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Jonathan G. Scammell - One of the best experts on this subject based on the ideXlab platform.
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regulation and distribution of Squirrel Monkey chorionic gonadotropin and secretogranin ii in the pituitary
General and Comparative Endocrinology, 2011Co-Authors: Audrey A Vasauskas, Tina R Hubler, Christina Mahanic, Susan V Gibson, Andrea G Kahn, Jonathan G. ScammellAbstract:Secretogranin II (SgII) is a member of the granin family of proteins found in neuroendocrine and endocrine cells. The expression and storage of SgII in the pituitary gland of Old World primates and rodents have been linked with those of luteinizing hormone (LH). However, New World primates including Squirrel Monkeys do not express LH in the pituitary gland, but rather CG is expressed. If CG takes on the luteotropic role of LH in New World primates, SgII may be associated with the expression and storage of CG in the pituitary gland. The goal of this study was to evaluate the regulation and distribution of CG and SgII in the Squirrel Monkey. A DNA fragment containing approximately 750 bp of Squirrel Monkey SgII promoter was isolated from genomic DNA and found to contain a cyclic AMP response element that is also present in the human SgII promoter and important for GnRH responsiveness. The Squirrel Monkey and human SgII promoters were similarly activated by GnRH in luciferase reporter gene assays in LβT2 cells. Double immunofluorescence microscopy demonstrated close association of SgII and CG in gonadotrophs of Squirrel Monkey pituitary gland. These results suggest that CG and SgII have a similar intercellular distribution and are coregulated in Squirrel Monkey pituitary gland.
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cortisol metabolism in the bolivian Squirrel Monkey saimiri boliviensis boliviensis
Comparative Medicine, 2006Co-Authors: Jonathan G. Scammell, Lawrence E. Williams, Jenne M Westberry, Patti W Sadosky, Ravinder J Singh, Robert L Taylor, Tina R Hubler, Susan V Gibson, Cedric H L ShackletonAbstract:Abstract New World Squirrel Monkeys (Saimiri spp.) have high circulating cortisol levels but normal electrolytes and blood pressures. The goal of the present study was to gain insight into adaptive mechanisms used by Bolivian Squirrel Monkeys to minimize the effects of high cortisol on mineralocorticoid receptor (MR) activity and electrolyte and water balance. Aldosterone levels in serum from 10 Squirrel Monkeys were 17.7 +/- 3.4 ng/dl (normal range in humans, 4 to 31 ng/dl), suggesting that Squirrel Monkeys do not exhibit a compensatory increase in aldosterone. The Squirrel Monkey MR was cloned and expressed in COS-7 cells and found to have similar responsiveness to cortisol and aldosterone as human MR, suggesting that Squirrel Monkey MR is not inherently less responsive to cortisol. To determine whether altered metabolism of cortisol might contribute to MR protection in Squirrel Monkeys, serum and urinary cortisol and cortisone were measured, and a comprehensive urinary corticosteroid metabolite profile was performed in samples from anesthetized and awake Squirrel Monkeys. The levels of cortisone exceeded those of cortisol in serum and urine, suggesting increased peripheral 11beta-hydroxysteroid dehydrogenase 2 activity in Squirrel Monkeys. In addition, a significant fraction (approximately 20%) of total corticosteroids excreted in the urine of Squirrel Monkeys appeared as 6beta-hydroxycortisol, compared with that in man (1%). Therefore, changes in cortisol metabolism likely contribute to adaptive mechanisms used by Bolivian Squirrel Monkeys to minimize effects of high cortisol.
