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PubMed1996

Numerical representations in primates.

Research has demonstrated that human infants and nonhuman primates have a rudimentary numerical system that enables them to count objects or events. More recently, however, studies using a preferential looking paradigm have suggested that preverbal human infants are capable of simple arithmetical operations, such as adding and subtracting a small number of visually presented objects. These findings implicate a relatively sophisticated representational system in the absence of language. To explore the evolutionary origins of this capacity, we present data from an experiment with wild rhesus monkeys (Macaca mulatta) that methodologically mirrors those conducted on human infants. Results suggest that rhesus monkeys detect additive and subtractive changes in the number of objects present in their visual field. Given the methodological and empirical similarities, it appears that nonhuman primates such as rhesus monkeys may also have access to arithmetical representations, although alternative explanations must be considered for both primate species.

Animals↗

PubMed1998

The common marmoset: a new world primate species with limited Mhc class II variability.

The common marmoset (Callithrix jacchus) is a New World primate species that is highly susceptible to fatal infections caused by various strains of bacteria. We present here a first step in the molecular characterization of the common marmoset's Mhc class II genes by nucleotide sequence analysis of the polymorphic exon 2 segments. For this study, genetic material was obtained from animals bred in captivity as well as in the wild. The results demonstrate that the common marmoset has, like other primates, apparently functional Mhc-DR and -DQ regions, but the Mhc-DP region has been inactivated. At the -DR and -DQ loci, only a limited number of lineages were detected. On the basis of the number of alleles found, the -DQA and -B loci appear to be oligomorphic, whereas only a moderate degree of polymorphism was observed for two of three Mhc-DRB loci. The contact residues in the peptide-binding site of the Caja-DRB1*03 lineage members are highly conserved, whereas the -DRB*W16 lineage members show more divergence in that respect. The latter locus encodes five oligomorphic lineages whose members are not observed in any other primate species studied, suggesting rapid evolution, as illustrated by frequent exchange of polymorphic motifs. All common marmosets tested were found to share one monomorphic type of Caja-DRB*W12 allele probably encoded by a separate locus. Common marmosets apparently lack haplotype polymorphism because the number of Caja-DRB loci present per haplotype appears to be constant. Despite this, however, an unexpectedly high number of allelic combinations are observed at the haplotypic level, suggesting that Caja-DRB alleles are exchanged frequently between chromosomes by recombination, promoting an optimal distribution of limited Mhc polymorphisms among individuals of a given population. This peculiar genetic make up, in combination with the limited variability of the major histocompatability complex class II repertoire, may contribute to the common marmoset's susceptibility to particular bacterial infections.

Alleles↗

PubMed1998

Changes in cell-cycle kinetics during the development and evolution of primate neocortex.

The evolutionary expansion of neocortical size in mammals is particularly prominent in anthropoid primates (i.e., monkeys, apes, and humans) and reflects an increased number of cortical cells, yet the developmental basis for this increase remains undefined. Cortical cell production depends on the length of the cell-division cycle of progenitor cells during neurogenesis, which previously has been measured only in smaller-brained rodents. To investigate whether cortical expansion in primates reflects modification of cell-cycle kinetics, we determined cell-cycle length during neurogenesis in the proliferative cerebral ventricular zone of fetal rhesus monkeys, by using cumulative S-phase labeling with bromodeoxyuridine. Cell-cycle durations in monkeys were as much as 5 times longer than those reported in rodents. Nonetheless, substantially more total rounds of cell division elapsed during the prolonged neurogenetic period of the monkey cortex, providing a basis for increased cell production. Moreover, unlike the progressive slowing that occurs during cortical development in rodents, cell division accelerated during neurogenesis of the enlarged cortical layers in monkeys. These findings suggest that evolutionary modification of the duration and number of progenitor cell divisions contributed to both the expansion and laminar elaboration of the primate neocortex.

Animals↗

PubMed2001

Nontropic actions of neurotrophins: subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation.

