual system of the marmoset monkey.

    Science.gov (United States)

    Solomon, Samuel G; Rosa, Marcello G P

    2014-01-01

    Humans are diurnal primates with high visual acuity at the center of gaze. Although primates share many similarities in the organization of their visual centers with other mammals, and even other species of vertebrates, their visual pathways also show unique features, particularly with respect to the organization of the cerebral cortex. Therefore, in order to understand some aspects of human visual function, we need to study non-human primate brains. Which species is the most appropriate model? Macaque monkeys, the most widely used non-human primates, are not an optimal choice in many practical respects. For example, much of the macaque cerebral cortex is buried within sulci, and is therefore inaccessible to many imaging techniques, and the postnatal development and lifespan of macaques are prohibitively long for many studies of brain maturation, plasticity, and aging. In these and several other respects the marmoset, a small New World monkey, represents a more appropriate choice. Here we review the visual pathways of the marmoset, highlighting recent work that brings these advantages into focus, and identify where additional work needs to be done to link marmoset brain organization to that of macaques and humans. We will argue that the marmoset monkey provides a good subject for studies of a complex visual system, which will likely allow an important bridge linking experiments in animal models to humans.

  9. Characterization of [(11)C]Cimbi-36 as an agonist PET radioligand for the 5-HT(2A) and 5-HT(2C) receptors in the nonhuman primate brain

    DEFF Research Database (Denmark)

    Finnema, Sjoerd J; Stepanov, Vladimir; Ettrup, Anders

    2014-01-01

    a more meaningful assessment of available receptors than antagonist radioligands. In the current study we characterized [(11)C]Cimbi-36 receptor binding in the primate brain. On five experimental days, a total of 14 PET measurements were conducted in three female rhesus monkeys. On each day, PET...

  10. Animal models of age related macular degeneration

    OpenAIRE

    Pennesi, Mark E.; Neuringer, Martha; Courtney, Robert J.

    2012-01-01

    Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the ...

  11. Neurobiological roots of language in primate audition: common computational properties.

    Science.gov (United States)

    Bornkessel-Schlesewsky, Ina; Schlesewsky, Matthias; Small, Steven L; Rauschecker, Josef P

    2015-03-01

    Here, we present a new perspective on an old question: how does the neurobiology of human language relate to brain systems in nonhuman primates? We argue that higher-order language combinatorics, including sentence and discourse processing, can be situated in a unified, cross-species dorsal-ventral streams architecture for higher auditory processing, and that the functions of the dorsal and ventral streams in higher-order language processing can be grounded in their respective computational properties in primate audition. This view challenges an assumption, common in the cognitive sciences, that a nonhuman primate model forms an inherently inadequate basis for modeling higher-level language functions.

  12. Optogenetics Advances in Primate Visual Pathway.

    Science.gov (United States)

    Jazayeri, Mehrdad; Remington, Evan

    2016-04-06

    In this issue of Neuron, Klein et al. (2016) used cell-type-specific optogenetics and electrical microstimulation to characterize the koniocellular geniculocortical projections in nonhuman primates. Their work offers a powerful platform for refining our understanding of the mechanisms of visual information processing in the lateral geniculate nucleus and primary visual cortex.

  13. Captivity humanizes the primate microbiome

    Science.gov (United States)

    Vangay, Pajau; Huang, Hu; Ward, Tonya; Hillmann, Benjamin M.; Al-Ghalith, Gabriel A.; Travis, Dominic A.; Long, Ha Thang; Tuan, Bui Van; Minh, Vo Van; Cabana, Francis; Nadler, Tilo; Toddes, Barbara; Murphy, Tami; Glander, Kenneth E.; Johnson, Timothy J.; Knights, Dan

    2016-01-01

    The primate gastrointestinal tract is home to trillions of bacteria, whose composition is associated with numerous metabolic, autoimmune, and infectious human diseases. Although there is increasing evidence that modern and Westernized societies are associated with dramatic loss of natural human gut microbiome diversity, the causes and consequences of such loss are challenging to study. Here we use nonhuman primates (NHPs) as a model system for studying the effects of emigration and lifestyle disruption on the human gut microbiome. Using 16S rRNA gene sequencing in two model NHP species, we show that although different primate species have distinctive signature microbiota in the wild, in captivity they lose their native microbes and become colonized with Prevotella and Bacteroides, the dominant genera in the modern human gut microbiome. We confirm that captive individuals from eight other NHP species in a different zoo show the same pattern of convergence, and that semicaptive primates housed in a sanctuary represent an intermediate microbiome state between wild and captive. Using deep shotgun sequencing, chemical dietary analysis, and chloroplast relative abundance, we show that decreasing dietary fiber and plant content are associated with the captive primate microbiome. Finally, in a meta-analysis including published human data, we show that captivity has a parallel effect on the NHP gut microbiome to that of Westernization in humans. These results demonstrate that captivity and lifestyle disruption cause primates to lose native microbiota and converge along an axis toward the modern human microbiome. PMID:27573830

  14. Development and Evaluation of a Signal Acquisition System for the Movements of Upper Limbs in Nonhuman Primates%非人灵长类动物上肢运动信号采集系统的构建与实验研究

    Institute of Scientific and Technical Information of China (English)

    匡星; 杨琳; 张良清; 李光林

    2013-01-01

      本文构建了一种用于非人灵长类动物的上肢运动信号采集系统。该系统包括上肢行为训练单元和肌电信号采集单元。通过对上肢行为训练单元的设计、加工制作并与肌电信号采集单元相结合,构建可操作性较强的非人灵长类动物上肢运动信号采集系统。该系统采用取食和饮水这两种日常行为动作来激励动物的上肢运动,为动物行为训练与运动信号采集提供了方便,并通过实验初步验证了该系统的有效性。与其他类似系统相比较,该系统在动物上肢肌电信号采集方面实用性更强,且适用于不同体积大小的非人灵长类动物。%In this paper, a signal acquisition system was designed and developed for the movements of upper limbs of nonhuman primates. The system included a behavior-training unit of upper limbs and a myoelectric signal-acquisition unit. Two daily behaviors of feeding and drinking were employed to stimulate the motions of animals’ upper limbs for the convenience of the behavior training and signal acquisition. The feasibility of the training system was confirmed by the preliminary experiments on monkeys. Compared with the traditional systems, the system proposed in this study was more convenient for the signal acquisition of the arms of animals, and more suitable for nonhuman primates with different sizes.