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structure function analysis of Squirrel Monkey fk506 binding protein 51 a potent inhibitor of glucocorticoid receptor activity
Endocrinology, 2005Co-Authors: Wesley B Denny, Viravan Prapapanich, David F Smith, Jonathan G. ScammellAbstract:FK506-binding protein 51 (FKBP51) and FKBP52 are large molecular weight immunophilins that are part of the mature glucocorticoid receptor (GR) heterocomplex. These proteins possess peptidyl-prolyl isomerase (PPIase) and tetratricopeptide repeats (TPR) domains that are important for modulation of GR activity. A naturally occurring animal model of glucocorticoid resistance, the Squirrel Monkey, results from the relative overexpression of FKBP51 that renders the GR in a low-affinity state. In vitro studies demonstrated that the Squirrel Monkey form of FKBP51 is greater than 6-fold more potent than human FKBP51 in this respect. The goals of these studies were to determine the roles of the TPR and PPIase domains in the inhibitory activity of Squirrel Monkey FKBP51 and to gain insight into structural features of Squirrel Monkey FKBP51 responsible for potent inhibition of dexamethasone-stimulated GR activity. Mutations in the TPR of Squirrel Monkey FKBP51 that inhibit association with heat shock protein 90 blocked GR inhibitory activity. Mutations that abrogate the PPIase activity of Squirrel Monkey FKBP51 had no effect on GR inhibitory activity. Chimeras of Squirrel Monkey and human FKBP51 were tested to identify domains responsible for their different inhibitory potencies. Amino acid differences in domains FK1 and FK2 between Squirrel Monkey and human FKBP51 contribute equally to the enhanced inhibitory activity of Squirrel Monkey FKBP51. Furthermore, Squirrel Monkey FKBP51 in which either FK1 or FK2 was deleted lacked GR inhibitory activity. Thus, the potent inhibitory activity of Squirrel Monkey FKBP51 involves both FK domains and the heat shock protein 90-binding TPR domain.
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Squirrel Monkey immunophilin fkbp51 is a potent inhibitor of glucocorticoid receptor binding
Endocrinology, 2000Co-Authors: Wesley B Denny, Donna L. Valentine, Philip D. Reynolds, David F Smith, Jonathan G. ScammellAbstract:Squirrel Monkeys have high circulating cortisol to compensate for expression of low-affinity glucocorticoid receptors (GRs). We have demonstrated that the FK506-binding immunophilin FKBP51 is elevated in Squirrel Monkey lymphocytes (SML) and, in preliminary studies, have shown that Squirrel Monkey FKBP51 is inhibitory to GR binding. In this report, we have demonstrated that elevated FKBP51 is the unequivocal cause of glucocorticoid resistance in SML in the following ways: 1) FK506 increased GR binding in cytosol from SML in a concentration-dependent manner, an effect reproduced by rapamycin but not cyclosporin A. The apparent Kd (6.1 nm) and rank-order of steroid displacement of[ 3H]dexamethasone binding in FK506-treated SML cytosol are characteristic of high-affinity GR binding. 2) cytosol from COS-7 cells expressing Squirrel Monkey FKBP51 inhibited GR binding in cytosol from human lymphocytes by 74%. Cytosol from COS-7 cells expressing human FKBP51 inhibited GR binding by 23%. 3) expression of Squirrel ...
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glucocorticoid resistance in the Squirrel Monkey is associated with overexpression of the immunophilin fkbp51
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Philip D. Reynolds, Y Ruan, D F Smith, Jonathan G. ScammellAbstract:Squirrel Monkeys are neotropical primates that have high circulating cortisol to compensate for expression of glucocorticoid receptors (GRs) with reduced affinity. The low binding affinity of Squirrel Monkey GR does not result from substitutions in the receptor, because Squirrel Monkey GR expressed in vitro exhibits high affinity. Rather, Squirrel Monkeys express a soluble factor that, in mixing studies of cytosol from Squirrel Monkey lymphocytes (SML) and mouse L929 cells, reduced GR binding affinity by 11-fold. In an effort to identify this factor, the cellular levels of components of the GR heterocomplex in SML and human lymphocytes (HL) were compared. The immunophilin FKBP51 was 13-fold higher in SML than in HL cytosol; FKBP52 in SML was 42% of that in HL cytosol. A role for changes in immunophilins, causing glucocorticoid resistance in neotropical primates, is supported by the following: the changes in FKBP51 and FKBP52 were observed in cells from other neotropical primates with glucocorticoid resistance; the elevated level of FKBP51 was reflected in an abundance of FKBP51 in heat shock protein 90 complexes in SML; when cytosols of SML and L929 cells were mixed, the decrease in GR binding was associated with incorporation of FKBP51 into GR heterocomplexes; the effect of SML cytosol on GR binding was reproduced with cytosol from COS cells expressing Squirrel Monkey FKBP51; and both the effect of SML cytosol on GR binding and the incorporation of FKBP51 into GR heterocomplexes were blocked by FK506. Regulation of GR binding by FKBP51 represents a previously unrecognized mechanism for regulating glucocorticoid sensitivity.