Normal aging is associated with a significant reduction in cognitive function across primate species. However, the structural and molecular basis for this age-related decline in neural function has yet to be defined clearly. Extensive cell loss does not occur as a consequence of normal aging in human and nonhuman primate species. More recent studies have demonstrated significant reductions in functional neuronal markers in subcortical brain regions in primates as a consequence of aging, including dopaminergic and cholinergic systems, although corresponding losses in cortical innervation from these neurons have not been investigated. In the present study, we report that aging is associated with a significant 25% reduction in cortical innervation by cholinergic systems in rhesus monkeys (P < 0.001). Further, these age-related reductions are ameliorated by cellular delivery of human nerve growth factor to cholinergic somata in the basal forebrain, restoring levels of cholinergic innervation in the cortex to those of young monkeys (P = 0.89). Thus, (i) aging is associated with a significant reduction in cortical cholinergic innervation; (ii) this reduction is reversible by growth-factor delivery; and (iii) growth factors can remodel axonal terminal fields at a distance, representing a nontropic action of growth factors in modulating adult neuronal structure and function (i.e., administration of growth factors to cholinergic somata significantly increases axon density in terminal fields). These findings are relevant to potential clinical uses of growth factors to treat neurological disorders.

Aging↗

PubMed2001

Molecular basis of evolutionary loss of the alpha 1,3-galactosyltransferase gene in higher primates.

Galactose-alpha1,3-galactose (alphaGal) epitopes, the synthesis of which requires the enzyme product of alpha1,3-galactosyltransferase (alpha1,3GT), are sugar chains on the cell surface of most mammalian species. Notable exceptions are higher primates including Old World monkeys, apes, and humans. The alphaGal-negative species as well as mice with deletion of the alpha1,3GT gene produce abundant anti-alphaGal antibodies. The evolutionary loss of alphaGal epitopes has been attributed to point mutations in the coding region of the gene. Because no transcripts could be found in the higher primate species with Northern blot analysis, a potential alternative explanation has been loss of upstream regulation of the gene. Here, we have demonstrated that the rhesus promoter is functional. More importantly, a variety of full-length transcripts were detected with sensitive PCR-based methods in the tissues of rhesus monkeys, orangutans, and humans. Five crucial mutations were delineated in the coding region of the human and rhesus and three in the orangutan, any one of which could be responsible for inactivation of the alpha1,3GT gene. Two of the mutations were shared by all three higher primates. These findings, which elucidate the molecular basis for the evolutionary loss of alphaGal expression, may have implications in medical research.

Amino Acid Sequence↗

PubMed2003

Fidelity of primate cell repair of a double-strand break within a (CTG).(CAG) tract. Effect of slipped DNA structures.

At least 15 human diseases are caused by the instability of gene-specific (CTG).(CAG) repeats. The precise mechanism of instability remains unknown, though bacterial and yeast models have suggested a role for aberrant repair of double-strand breaks (DSBs). Using an established primate DSB repair system, we have investigated the fidelity of repair of a DSB within a (CTG).(CAG) repeat tract. DSB repair substrates were generated from plasmids that are stably replicated in their circular form, permitting us to highlight the effects of DSB repair on repeat stability and minimize the contribution of replication. DSBs were introduced into repeat-containing plasmids using a unique BsmI site, such that the entire repeat tract comprised one free end of the linearized plasmid. Substrates containing 17, 47, and 79 repeats, in either their linear duplex form or containing slipped structures (out-of-register interstrand mispairings at repeat sequences), were transiently transfected into primate cells. Linearized plasmids with repeats were repaired with mildly reduced efficiency, while the presence of slipped structures considerably reduced repair efficiency. The repaired products were characterized for alterations within the repeat tract and flanking sequence. DSB repair induced predominantly repeat deletions. Notably, a polarized/directional deletion effect was observed, in that the repetitive end of the DSB was preferentially removed. This phenomenon was dramatically enhanced when slipped structures were present within the repeat tract, providing the first evidence for error-prone processing of slipped-strand structures. These results suggest the existence of primate nuclease activities that are specific for (CTG).(CAG) repeats and the structures they form.