  15. 非人灵长类动物异常行为与5-HTTLPR关系研究进展%Advances research on relationship between abnormal behavior and 5-HTTLPR in non--human primates

    Institute of Scientific and Technical Information of China (English)

    黄璋琼; 孙晓梅; 叶尤松; 江勤芳; 代解杰

    2011-01-01

    非人灵长类动物饲养环境被改变或受到控制时将会干扰动物作出正常反应,常表现出许多异常行为(abnormal behavior),与人类相似,这些异常行为多是心理疾患的具体表现,人和非人灵长类动物的异常行为是遗传因素和环境因素相互作用的结果,其中遗传因素是指5-HTTLPR.现将近年来有关非人灵长类动物异常行为与5-HTTLPR多态性的关系进展作一概述.%When breeding environment changed or under constraint, the rhesus macaque reaction could be interfered,might result in some abnormal behaviors. Similar to human - beings, these behaviors are manifestation of psychological diseases , abnormal behaviors of human - beings and non - human primates were interaction results of genetic factors and environment factors. Genetic facror was 5 - HTTLPR. Now we summarize the advances research of relationship between ahnormal behaviors of non - human primates and 5 - HTTLPR polymorphism

  16. Sporadic premature aging in a Japanese monkey: a primate model for progeria.

    Science.gov (United States)

    Oishi, Takao; Imai, Hiroo; Go, Yasuhiro; Imamura, Masanori; Hirai, Hirohisa; Takada, Masahiko

    2014-01-01

    In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged) monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.

  17. Sporadic premature aging in a Japanese monkey: a primate model for progeria.

    Directory of Open Access Journals (Sweden)

    Takao Oishi

    Full Text Available In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.

  18. Impending extinction crisis of the world’s primates: Why primates matter

    Science.gov (United States)

    Estrada, Alejandro; Garber, Paul A.; Rylands, Anthony B.; Roos, Christian; Fernandez-Duque, Eduardo; Di Fiore, Anthony; Nekaris, K. Anne-Isola; Nijman, Vincent; Heymann, Eckhard W.; Lambert, Joanna E.; Rovero, Francesco; Barelli, Claudia; Setchell, Joanna M.; Gillespie, Thomas R.; Mittermeier, Russell A.; Arregoitia, Luis Verde; de Guinea, Miguel; Gouveia, Sidney; Dobrovolski, Ricardo; Shanee, Sam; Shanee, Noga; Boyle, Sarah A.; Fuentes, Agustin; MacKinnon, Katherine C.; Amato, Katherine R.; Meyer, Andreas L. S.; Wich, Serge; Sussman, Robert W.; Pan, Ruliang; Kone, Inza; Li, Baoguo

    2017-01-01

    Nonhuman primates, our closest biological relatives, play important roles in the livelihoods, cultures, and religions of many societies and offer unique insights into human evolution, biology, behavior, and the threat of emerging diseases. They are an essential component of tropical biodiversity, contributing to forest regeneration and ecosystem health. Current information shows the existence of 504 species in 79 genera distributed in the Neotropics, mainland Africa, Madagascar, and Asia. Alarmingly, ~60% of primate species are now threatened with extinction and ~75% have declining populations. This situation is the result of escalating anthropogenic pressures on primates and their habitats—mainly global and local market demands, leading to extensive habitat loss through the expansion of industrial agriculture, large-scale cattle ranching, logging, oil and gas drilling, mining, dam building, and the construction of new road networks in primate range regions. Other important drivers are increased bushmeat hunting and the illegal trade of primates as pets and primate body parts, along with emerging threats, such as climate change and anthroponotic diseases. Often, these pressures act in synergy, exacerbating primate population declines. Given that primate range regions overlap extensively with a large, and rapidly growing, human population characterized by high levels of poverty, global attention is needed immediately to reverse the looming risk of primate extinctions and to attend to local human needs in sustainable ways. Raising global scientific and public awareness of the plight of the world’s primates and the costs of their loss to ecosystem health and human society is imperative. PMID:28116351

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

    Science.gov (United States)

    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. PMID:27660620

  20. A unified framework for the organisation of the primate auditory cortex

    Directory of Open Access Journals (Sweden)

    Simon eBaumann

    2013-04-01

    Full Text Available In nonhuman primates a scheme for the organisation of the auditory cortex is frequently used to localise auditory processes. The scheme allows a common basis for comparison of functional organisation across nonhuman primate species. However, although a body of functional and structural data in nonhuman primates supports an accepted scheme of nearly a dozen neighbouring functional areas, can this scheme be directly applied to humans? Attempts to expand the scheme of auditory cortical fields in humans have been severely hampered by a recent controversy about the organisation of tonotopic maps in humans, centred on two different models with radically different organisation. We point out observations that reconcile the previous models and suggest a distinct model in which the human cortical organisation is much more like that of other primates. This unified framework allows a more robust and detailed comparison of auditory cortex organisation across primate species including humans.

  1. Percussive technology in human evolution: an introduction to a comparative approach in fossil and living primates.

    Science.gov (United States)

    de la Torre, Ignacio; Hirata, Satoshi

    2015-11-19

    Percussive technology is part of the behavioural suite of several fossil and living primates. Stone Age ancestors used lithic artefacts in pounding activities, which could have been most important in the earliest stages of stone working. This has relevant evolutionary implications, as other primates such as chimpanzees and some monkeys use stone hammer-and-anvil combinations to crack hard-shelled foodstuffs. Parallels between primate percussive technologies and early archaeological sites need to be further explored in order to assess the emergence of technological behaviour in our evolutionary line, and firmly establish bridges between Primatology and Archaeology. What are the anatomical, cognitive and ecological constraints of percussive technology? How common are percussive activities in the Stone Age and among living primates? What is their functional significance? How similar are archaeological percussive tools and those made by non-human primates? This issue of Phil. Trans. addresses some of these questions by presenting case studies with a wide chronological, geographical and disciplinary coverage. The studies presented here cover studies of Brazilian capuchins, captive chimpanzees and chimpanzees in the wild, research on the use of percussive technology among modern humans and recent hunter-gatherers in Australia, the Near East and Europe, and archaeological examples of this behaviour from a million years ago to the Holocene. In summary, the breadth and depth of research compiled here should make this issue of Philosophical Transactions of the Royal Society B, a landmark step forward towards a better understanding of percussive technology, a unique behaviour shared by some modern and fossil primates.