Henrieta Scholtzova - One of the best experts on this subject based on the ideXlab platform.
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class c cpg oligodeoxynucleotide immunomodulatory response in aged Squirrel Monkey saimiri boliviensis boliviensis
Frontiers in Aging Neuroscience, 2020Co-Authors: Pramod N. Nehete, Bharti P. Nehete, Sriram Chitta, Henrieta Scholtzova, Lawrence E. Williams, Akash G Patel, Margish Ramani, Thomas WisniewskiAbstract:One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer’s disease (AD). Rodent models are often used for preclinical testing of the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the distribution of TLR9 between primates and rodents. The Squirrel Monkey (SQM), a well-established New World non-human primate (NHP), is known to be phylogenetically proximate to humans and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN’s immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here, closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model allowing for future therapeutic trials of innate immunity stimulation via TLR9 agonists for diverse indications including AD therapeutics.
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class c cpg oligodeoxynucleotide immunomodulatory response in aged Squirrel Monkey saimiri boliviensis boliviensis
Frontiers in Aging Neuroscience, 2020Co-Authors: Pramod N. Nehete, Bharti P. Nehete, Sriram Chitta, Henrieta Scholtzova, Lawrence E. Williams, Akash G Patel, Thomas Wisniewski, Margish D RamaniAbstract:One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The Squirrel Monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.
Lawrence E. Williams - One of the best experts on this subject based on the ideXlab platform.
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class c cpg oligodeoxynucleotide immunomodulatory response in aged Squirrel Monkey saimiri boliviensis boliviensis
Frontiers in Aging Neuroscience, 2020Co-Authors: Pramod N. Nehete, Bharti P. Nehete, Sriram Chitta, Henrieta Scholtzova, Lawrence E. Williams, Akash G Patel, Margish Ramani, Thomas WisniewskiAbstract:One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer’s disease (AD). Rodent models are often used for preclinical testing of the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the distribution of TLR9 between primates and rodents. The Squirrel Monkey (SQM), a well-established New World non-human primate (NHP), is known to be phylogenetically proximate to humans and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN’s immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here, closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model allowing for future therapeutic trials of innate immunity stimulation via TLR9 agonists for diverse indications including AD therapeutics.
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class c cpg oligodeoxynucleotide immunomodulatory response in aged Squirrel Monkey saimiri boliviensis boliviensis
Frontiers in Aging Neuroscience, 2020Co-Authors: Pramod N. Nehete, Bharti P. Nehete, Sriram Chitta, Henrieta Scholtzova, Lawrence E. Williams, Akash G Patel, Thomas Wisniewski, Margish D RamaniAbstract:One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The Squirrel Monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.
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clinical neuropathological and immunohistochemical features of sporadic and variant forms of creutzfeldt jakob disease in the Squirrel Monkey saimiri sciureus
Journal of General Virology, 2007Co-Authors: Lawrence E. Williams, Paul Brown, James W Ironside, R G Will, Diane Ritchie, Thomas R Kreil, Susan V Gibson, Christian R. AbeeAbstract:The Squirrel Monkey (Saimiri sciureus) has been shown to be nearly as susceptible as the chimpanzee to experimentally induced Creutzfeldt–Jakob disease (CJD), and has been used extensively in diagnostic and pathogenetic studies. However, no information is available concerning the clinicopathological characteristics of different strains of human transmissible spongiform encephalopathy (TSE) in this species, in particular, strains of sporadic and variant CJD (sCJD and vCJD, respectively). Brain homogenates from patients with sCJD or vCJD were inoculated intracerebrally at dilutions of 10−1 or 10−3 into the left frontal cortex of Squirrel Monkeys. Animals were kept under continuous clinical surveillance during the preclinical and clinical phases of disease, and regularly underwent standardized behavioural testing. Brains from three animals in the sCJD and vCJD groups were examined histopathologically and immunohistochemically for the presence of pathognomonic misfolded protein (PrPTSE). Overall, incubation periods and durations of illness were slightly shorter in Monkeys infected with sCJD than in those infected with vCJD, but the earliest signs of illness (ataxia and tremors) were the same in both groups. Clinical disease in the sCJD Monkeys was somewhat more severe and of shorter duration. Post-mortem examinations revealed distinctive patterns of spongiform change and PrPTSE distribution in the brains of sCJD and vCJD animals, similar to those seen in humans except that amyloid plaques were not present. PrPTSE was uniformly absent from peripheral lymphoid tissues in both groups of animals. Human strains of sCJD and vCJD cause distinguishable clinicopathological features in the Squirrel Monkey that can provide a baseline for the evaluation of future therapeutic studies.