Animals↗

PubMed2004

A primate-dominant third glycosylation site of the beta2-adrenergic receptor routes receptors to degradation during agonist regulation.

beta(2)-adrenergic receptors (beta(2)AR) of all species are N-linked glycosylated at amino terminus residues approximately 6 and approximately 15. However, the human beta(2)AR has a potential third N-glycosylation site at ECL2 residue 187. To determine whether this residue is glycosylated and to ascertain function, all possible single/multiple Asn --> Gln mutations were made in the human beta(2) AR at positions 6, 15, and 187 and were expressed in Chinese hamster fibroblast cells. Substitution of Asn-187 alone or with Asn-6 or Asn-15 decreased the apparent molecular mass of the receptor on SDS-PAGE in a manner consistent with Asn-187 glycosylation. All receptors bound the agonist isoproterenol and functionally coupled to adenylyl cyclase. However, receptors without 187 glycosylation failed to display long term agonist-promoted down-regulation. In contrast, loss of Asn-6/Asn-15 glycosylation did not alter down-regulation. Cell surface distribution and agonist-promoted internalization of receptors and recruitment of beta-arrestin 2 were unaffected by the loss of 187 glycosylation. Furthermore, acutely internalized wild-type and Gln-187 receptors were both localized by confocal microscopy to early endosomes. During prolonged agonist exposure, wild-type beta(2)AR co-localized with lysosomes, consistent with trafficking to a degradation compartment. However, Gln-187 beta(2)AR failed to co-localize with lysosomes despite agonist treatments up to 18 h. Phylogenetic analysis revealed that this third glycosylation site is found in humans and other higher order primates but not in lower order primates such as the monkey. Nor is this third site found in rodents, which are frequently utilized as animal models. These data thus reveal a previously unrecognized beta(2)AR regulatory motif that appeared late in primate evolution and serves to direct internalized receptors to lysosomal degradation during long term agonist exposure.

Adenylyl Cyclases↗

PubMedDate not supplied

Experience with renal transplantation in the nonhuman primate: a modified ureteroneocystostomy to prevent urologic complications.

Nonhuman primates provide an optimal model for the evaluation of tolerance in the preclinical setting. Transplantation and management of nonhuman primates are technically demanding, and the purpose of this article is to review our extensive experience in renal transplantation in non-human primates, with particular emphasis on modifications of surgical techniques on urologic complications. We retrospectively reviewed our results with 329 renal transplants in rhesus monkeys over an 18-year period. The surgical technique and, in particular, the ureteroneocystostomy have evolved over this period of time. This review extensively details our current technique, the surgical and urologic complications, and their management. There were 329 renal transplants performed. There were 85 early deaths, or animals euthanized, within 30 days of the transplant operation. In the first 15 years, there were 27 (10.68%) surgical complications that required euthanasia, and in the last 3 years the complication rate has been reduced to 5 (7.3%, p < .05). The routine use of microsurgical techniques has reduced the incidence of arterial thrombosis (6.2% vs. 2.9%, p < .05). The incidence of ureteral strictures (15 vs. 0, p < .005) has been reduced by a modification of the ureteroneocystostomy technique detailed in the text. Renal transplantation in small rhesus monkeys is technically demanding. The routine use of microsurgical techniques and a modified ureteroneocystostomy has reduced the incidence of surgical complications.

Animals↗

PubMed2001

A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies.