  2. CRISPR/Cas9系统:构建非人灵长类动物疾病模型的新技术%CRISPR/Cas9 system:a new gene modification tool for establishing disease models in non-human primates

    Institute of Scientific and Technical Information of China (English)

    杨伟莉; 涂著池; 李晓江

    2014-01-01

    动物疾病模型在研究人类疾病致病机理和药物筛选中起到了关键作用。非人灵长类动物由于与人类更为接近,在探究人类神经退行性疾病、神经精神疾病及人类认知功能、神经环路等方面具有巨大的优势可成为研究和药物筛选的重要疾病模型。然而,由于缺乏大动物的胚胎干细胞系,传统的基因打靶技术难于用来建立灵长类动物疾病模型。最近发展的基因编辑新技术 CRISPR /Cas9系统在定向对基因进行修饰上展现出了巨大的潜力。本文将介绍 CRISPR /Cas9技术的发展和应用,以及非灵长类动物作为神经退行性疾病模型的优势和意义。%Animal models are highly valuable systems that have been extensively used to elucidate human disease pathogenesis and to find therapeutic ways to treat human diseases .Since non-human primates are close to humans,monkeys are important model species in exploring the mechanisms and treatment of human neurodegenerative diseases , neuropsychiatric disorders, cognitive function, and neural circuits.However, due to the lack of embryonic stem cell lines in large animals, the traditional gene targeting technology is difficult to establish primate animal models of human diseases . CRISPR/Cas9, as a recently developed tool for genome modifications , has been successfully used to target genomic loci in mouse, rat, monkey, and other species.Here, we discuss the utilization of CRISPR /Cas9 technology in establishing monkey models for studying human neurodegenerative diseases .

  3. Administration of Recombinant Human Thrombopoietin Soon after Irradiation Promotes Survival and Stimulates Hematopoietic Recovery in a Nonhuman Primate Model of Radiation-Induced Severe Acute Radiation Syndrome%重组人血小板生成素早期干预救治重症急性放射病猴的实验研究

    Institute of Scientific and Technical Information of China (English)

    邢爽; 从玉文; 罗庆良; 余祖胤; 熊国林; 谢玲; 李明; 郭玲玲; 王磊; 赵俊龙; 彭瑞云

    2011-01-01

    重组人血小板生成素(rhTPO)是一种能促进巨核系祖细胞增殖、分化生成血小板的造血因子,研究表明它能促进射线照射小鼠造血功能恢复,前期工作证明rhTPO早期干预可显著提高致死剂量照射小鼠的活存率.本文以7.0 Gy照射恒河猴为重度骨髓型急性放射病(ARS)模型,研究了rhTPO早期干预对重症ARS的治疗作用,并与WR2721和“500”的辐射防护作用进行了比较,结果发现rhTPO早期干预可明显促进ARS猴造血功能恢复,改善ARS猴症状,简化对症治疗措施,提高重度骨髓型ARS猴活存率,其对重度骨髓型ARS的防治作用优于现有的辐射防护药WR2721和“500”,有望开发成安全有效的新型辐射防治药物.%Accidental or intentional irradiation causes incidents involving acute radiation syndrome (ARS) victims. Thus, it is urgent to search for effective radioprotectors with no or low toxicity. Recombinant human thrombopoietin (rhTPO) is a megakaryocyte colony-stimulating factor. We have demonstrated previously that early administration of rhTPO soon after irradiation promotes survival of lethal dose irradiated mice. To evaluate the therapeutic effect of rhTPO short-term injection soon after radiation in nonhuman primates exposed to a high dose of gamma ray, rhesus monkeys received subcutaneously of early rhTPO 10 ug/kg injection at 0.5 and 24 h after or WR2721 30 mg/kg intramuscularly administration at 0.5 h before total body irradiated (TBI) with a 7 Gy gamma dose. Survival was monitored and hematopoiesis was evaluated at 40 d following early treatment. rhTPO short-term early injection (0.5 and 24 h) after 7 Gy TBI induced 100.0% survival versus 33.3% in irradiated controls, while 83.3% in WR2721 protected monkeys. rhTPO early treatment significantly promoted hematopoiesis recovery and apparently improved the quality of life, and additionally simplified supportive care in ARS rhesus monkeys. According to the survival and hematopoiesis

  4. Tree shrews at the German Primate Center

    OpenAIRE

    Fuchs, E

    2015-01-01

    For many years, Tupaia (family Tupaiidae), most commonly known as tree shrews, have been studied almost exclusively by zoologists resulting in a controversial debate on their taxonomic status among mammals. Today, tree shrews are placed in the order Scandentia; they are valuable, widely accepted and increasingly used model animals as an alternative to rodents and non-human primates in biomedical research. After a brief description on how tree shrews entered science and their...

  5. Distinct transcriptome expression of the temporal cortex of the primate Microcebus murinus during brain aging versus Alzheimer's disease-like pathology.

    Directory of Open Access Journals (Sweden)

    Ronza Abdel Rassoul

    Full Text Available Aging is the primary risk factor of neurodegenerative disorders such as Alzheimer's disease (AD. However, the molecular events occurring during brain aging are extremely complex and still largely unknown. For a better understanding of these age-associated modifications, animal models as close as possible to humans are needed. We thus analyzed the transcriptome of the temporal cortex of the primate Microcebus murinus using human oligonucleotide microarrays (Affymetrix. Gene expression profiles were assessed in the temporal cortex of 6 young adults, 10 healthy old animals and 2 old, "AD-like" animals that presented ß-amyloid plaques and cortical atrophy, which are pathognomonic signs of AD in humans. Gene expression data of the 14,911 genes that were detected in at least 3 samples were analyzed. By SAM (significance analysis of microarrays, we identified 47 genes that discriminated young from healthy old and "AD-like" animals. These findings were confirmed by principal component analysis (PCA. ANOVA of the expression data from the three groups identified 695 genes (including the 47 genes previously identified by SAM and PCA with significant changes of expression in old and "AD-like" in comparison to young animals. About one third of these genes showed similar changes of expression in healthy aging and in "AD-like" animals, whereas more than two thirds showed opposite changes in these two groups in comparison to young animals. Hierarchical clustering analysis of the 695 markers indicated that each group had distinct expression profiles which characterized each group, especially the "AD-like" group. Functional categorization showed that most of the genes that were up-regulated in healthy old animals and down-regulated in "AD-like" animals belonged to metabolic pathways, particularly protein synthesis. These data suggest the existence of compensatory mechanisms during physiological brain aging that disappear in "AD-like" animals. These results open