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cortisol metabolism in the bolivian Squirrel Monkey saimiri boliviensis boliviensis
Comparative Medicine, 2006Co-Authors: Jonathan G. Scammell, Lawrence E. Williams, Jenne M Westberry, Patti W Sadosky, Ravinder J Singh, Robert L Taylor, Tina R Hubler, Susan V Gibson, Cedric H L ShackletonAbstract:Abstract New World Squirrel Monkeys (Saimiri spp.) have high circulating cortisol levels but normal electrolytes and blood pressures. The goal of the present study was to gain insight into adaptive mechanisms used by Bolivian Squirrel Monkeys to minimize the effects of high cortisol on mineralocorticoid receptor (MR) activity and electrolyte and water balance. Aldosterone levels in serum from 10 Squirrel Monkeys were 17.7 +/- 3.4 ng/dl (normal range in humans, 4 to 31 ng/dl), suggesting that Squirrel Monkeys do not exhibit a compensatory increase in aldosterone. The Squirrel Monkey MR was cloned and expressed in COS-7 cells and found to have similar responsiveness to cortisol and aldosterone as human MR, suggesting that Squirrel Monkey MR is not inherently less responsive to cortisol. To determine whether altered metabolism of cortisol might contribute to MR protection in Squirrel Monkeys, serum and urinary cortisol and cortisone were measured, and a comprehensive urinary corticosteroid metabolite profile was performed in samples from anesthetized and awake Squirrel Monkeys. The levels of cortisone exceeded those of cortisol in serum and urine, suggesting increased peripheral 11beta-hydroxysteroid dehydrogenase 2 activity in Squirrel Monkeys. In addition, a significant fraction (approximately 20%) of total corticosteroids excreted in the urine of Squirrel Monkeys appeared as 6beta-hydroxycortisol, compared with that in man (1%). Therefore, changes in cortisol metabolism likely contribute to adaptive mechanisms used by Bolivian Squirrel Monkeys to minimize effects of high cortisol.
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hematology and serum chemistry reference values for mother reared Squirrel Monkey saimiri boliviensis boliviensis infants
2006Co-Authors: Lawrence E. WilliamsAbstract:These reference data were obtained from the database maintained at the Squirrel Monkey Breeding and Research Resource (supported by NIH NCRR P40-RR01254). The samples were collected as part of research protocols and clinical observations. Time of day was not controlled across samples, although the majority were collected between 7 am and 10 am (Tables 28-1 and 28-2). All samples were collected from non-fasted, awake (unanesthetized) Bolivian Squirrel Monkeys (Saimiri boliviensis boliviensis) that were manually restrained. A 1- or 3-ml syringe was used to collect 0.5–1.5ml of whole blood (amount depending on age) from the femoral vein. Following blood collection the animal was returned to its social group and/or placed back on its dam. The whole procedure required less than 2 min. Open image in new window Table 28-1. Serum Chemistry Reference Values for Bolivian Squirrel Monkeys Aged 1—12 Months Open image in new window Table 28-2. Hematology Reference Values for Bolivian Squirrel Monkeys Aged 1—12 Months
Don J. Melnick - One of the best experts on this subject based on the ideXlab platform.