Nonhuman primates may be used as human surrogates in inhalation exposure studies to assess either the (1) adverse health effects of airborne particulate matter or (2) therapeutic effects of aerosolized drugs and proteins. Mathematical models describing the behavior and fate of inhaled aerosols may be used to complement such laboratory investigations. For example, the optimal conditions, in terms of ventilatory parameters (e.g., breathing frequency and tidal volume) and aerosol characteristics (e.g., geometric size and density), necessary to target drug delivery to specific sites within the respiratory tract may be estimated a priori with models. In this work a mathematical description of the rhesus monkey (Macaca mulatta) lung is presented for use with an aerosol deposition model. Deposition patterns of 0.01- to 5-microm-diameter monodisperse aerosols within lungs were calculated for 3 monkey lung models (using different descriptions of alveolated regions) and compared to human lung results obtained using a previously validated mathematical model of deposition physics. Our findings suggest that there are significant differences between deposition patterns in monkeys and humans. The nonhuman primates had greater exposures to inhaled substances, particularly on the basis of deposition per unit airway surface area. However, the different alveolar volumes in the rhesus monkey models had only minor effects on aerosol dosimetry within those lungs. By being aware of such quantitative differences, investigators can employ the respective primate models (human and nonhuman) to more effectively design and interpret the results of future inhalation exposure experiments.

Aerosols↗

PubMed2002

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

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

Amino Acid Sequence↗

PubMed1991

Calcium feedback and sensitivity regulation in primate rods.

Membrane current was recorded from a single primate rod with a suction pipette while the cell was bath perfused with solutions maintained at a temperature of approximately 38 degrees C. A transient inward current was observed at the onset of bright illumination after briefly exposing the outer segment in darkness to Ringer's (Locke) solution containing 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cGMP phosphodiesterase. After briefly removing external Na+ from around the outer segment in darkness, a similar current was observed upon Na+ restoration in bright light. By analogy to amphibian rods, this inward current was interpreted to represent the activity of an electrogenic Na(+)-dependent Ca2+ efflux, which under physiological conditions in the light is expected to reduce the free Ca2+ in the outer segment and provide negative feedback (the "Ca2+ feedback") to the phototransduction process. The exchange current had a saturated amplitude of up to approximately 5 pA and a decline time course that appeared to have more than one exponential component. In the absence of the Ca2+ feedback, made possible by removing the Ca2+ influx and efflux at the outer segment using a 0 Na(+)-0 Ca2+ external solution, the response of a rod to a dim flash was two to three times larger and had a longer time to peak than in physiological solution. These changes can be approximately accounted for by a simple model describing the Ca2+ feedback in primate rods. The dark hydrolytic rate for cGMP was estimated to be 1.2 s-1. The incremental hydrolytic rate, beta*(t), activated by one photoisomerization was approximately 0.09 s-1 at its peak, with a time-integrated activity, integral of beta*(t)dt, of approximately 0.033, both numbers being derived assuming spatial homogeneity in the outer segment. Finally, we have found that primate rods adapt to light in much the same way as amphibian and other mammalian rods, such as showing a Weber-Fechner relation between flash sensitivity and background light. The Ca2+ feedback model we have constructed can also explain this feature reasonably well.

1-Methyl-3-isobutylxanthine↗

PubMed1999

Ebola (subtype Reston) virus among quarantined nonhuman primates recently imported from the Philippines to the United States.

In April 1996, laboratory testing of imported nonhuman primates (as mandated by quarantine regulations) identified 2 cynomolgus macaques (Macaca fascicularis) infected with Ebola (subtype Reston) virus in a US-registered quarantine facility. The animals were part of a shipment of 100 nonhuman primates recently imported from the Philippines. Two additional infected animals, who were thought to be in the incubation phase, were identified among the remaining 48 animals in the affected quarantine room. The other 50 macaques, who had been held in a separate isolation room, remained asymptomatic, and none of these animals seroconverted during an extended quarantine period. Due to the rigorous routine safety precautions, the facility personnel had no unprotected exposures and remained asymptomatic, and no one seroconverted. The mandatory quarantine and laboratory testing requirements, put in place after the original Reston outbreak in 1989-1990, were effective for detecting and containing Ebola virus infection in newly imported nonhuman primates and minimizing potential human transmission.

Animals↗

PubMed1992

A comparison of regulatory features in primate lentiviruses.