  6. The ecology of primate material culture.

    Science.gov (United States)

    Koops, Kathelijne; Visalberghi, Elisabetta; van Schaik, Carel P

    2014-11-01

    Tool use in extant primates may inform our understanding of the conditions that favoured the expansion of hominin technology and material culture. The 'method of exclusion' has, arguably, confirmed the presence of culture in wild animal populations by excluding ecological and genetic explanations for geographical variation in behaviour. However, this method neglects ecological influences on culture, which, ironically, may be critical for understanding technology and thus material culture. We review all the current evidence for the role of ecology in shaping material culture in three habitual tool-using non-human primates: chimpanzees, orangutans and capuchin monkeys. We show that environmental opportunity, rather than necessity, is the main driver. We argue that a better understanding of primate technology requires explicit investigation of the role of ecological conditions. We propose a model in which three sets of factors, namely environment, sociality and cognition, influence invention, transmission and retention of material culture.

  7. Primate vocalization, gesture, and the evolution of human language.

    Science.gov (United States)

    Arbib, Michael A; Liebal, Katja; Pika, Simone

    2008-12-01

    The performance of language is multimodal, not confined to speech. Review of monkey and ape communication demonstrates greater flexibility in the use of hands and body than for vocalization. Nonetheless, the gestural repertoire of any group of nonhuman primates is small compared with the vocabulary of any human language and thus, presumably, of the transitional form called protolanguage. We argue that it was the coupling of gestural communication with enhanced capacities for imitation that made possible the emergence of protosign to provide essential scaffolding for protospeech in the evolution of protolanguage. Similarly, we argue against a direct evolutionary path from nonhuman primate vocalization to human speech. The analysis refines aspects of the mirror system hypothesis on the role of the primate brain's mirror system for manual action in evolution of the human language-ready brain.

  8. Poor Memory Performance in Aged Cynomolgus Monkeys with Hippocampal Atrophy, Depletion of Amyloid Beta 1-42 and Accumulation of Tau Proteins in Cerebrospinal Fluid

    DEFF Research Database (Denmark)

    Darusman, Huda S; Pandelaki, Jacub; Mulyadi, Rahmad

    2014-01-01

    , aged cynomolgus monkeys were divided into two groups to compare high-performing (n=6) and low-performing (n=6) subjects. Both groups were tested for biomarkers related to Alzheimer's disease and their brains were scanned using structural magnetic resonance imaging. RESULTS: The subjects with poor DRT......-impaired Cynomolgus monkeys may be useful as a spontaneous non-human primate model for investigations of age-related neurodegenerative diseases....

  9. Tolerance in Nonhuman Primates by Delayed Mixed Chimerism

    Science.gov (United States)

    2014-10-01

    arise from venous congestion as a result of kinking or thrombosis in the low pressure venous system. Again in both cases, arterial insufficiency...number of potential factors identified where minor optimizations might be helpful in reducing the risk of technical failure. In M4313 it was noted...which improvement would enhance quality of life, improve the risk -benefit ratio and ultimately expand availability of these procedures to severely

  10. 76 FR 677 - Requirements for Importers of Nonhuman Primates

    Science.gov (United States)

    2011-01-05

    ... exhibition purposes. On the other hand, if the zoo employs researchers and requests a permit so that staff... to use for disinfection), design (such as the use of squeeze- back cages for controlling animals... the NHPs on a flight, proper handling of the crates as they are unloaded, and adequate disinfection...

  11. The organization of conspecific face space in nonhuman primates.

    Science.gov (United States)

    Parr, Lisa A; Taubert, Jessica; Little, Anthony C; Hancock, Peter J B

    2012-01-01

    Humans and chimpanzees demonstrate numerous cognitive specializations for processing faces, but comparative studies with monkeys suggest that these may be the result of recent evolutionary adaptations. The present study utilized the novel approach of face space, a powerful theoretical framework used to understand the representation of face identity in humans, to further explore species differences in face processing. According to the theory, faces are represented by vectors in a multidimensional space, the centre of which is defined by an average face. Each dimension codes features important for describing a face's identity, and vector length codes the feature's distinctiveness. Chimpanzees and rhesus monkeys discriminated male and female conspecifics' faces, rated by humans for their distinctiveness, using a computerized task. Multidimensional scaling analyses showed that the organization of face space was similar between humans and chimpanzees. Distinctive faces had the longest vectors and were the easiest for chimpanzees to discriminate. In contrast, distinctiveness did not correlate with the performance of rhesus monkeys. The feature dimensions for each species' face space were visualized and described using morphing techniques. These results confirm species differences in the perceptual representation of conspecific faces, which are discussed within an evolutionary framework.

  12. Safeguarding nonhuman primate iPS cells with suicide genes.

    Science.gov (United States)

    Zhong, Bonan; Watts, Korashon L; Gori, Jennifer L; Wohlfahrt, Martin E; Enssle, Joerg; Adair, Jennifer E; Kiem, Hans-Peter

    2011-09-01

    The development of technology to generate induced pluripotent stem (iPS) cells constitutes one of the most exciting scientific breakthroughs because of the enormous potential for regenerative medicine. However, the safety of iPS cell-related products is a major concern for clinical translation. Insertional mutagenesis, possible oncogenic transformation of iPS cells or their derivatives, or the contamination of differentiated iPS cells with undifferentiated cells, resulting in the formation of teratomas, have remained considerable obstacles. Here, we demonstrate the utility of suicide genes to safeguard iPS cells and their derivatives. We found suicide genes can control the cell fate of iPS cells in vitro and in vivo without interfering with their pluripotency and self-renewal capacity. This study will be useful to evaluate the safety of iPS cell technology in a clinically highly relevant, large animal model and further benefit the clinical use of human iPS cells.

  13. Ultrastructural localization of acid phosphatase in nonhuman primate vaginal epithelium.

    Science.gov (United States)

    King, B F

    1985-01-01

    The vagina of the rhesus monkey is lined by a stratified squamous epithelium. However, little is known regarding the cytochemical composition of its cell organelles and the substances found in the intercellular spaces. In this study we have examined the ultrastructural distribution of acid phosphatase in the vaginal epithelium. In basal and parabasal cells reaction product was found in some Golgi cisternae and vesicles and in a variety of cytoplasmic granules. Reaction product was also found in some, but not all, membrane-coating granules. In the upper layers of the epithelium, the membrane-coating granules extruded their contents and acid phosphatase was localized in the intercellular spaces. The possible roles of acid phosphatase in keratinization, desquamation, or modification of substances in the intercellular compartment are discussed.