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Subspecies of the Central American Squirrel Monkey (Saimiri oerstedii) as Units for Conservation
International Journal of Primatology, 2012Co-Authors: Mary E. Blair, Gustavo A. Gutiérrez-espeleta, Don J. MelnickAbstract:The accurate diagnosis of conservation units now typically includes recognition of genetic diversity and unique evolutionary lineages and is necessary to inform the conservation management of endangered species. We evaluated whether the two currently recognized subspecies of the endangered Central American Squirrel Monkey (Saimiri oerstedii) in Costa Rica are evolutionarily significant units (ESUs) that should be managed separately in conservation efforts. We used previously published sequences of 50 individuals of Saimiri oerstedii for 880 bp of the mtDNA d-loop and genotypes of 244 individuals for 16 microsatellites and conducted novel analyses to characterize genetic differentiation between subspecies of Saimiri oerstedii. We measured sequence differentiation and inferred an intraspecific molecular phylogeny and a haplotype network, and found consistent results supporting statistically significant divergence and reciprocal monophyly between subspecies. A population aggregation analysis also supported Saimiri oerstedii citrinellus and S. o. oerstedii as diagnosably distinct units. These results confirm previous genetic studies with smaller sample sizes and are consistent with other factors including differences in pelage and morphology and divergence at nuclear markers. Conservation managers should manage these subspecies separately to prevent the loss of genetic diversity via artificially induced outbreeding. High levels of genetic diversity may buffer populations against outside extinction pressures, to which Saimiri oerstedii are vulnerable because of their dwindling habitat and small population size.
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genetic evidence for dispersal by both sexes in the central american Squirrel Monkey saimiri oerstedii citrinellus
American Journal of Primatology, 2012Co-Authors: Mary E. Blair, Don J. MelnickAbstract:Sex-biased dispersal (SBD) is common in many vertebrates, including primates. However, dispersal patterns in New World primates may vary among closely related taxa or populations in different local environments. Here, we test for SBD in an endangered New World primate, the Central American Squirrel Monkey (Saimiri oerstedii citrinellus). Previous studies of behavioral ecology suggest predominantly female dispersal in S.o. oerstedii in the Southern Pacific region of Costa Rica. However, our genetic data do not support strongly female-biased dispersal in S.o. citrinellus in the Central Pacific region. Our tests for SBD using microsatellite data including comparisons of isolation-by-distance, AIc, and FST values between males and females were not significant. Also, we found greater population genetic structure in mitochondrial markers than in microsatellite markers, indicative of predominantly male dispersal. We conclude that both sexes disperse in S.o. citrinellus, and that males probably disperse over longer distances. We discuss how spatial and temporal variation among local populations should be taken into account when studying dispersal patterns and especially sex bias. Am. J. Primatol. 74:37–47, 2012. © 2011 Wiley Periodicals, Inc.
Pramod N. Nehete - One of the best experts on this subject based on the ideXlab platform.
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class c cpg oligodeoxynucleotide immunomodulatory response in aged Squirrel Monkey saimiri boliviensis boliviensis
Frontiers in Aging Neuroscience, 2020Co-Authors: Pramod N. Nehete, Bharti P. Nehete, Sriram Chitta, Henrieta Scholtzova, Lawrence E. Williams, Akash G Patel, Margish Ramani, Thomas WisniewskiAbstract:One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer’s disease (AD). Rodent models are often used for preclinical testing of the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the distribution of TLR9 between primates and rodents. The Squirrel Monkey (SQM), a well-established New World non-human primate (NHP), is known to be phylogenetically proximate to humans and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN’s immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here, closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model allowing for future therapeutic trials of innate immunity stimulation via TLR9 agonists for diverse indications including AD therapeutics.
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class c cpg oligodeoxynucleotide immunomodulatory response in aged Squirrel Monkey saimiri boliviensis boliviensis
Frontiers in Aging Neuroscience, 2020Co-Authors: Pramod N. Nehete, Bharti P. Nehete, Sriram Chitta, Henrieta Scholtzova, Lawrence E. Williams, Akash G Patel, Thomas Wisniewski, Margish D RamaniAbstract:One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The Squirrel Monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.