Historically, research into the regulation of gene expression in primate lentiviruses has focused on human immunodeficiency virus type 1 (HIV-1), the primary cause of acquired immunodeficiency syndrome (AIDS) in humans. The increasing emergence of HIV-2 as a human pathogen, and the importance of the various simian immunodeficiency viruses (SIV) as models for the treatment and prevention of HIV-1-induced disease, suggest that an understanding of gene regulation in these related viruses will become increasingly important. Here, the present state of knowledge in this latter field is reviewed. In general, while the data support the hypothesis that viral gene expression is regulated by very similar mechanisms in all primate lentiviruses, it also is clear that differences in detail do exist. These differences may influence the pathogenic potential of the different strains of primate lentiviruses and must be considered in evaluating SIV as an appropriate in vivo model for HIV-1.

Amino Acid Sequence↗

PubMed1993

Absence of long-term gonadotoxicity in primates receiving extracorporeal shock wave application.

Extracorporeal shock wave lithotripsy (SWL) is becoming popular in the management of lower ureteral calculi; however, the quantity of data on its potential gonadotoxic effects are limited. Eight nonhuman primates had baseline measurements of testicular volume, semen analysis, serum testosterone and FSH assays, and DNA flow cytometric analysis of testicular aspirates. The anesthetized primates were lowered into a Dornier XL-1 lithotripter and at a 20 kV power setting had various numbers of shocks (0, 500, 1500) directed at each testis. Sequential studies were done at 6-week intervals for 9 months. The control group showed no significant change in any measure. Semen analysis, testosterone, and FSH results were variable and without statistically significant differences. There were changes in the DNA histograms, with the tetraploid (4N) group of cells being the most sensitive. All changes caused by SWL application returned to baseline by 9 months. Data from this primate study document no apparent long-term male gonadotoxicity from SWL, but the authors suggest measures to protect the testis during clinical use.

Animals↗

PubMed1996

Gene transfer into hematopoietic stem cells of nonhuman primates.

Nonhuman primates provide an appropriate preclinical large-animal model to test the efficacy of bone marrow gene therapy procedures. Successful retroviral vector-mediated gene transfer into monkey pluripotent hematopoietic stem cells (PHSC) has closed the gap between gene transfer experiments in mouse models and clinical application of bone marrow gene therapy. After initial bone marrow transplant failures, ex vivo bone marrow culture conditions were found that sufficiently supported maintenance of the long-term repopulating ability of genetically modified autologous monkey grafts. The efficiency of gene transfer into primate PHSC has, however, remained at least one order of magnitude lower than has been achieved in mice. Similar gene transfer efficiencies have been obtained with total bone marrow grafts, CD34+ bone marrow grafts, and mobilized peripheral blood progenitor cell grafts; however, various attempts to increase the transduction efficiency have been without significant success. Primate PHSC seem to require quite different culture conditions for their maintenance and transduction than mouse PHSC, in particular regarding hematopoietic growth factor addition. In contrast to observations in other species, some form of conditioning appeared essential for engraftment of transduced PHSC in monkeys. Although it has been shown that mouse retroviruses can replicate in monkeys and are capable of inducing neoplasms, experiments in monkeys have sufficiently confirmed the safety of current gene transfer procedures to allow their clinical application.

Animals↗

PubMed1997

Liver-directed gene transfer in non-human primates.