  14. Promoting Autoimmune Diabetes in Non-Human Primates

    Science.gov (United States)

    2014-04-01

    the mediastinum. After the completion of total thymectomy, hemostasis is obtained by electrocautery. If necessary, one or 2 small drains ( Jackson ...obtained by pressure. Small drains ( Jackson -pratt or equivalent) were not considered necessary for checking post-operative bleeding since no fluid...the second monkey ( Percy , #150-11), in contrast to the 70% removal in the first one (Leo, #149-11). The close to complete removal of the thymus enable

  15. Serum Antibody Responses to Oral Microorganisms in Nonhuman Primates

    Science.gov (United States)

    1991-05-01

    of periodontal disease in humans. Early studies by Genco et al. (1980) in localized juvenile periodontitis (IP) patients demonstrated the presence of...1965), Evans et al. (1966) and Genco et al. (1974) have shown that antibodies in human serum are reactive with oral microorganisms. A variety of assays...homologous infection. Oral Microbiol. Immunol. 2:53-59. Ebersole, J.L., Taubman, M.A., Smith, D.J., Genco , R.J. and Frey, D.E. (1982) Human immune

  16. Heterozygous embryonic stem cell lines derived from nonhuman primate parthenotes.

    Science.gov (United States)

    Dighe, Vikas; Clepper, Lisa; Pedersen, Darlene; Byrne, James; Ferguson, Betsy; Gokhale, Sumita; Penedo, M Cecilia T; Wolf, Don; Mitalipov, Shoukhrat

    2008-03-01

    Monoparental parthenotes represent a potential source of histocompatible stem cells that should be isogenic with the oocyte donor and therefore suitable for use in cell or tissue replacement therapy. We generated five rhesus monkey parthenogenetic embryonic stem cell (PESC) lines with stable, diploid female karyotypes that were morphologically indistinguishable from biparental controls, expressed key pluripotent markers, and generated cell derivatives representative of all three germ layers following in vivo and in vitro differentiation. Interestingly, high levels of heterozygosity were observed at the majority of loci that were polymorphic in the oocyte donors. Some PESC lines were also heterozygous in the major histocompatibility complex region, carrying haplotypes identical to those of the egg donor females. Expression analysis revealed transcripts from some imprinted genes that are normally expressed from only the paternal allele. These results indicate that limitations accompanying the potential use of PESC-derived phenotypes in regenerative medicine, including aberrant genomic imprinting and high levels of homozygosity, are cell line-dependent and not always present. PESC lines were derived in high enough yields to be practicable, and their derivatives are suitable for autologous transplantation into oocyte donors or could be used to establish a bank of histocompatible cell lines for a broad spectrum of patients.

  17. Functional Properties of Nonhuman Primate Antibody to Prophyromonas Gingivalis

    Science.gov (United States)

    1993-05-01

    levels to plaque microorganisms. Journal of Clinical Periodontology . 15:544-550. Beard, L.J., Ferrante, A., Oxelius, V.A., and Maxwell, G.M. (1986) IgG...intermedius to indicate progressive periodontitis; a retrospective study. Journal of Clinical Periodontology . 14:95-99. Brecx, M.C., Nalbandian, J., Ooya...predominant cultivable microbiota of active and inactive lesions of destructive periodontal diseases. Journal of Clinical Periodontology . 15:316-323

  18. Smallpox DNA Vaccine Protects Nonhuman Primates Against Lethal Monkeypox

    Science.gov (United States)

    2004-05-01

    threatening (e.g., eczema vac- cinatum, encephalitis, and progressive vaccinia) (6). Serious adverse events that are not necessarily causally associated...This outbreak (71 suspected and 35 laboratory-confirmed cases as of 8 July 2003) may have been transmitted from prairie dogs that were infected after

  19. Emotions, stress, and maternal motivation in primates.

    Science.gov (United States)

    Maestripieri, Dario

    2011-06-01

    Recent research conducted with nonhuman primates confirms that adaptive emotional processes, such as maternal attraction arousability and maternal anxiety arousability, enhance and sustain female motivation to interact with infants, invest in them, and protect them during the postpartum period. Changes in these emotional processes, and concomitant changes in maternal motivation, facilitate the reduction and eventual termination of maternal investment associated with infant weaning. Although laboratory studies of rodents and socially deprived rhesus monkeys have suggested that nulliparous females are neophobic and find infant stimuli aversive, recent primate research indicates that neophobia or aversion to infant stimuli do not occur in females with normal developmental experience. Furthermore, although some rodent and human studies have shown that lactation is accompanied by physiological hyporesponsiveness to stress, other studies of rodents, nonhuman primates, and humans indicate that mothers are highly vulnerable to stress and that stress-induced dysregulation of emotions can interfere with maternal motivation and parenting behavior. It is possible that some aspects of the emotional and experiential regulation of maternal motivation and parental behavior are different in different mammalian species. However, variation in the environments in which subjects are tested and in their developmental experience may also be responsible for the some discrepancies between the results of different studies.

  20. Detection of arboviruses of public health interest in free-living New World primates (Sapajus spp.; Alouatta caraya) captured in Mato Grosso do Sul, Brazil.

    OpenAIRE

    2014-01-01

    Introduction A sero-epidemiological survey was undertaken to detect the circulation of arboviruses in free-living non-human primates. Methods Blood samples were obtained from 16 non-human primates (13 Sapajus spp. and three Alouatta caraya) that were captured using terrestrial traps and anesthetic darts in woodland regions in the municipalities of Campo Grande, Aquidauana, Jardim, Miranda and Corumbá in the State of Mato Grosso do Sul, Brazil. The samples were sent to the Instituto Eva...

  1. Age-Related Changes in the Central Nervous System in Selected Domestic Mammals and Primates

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    Maciej Firląg

    2013-04-01

    Full Text Available Aging is a process which operates at many levels of physiological, genetic and molecular organizationand leads inevitably to death [18]. Brain macroscopic changes by MRI investigation during aging were observed in humans and dogs but chimpanzees did not display significant changes. This suggestion led to the statement that brain aging is different in various species. Although human brain changes, e.g. β-amyloid storage, neurofibrillary tangle formation, lipofuscin, are relatively well known, we are still looking for a suitable animal model to study the mechanisms of aging and neurodegenerative diseases. Therefore, this paper presents a comparative analysis of the changes described in the brains of senile dog, horse and gorilla. In addition we present the latest, non-invasive methods that can be applied in the diagnosisof old age in mammals. Our considerations have shown that the best animal model for further studies and observations on aging is the dog. 

  2. Evolution of the hepcidin gene in primates

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    Tossi Alessandro

    2008-03-01

    Full Text Available Abstract Background Hepcidin/LEAP-1 is an iron regulatory hormone originally identified as an antimicrobial peptide. As part of a systematic analysis of the evolution of host defense peptides in primates, we have sequenced the orthologous gene from 14 species of non-human primates. Results The sequence of the mature peptide is highly conserved amongst all the analyzed species, being identical to the human one in great apes and gibbons, with a single residue conservative variation in Old-World monkeys and with few substitutions in New-World monkeys. Conclusion Our analysis indicates that hepcidin's role as a regulatory hormone, which involves interaction with a conserved receptor (ferroportin, may result in conservation over most of its sequence, with the exception of the stretch between residues 15 and 18, which in New-World monkeys (as well as in other mammals shows a significant variation, possibly indicating that this structural region is involved in other functions.

  3. Optogenetics in primates: a shining future?

    Science.gov (United States)

    Gerits, Annelies; Vanduffel, Wim

    2013-07-01

    To understand the functional role of specific neurons in micro- and macro-brain circuitry, health, and disease, it is critical to control their activity precisely. This ambitious goal was first achieved by optogenetics, allowing researchers to increase or decrease neural activity artificially with high temporal and spatial precision. In contrast to the revolution optogenetics engendered in invertebrate and rodent research, only a few studies have reported optogenetic-induced neuronal and behavioral effects in primates. Such studies are nonetheless critical before optogenetics can be applied in a clinical setting. Here, we review the state-of-the-art tools for performing optogenetics in mammals, emphasizing recent neuronal and behavioral results obtained in nonhuman primates.

  4. Criteria for feasibility, health and welfare assessment of requirement to use second and subsequent generations of non-human primates or animals from self-sustaining colonies in research Critères d’évaluation de la faisabilité, de l’incidence sanitaire et des répercussions sur le bien-être animal, relatifs à l'obligation future d'utiliser des primates non humains issus uniquement des animaux de deuxième génération et plus ou des animaux provenant de colonies d'élevage auto-entretenues pour la recherche expérimentale

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    David Smith

    2011-10-01

    Full Text Available The European Directive 2010/63/EU on the protection of animals used for scientific purposes requires that a feasibility study must be conducted by the European Commission to determine if all sourcing of non-human primates from parents bred in captivity (F2 or from self-sustaining colonies can be achieved. This study should also include an assessment of animal health and welfare. Prior to the initiation of the European Commission’s study, it was considered by EFPIA and FELASA that the criteria to be used in the feasibility, health and welfare assessment should be established by experts to help expedite such a study. This paper identifies those criteria which may be useful in making policy decisions on the confirmation or reconsideration of the timetable for implementation of the F2 requirement. A key requirement before a number of criteria can be assessed is the generation of base-line data relating to the supply and future demand of non-human primates and the health and welfare status of current breeding colonies supplying the European market. Three groups of criteria have been indentified, namely feasibility, science and research and welfare. Within each group, a number of parameters are defined and their rationale for inclusion, together with suggested information points, is discussed.La directive européenne 2010/63/EU sur la protection des animaux utilisés à des fins scientifiques exige qu'une étude de faisabilité soit conduite par la Commission européenne afin de déterminer si l’approvisionnement en primates non-humains à partir de géniteurs élevés en captivité (F2 ou de colonies d'élevage autosuffisantes, peut être possible. Cette étude devra également inclure une évaluation de la santé des animaux et de leur bien-être. Avant le début de cette étude par la Commission européenne, l'EFPIA et FELASA ont estimé que les critères à utiliser pour les évaluations de la faisabilité, de la santé des animaux et du bien

  5. Magnetic resonance imaging in primates. The example of the mouse lemur (Microcebus murinus: From detection of pathological aging to therapeutic evaluations Imagerie par résonance magnétique chez les primates. L’exemple du microcèbe murin (Microcebus murinus : De la détection du vieillissement cérébral pathologique à l'évaluation thérapeutique

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    Nadine El Tannir El Tayara

    2011-02-01

    Full Text Available Cerebral aging is a major public health issue in our societies as the aged population increases dramatically. It leads in many cases to neurodegenerative diseases such as Alzheimer disease (AD. Rodents and particularly transgenic mice are widely used as models for research on physiopathology of cerebral aging, neurodegenerative diseases and for the evaluation of therapies. However these models do not mimic all the pathophysiological aspects of human diseases. Complementary models such as non-human primates are phylogenetically close to humans and thus more predictive of drug efficiency in humans. Mouse lemur (Microcebus murinus is a small primate (about 12cm, 100g described as a useful model of cerebral aging and as a potential model of AD. Indeed several animals develop age-associated cerebral alterations like amyloidosis and other cerebral changes. Non invasive medical imaging methods such as magnetic resonance imaging (MRI can be used to follow-up brain changes in these animals. In this review, we present how mouse lemurs can be followed-up by MRI and how MRI can be used during therapeutic evaluations and other applications in this model. MR images can be used to follow-up cerebral anatomy in mouse lemurs. It allows for the description of age-associated atrophic processes, age-associated iron accumulation, and vascular anatomy (thanks to MR angiography. Cerebral glucose uptake can be studied in mouse lemurs with other in vivo imaging modalities such as positron emission tomography (PET. In this case, MRI can be used as a support for quantification of radioligand uptake in specific structures. Ex vivo MR imaging is another MR protocol that can be used to describe cerebral aging in lemurs. It provides high resolution 3D histological brain images and allows for studying exquisite anatomical details or microhemorrhages. Finally, MRI can be used to practice cerebral surgery in lemurs and determine coordinates for stereotactic injections. It can

  6. A comparative neurological approach to emotional expressions in primate vocalizations.

    Science.gov (United States)

    Gruber, Thibaud; Grandjean, Didier

    2017-02-01

    Different approaches from different research domains have crystallized debate over primate emotional processing and vocalizations in recent decades. On one side, researchers disagree about whether emotional states or processes in animals truly compare to those in humans. On the other, a long-held assumption is that primate vocalizations are innate communicative signals over which nonhuman primates have limited control and a mirror of the emotional state of the individuals producing them, despite growing evidence of intentional production for some vocalizations. Our goal is to connect both sides of the discussion in deciphering how the emotional content of primate calls compares with emotional vocal signals in humans. We focus particularly on neural bases of primate emotions and vocalizations to identify cerebral structures underlying emotion, vocal production, and comprehension in primates, and discuss whether particular structures or neuronal networks solely evolved for specific functions in the human brain. Finally, we propose a model to classify emotional vocalizations in primates according to four dimensions (learning, control, emotional, meaning) to allow comparing calls across species.