To develop a primate model for liver-directed gene therapy, we studied several gene transfer vehicles and routes in eight rhesus monkeys (Macaca mulatta). For this purpose, we used first-generation, replication-deficient adenoviral vectors carrying the Escherichia coli lacZ gene (Ad.CMVlacZ) or a lacZ-containing plasmid (pCMV beta) with lipofectamine for transfection. The reporter gene construct was infused into either the portal vasculature, common bile duct, or saphenous vein. Adenovirus-mediated gene transfer via the portal vein resulted in expression of lacZ in over 70% of hepatocytes by days 3-7, but was accompanied by acute hepatitis. Adenovirus-mediated gene transfer via the common bile duct resulted in lacZ expression in less than 10% of hepatocytes and was accompanied by portal inflammation. The animals mounted a significant immune response, as demonstrated by adenoviral antigen-induced T-cell proliferation and production of neutralizing anti-adenovirus antibodies and antibodies to E. coli beta-galactosidase (beta-Gal). Activation of the immune response was associated with rapid decrease of the reporter gene by days 13-21. Lipofectamine-mediated gene transfer was inefficient, and no lacZ expression in the liver was detected. To limit the host immune response, 4 animals were immunosuppressed by cyclophosphamide/prednisone and then infused with the Ad.CMVlacZ via the portal vein or the saphenous vein. The monkeys showed sustained expression of lacZ for up to 35 days with no evidence of inflammation. The primates transduced via the saphenous vein showed a level of beta-Gal expression in the liver similar to that of the portal vein-infused animals. In conclusion, adenovirus-mediated gene transfer to non-human primate livers via the portal vein or saphenous vein is efficient, but it results in transient expression and is accompanied by an immune response to both vector and transgene products and acute hepatitis, whereas lipofectamine-mediated transfer is inefficient. Manipulation of the host immune response may expand potential applications of adenoviral vectors for liver-directed gene transfer.

Adenoviridae↗

PubMed1995

Primate erythrocyte (E) complement receptor (CR1) as an anchor site for bispecific-based therapies to clear pathogens or autoantibodies safely from the circulation.

We have prepared cross-linked, bispecific complexes [heteropolymers (HP) and antigen-based heteropolymers (AHP)] that facilitate complement-independent binding of target model pathogens or autoantibodies to primate erythrocytes (E) via complement receptors (CR1). The method is based on using monoclonal antibodies (mAb) specific for CR1 that either are cross-linked to an mAb specific for a prototype pathogen (e.g., IgE) or are cross-linked to an autoantigen (e.g., dsDNA) that is recognized by circulating pathogenic autoantibodies in the autoimmune disease systemic lupus erythematosus (SLE). The underlying assumption in this research is that complexed ligands containing IgG bound to primate E CR1 should be recognized and processed via the same mechanism by which complement-opsonized immune complexes bound to E CR1 are cleared from the circulation and phagocytosed in the liver and spleen. Our work in experimental monkey models has demonstrated that binding of substrates to primate E via this method does indeed lead to the safe and rapid clearance of the target pathogens or autoantibodies from the circulation, without any lysis or loss of the E. Although a number of questions must still be resolved, it may be possible to generalize these findings and use this CR1-based approach to develop a simple noninvasive bispecific therapy that can be used to clear pathogens or autoantibodies from the circulation.

Animals↗

PubMed1985

Interval nitrogen excretion and maintenance nitrogen requirements for parenteral nutrition in primates.

This paper discusses a regression technique for determining maintenance nitrogen requirements in well-nourished primates (M fascicularis) on total parenteral nutrition. Animals were administered a continuous glucose infusion, and parenteral nitrogen intake was varied at constant time intervals in a random order (from 0 to 1 g nitrogen/kg/day). Interval nitrogen balance (intake minus urinary nitrogen output) was plotted against interval nitrogen intake. The x-intercept was defined as the maintenance nitrogen requirement. First, 24-h intervals were used at a nonprotein caloric intake of 85 kcal/kg/day (approximately 175% of primate resting energy expenditure) and the nutritional adequacy of the estimated requirement evaluated prospectively. Next, 8-h balance intervals were used and the maintenance nitrogen requirements predicted by this abbreviated technique were compared to those obtained using the longer method. Finally, the short-interval technique was repeated at two other levels of continuous glucose infusion (60 kcal/kg/day and 8 kcal/kg/day) and the effect on predicted nitrogen requirement examined. Maintenance parenteral nitrogen requirements for primates may be determined in 48 h using the abbreviated techniques.

Animals↗