  7. Theories about evolutionary origins of human hepatitis B virus in primates and humans

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    Breno Frederico de Carvalho Dominguez Souza

    2014-09-01

    Full Text Available Introduction: The human hepatitis B virus causes acute and chronic hepatitis and is considered one of the most serious human health issues by the World Health Organization, causing thousands of deaths per year. There are similar viruses belonging to the Hepadnaviridae family that infect non-human primates and other mammals as well as some birds. The majority of non-human primate virus isolates were phylogenetically close to the human hepatitis B virus, but like the human genotypes, the origins of these viruses remain controversial. However, there is a possibility that human hepatitis B virus originated in primates. Knowing whether these viruses might be common to humans and primates is crucial in order to reduce the risk to humans. Objective: To review the existing knowledge about the evolutionary origins of viruses of the Hepadnaviridae family in primates. Methods: This review was done by reading several articles that provide information about the Hepadnaviridae virus family in non-human primates and humans and the possible origins and evolution of these viruses. Results: The evolutionary origin of viruses of the Hepadnaviridae family in primates has been dated back to several thousand years; however, recent analyses of genomic fossils of avihepadnaviruses integrated into the genomes of several avian species have suggested a much older origin of this genus. Conclusion: Some hypotheses about the evolutionary origins of human hepatitis B virus have been debated since the '90s. One theory suggested a New World origin because of the phylogenetic co-segregation between some New World human hepatitis B virus genotypes F and H and woolly B virus in basal sister-relationship to the Old monkey human hepatitis World non-human primates and human hepatitis B virus variants. Another theory suggests an Old World origin of human hepatitis B virus, and that it would have been spread following prehistoric human migrations over 100,000 years ago. A third theory

  8. Comparative primate neurobiology and the evolution of brain language systems.

    Science.gov (United States)

    Rilling, James K

    2014-10-01

    Human brain specializations supporting language can be identified by comparing human with non-human primate brains. Comparisons with chimpanzees are critical in this endeavor. Human brains are much larger than non-human primate brains, but human language capabilities cannot be entirely explained by brain size. Human brain specializations that potentially support our capacity for language include firstly, wider cortical minicolumns in both Broca's and Wernicke's areas compared with great apes; secondly, leftward asymmetries in Broca's area volume and Wernicke's area minicolumn width that are not found in great apes; and thirdly, arcuate fasciculus projections beyond Wernicke's area to a region of expanded association cortex in the middle and inferior temporal cortex involved in processing word meaning.

  9. Localization of b-defensin genes in non human primates

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    M Ventura

    2009-06-01

    Full Text Available Defensins are a family of host defence peptides that play an important role in the innate immunity of mammalian and avian species. In humans, four b-defensins have been isolated so far, corresponding to the products of the genes DEFB1 (h-BD1, GenBank accession number NM_005218; DEFB4 (h-Bd2, NM_004942.2, DEFB103 (h-BD3, NM_018661; and DEFB104 (hBD4, NM_080389 mapping on chromosome 8p23.22. We have localized b- defensin genes on metaphasic chromosomes of great apes and several non-human primate species to determine their physical mapping. Using fluorescent in situ hybridization and BAC probes containing the four b-defensin genes, we have mapped the homologous regions to the b-defensin genes on chromosome 8p23-p.22 in non-human primates, while no signals were detected on prosimians chromosomes.

  10. Transgenic Primate Research Paves the Path to a Better Animal Model: Are We a Step Closer to Curing Inherited Human Genetic Disorders?

    Institute of Scientific and Technical Information of China (English)

    Anthony W.S. Chan

    2009-01-01

    While the advancement of transgenic primate models has led to a new era in modeling human conditions and has a clear impact on elucidating the mechanism of human genetic diseases, some thoughts should be considered if non-human primates are the appropriate model.

  11. Retrovirus Studies in Nonhuman Primates at Four Regional Primate Research Centers.

    Science.gov (United States)

    1989-12-31

    recombinant envelope glycoprotein, gp 120 of SIV has been expressed and produced in Chinese hamster ovary cells. The glycoprotein has been purified...cases of shigellosis were diagnosed. Giardia was identified in only one animal and was nonresponsive to therapy. Lymphadenopathy occurred rarely in this...We have isolated molecular clones of 316 that confer macrophages tropism when recombined with the 239 parent. The precise molecular changes that

  12. Retrovirus Studies in Nonhuman Primates at Four Regional Primate Research Centers.

    Science.gov (United States)

    1990-09-30

    due to loss of lymphocytes was apparent 8 weeks after inoculation. No epithelial damage or loss of Hassall’s corpuscles was observed. Culture was the...from cytomegalovirus and rhesus Epstein- Barr virus, and that had no etiologic agent other than SIV detected in the lung were studied. The following

  13. Delayed response task performance as a function of age in cynomolgus monkeys (Macaca fascicularis)

    DEFF Research Database (Denmark)

    Darusman, H S; Call, J; Sajuthi, D

    2014-01-01

    We compared delayed response task performance in young, middle-aged, and old cynomolgus monkeys using three memory tests that have been used with non-human primates. Eighteen cynomolgus monkeys-6 young (4-9 years), 6 middle-aged (10-19 years), and 6 old (above 20 years)-were tested. In general......, the old monkeys scored significantly worse than did the animals in the two other age groups. Longer delays between stimulus presentation and response increased the performance differences between the old and younger monkeys. The old monkeys in particular showed signs of impaired visuo-spatial memory...

  14. Impaired spatial information processing in aged monkeys with preserved recognition memory.

    Science.gov (United States)

    Rapp, P R; Kansky, M T; Roberts, J A

    1997-05-27

    Spatial information processing was examined in a non-human primate model of cognitive aging, using procedures formally similar to tasks designed for rats. The test apparatus was a large open field containing eight reward locations. Monkeys rapidly learned to visit each location once per trial, and probe manipulations confirmed that young animals navigated according to the distribution of cues surrounding the maze. In contrast, aged monkeys solved the task using a response sequencing strategy, independent of extramaze spatial information. Object recognition memory was normal in the aged group. The results reveal substantial correspondence in the cognitive effects of aging across rat and primate models, and they establish appropriate procedures for testing the long-standing proposal that the role of the hippocampus in normal spatial learning is similarly conserved.

  15. Enrichment and aggression in primates.

    Science.gov (United States)

    Honess, P E; Marin, C M

    2006-01-01

    There is considerable evidence that primates housed under impoverished conditions develop behavioural abnormalities, including, in the most extreme example, self-harming behaviour. This has implications for all contexts in which primates are maintained in captivity from laboratories to zoos since by compromising the animals' psychological well-being and allowing them to develop behavioural abnormalities their value as appropriate educational and research models is diminished. This review examines the extensive body of literature documenting attempts to improve living conditions with a view to correcting behavioural abnormalities and housing primates in such a way that they are encouraged to exhibit a more natural range and proportion of behaviours, including less self-directed and social aggression. The results of housing, feeding, physical, sensory and social enrichment efforts are examined with specific focus on their effect on aggressive behaviour and variation in their use and efficacy. It is concluded that while inappropriate or poorly distributed enrichment may encourage aggressive competition, enrichment that is species, sex, age and background appropriate can dramatically reduce aggression, can eliminate abnormal behaviour and substantially improve the welfare of primates maintained in captivity.

  16. Allelic lineages of the ficolin genes (FCNs are passed from ancestral to descendant primates.

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    Tina Hummelshøj

    Full Text Available The ficolins recognize carbohydrates and acetylated compounds on microorganisms and dying host cells and are able to activate the lectin pathway of the complement system. In humans, three ficolin genes have been identified: FCN1, FCN2 and FCN3, which encode ficolin-1, ficolin-2 and ficolin-3, respectively. Rodents have only two ficolins designated ficolin-A and ficolin-B that are closely related to human ficolin-1, while the rodent FCN3 orthologue is a pseudogene. Ficolin-2 and ficolin-3 have so far only been observed in humans. Thus, we performed a systematic investigation of the FCN genes in non-human primates. The exons and intron-exon boundaries of the FCN1-3 genes were sequenced in the following primate species: chimpanzee, gorilla, orangutan, rhesus macaque, cynomolgus macaque, baboon and common marmoset. We found that the exon organisation of the FCN genes was very similar between all the non-human primates and the human FCN genes. Several variations in the FCN genes were found in more than one primate specie suggesting that they were carried from one species to another including humans. The amino acid diversity of the ficolins among human and non-human primate species was estimated by calculating the Shannon entropy revealing that all three proteins are generally highly conserved. Ficolin-1 and ficolin-2 showed the highest diversity, whereas ficolin-3 was more conserved. Ficolin-2 and ficolin-3 were present in non-human primate sera with the same characteristic oligomeric structures as seen in human serum. Taken together all the FCN genes show the same characteristics in lower and higher primates. The existence of trans-species polymorphisms suggests that different FCN allelic lineages may be passed from ancestral to descendant species.

  17. Primate vocal communication: a useful tool for understanding human speech and language evolution?

    Science.gov (United States)

    Fedurek, Pawel; Slocombe, Katie E

    2011-04-01

    Language is a uniquely human trait, and questions of how and why it evolved have been intriguing scientists for years. Nonhuman primates (primates) are our closest living relatives, and their behavior can be used to estimate the capacities of our extinct ancestors. As humans and many primate species rely on vocalizations as their primary mode of communication, the vocal behavior of primates has been an obvious target for studies investigating the evolutionary roots of human speech and language. By studying the similarities and differences between human and primate vocalizations, comparative research has the potential to clarify the evolutionary processes that shaped human speech and language. This review examines some of the seminal and recent studies that contribute to our knowledge regarding the link between primate calls and human language and speech. We focus on three main aspects of primate vocal behavior: functional reference, call combinations, and vocal learning. Studies in these areas indicate that despite important differences, primate vocal communication exhibits some key features characterizing human language. They also indicate, however, that some critical aspects of speech, such as vocal plasticity, are not shared with our primate cousins. We conclude that comparative research on primate vocal behavior is a very promising tool for deepening our understanding of the evolution of human speech and language, but much is still to be done as many aspects of monkey and ape vocalizations remain largely unexplored.

  18. Biologic data of Macaca mulatta, Macaca fascicularis, and Saimiri sciureusused for research at the fiocruz primate center

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    Márcia Cristina Ribeiro Andrade

    2004-10-01

    Full Text Available Physiological parameters of laboratory animals used for biomedical research is crucial for following several experimental procedures. With the intent to establish baseline biologic parameters for non-human primates held in closed colonies, hematological and morphometric data of captive monkeys were determined. Data of clinically healthy rhesus macaques (Macaca mulatta, cynomolgus monkeys (Macaca fascicularis, and squirrel monkeys (Saimiri sciureus were collected over a period of five years. Animals were separated according to sex and divided into five age groups. Hematological data were compared with those in the literature by Student's t test. Discrepancies with significance levels of 0.1, 1 or 5% were found in the hematological studies. Growth curves showed that the sexual dimorphism of rhesus monkeys appeared at an age of four years. In earlier ages, the differences between sexes could not be distinguished (p < 0.05. Sexual dimorphism in both squirrel monkeys and cynomolgus monkeys occurred at an age of about 32 months. Data presented in this paper could be useful for comparative studies using primates under similar conditions.

  19. Morphology of the shoulder muscles in Sapajus apella (Primates: Cebidae

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    Mariana Oliveira Lima

    2013-03-01

    Full Text Available The study of nonhuman primates has been very important, due to the similarities with the human species. Many animal species, especially primates, have been used in medical and biological researches. Sapajus apella is a species with usual and abundant incidence in the Southeastern Region. This paper aimed to study the stabilizing muscles of the shoulder in the tufted capuchin monkey and compare them to those in human beings, with the purpose of providing information to anatomical and functional interpretations which will be useful for further studies on comparative anatomy. Four specimens of S. apella from the Human Anatomy Laboratory of Universidade Federal de Uberlandia were used. The specimens were prepared through dissection of the stabilizing muscles of the shoulder and preserved in formaldehyde solution. It was observed that the shoulder stab