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comparison of immunogenicity and safety outcomes of a malaria vaccine fmp013/alfq in rhesus macaques (macaca mulatta) of indian and chinese origin.indian-origin rhesus (inr) are preferred for research, but strict export restrictions continue to limit their use. chinese-origin rhesus (chr), although easier to procure, are genetically distinct from inr and differ in their immune response to infectious agents, such as the simian immunodeficiency virus. the most advanced malaria vaccine, rts,s (glaxosmithkline), is based on the circumsporozoite protein (csp) of plasmodium falciparum. the efficacy of rts,s vaccine in the field remains low and s ...201931775762
naturally occurring and experimentally induced rhesus macaque models for polycystic ovary syndrome: translational gateways to clinical application.indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (pcos) implicate both female hyperandrogenism and developmental molecular origins as core components of pcos etiopathogenesis. establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of pcos, includ ...201931783681
frontal and insular input to the dorsolateral temporal pole in primates: implications for auditory memory.the temporal pole (tp) has been involved in multiple functions from emotional and social behavior, semantic processing, memory, language in humans and epilepsy surgery, to the fronto-temporal neurodegenerative disorder (semantic) dementia. however, the role of the tp subdivisions is still unclear, in part due to the lack of quantitative data about tp connectivity. this study focuses in the dorsolateral subdivision of the tp: area 38dl. area 38dl main input originates in the auditory processing a ...201931780878
547 transcriptomes from 44 brain areas reveal features of the aging brain in non-human primates.brain aging is a complex process that depends on the precise regulation of multiple brain regions; however, the underlying molecular mechanisms behind this process remain to be clarified in non-human primates.201931779658
increased produce enrichment reduces trauma in socially-housed captive rhesus macaques (macaca mulatta).due to primate adaptations for sociality, captive rhesus macaques have optimal welfare and utility as a biomedical model when they can be maintained in outdoor social groups. as a despotic species; however, aggression can result in costly injuries and may result in temporary or permanent removal of specific individuals from social housing. enrichment items, such as toys, climbing structures, and foraging material, are employed to keep captive animals occupied. we hypothesized that produce enrich ...201931778253
microinjectrode system for combined drug infusion and electrophysiology.this microinjectrode system is designed for drug infusion, electrophysiology, and delivery and retrieval of experimental probes, such as microelectrodes and nanosensors, optimized for repeated use in awake, behaving animals. the microinjectrode system can be configured for multiple purposes: (1) simple arrangement of the cannula for placement of an experimental probe that would otherwise be too fragile to penetrate the dura mater, (2) microfluidic infusion of a drug, either independently or coup ...201931789311
high rates of aggression do not predict rates of trauma in captive groups of macaques.socially inflicted traumas are a major concern for the management of captive groups of rhesus macaques. rhesus macaques are the most commonly used nonhuman primate in biomedical research, and social housing is optimal for promoting psychological well-being. however, trauma is frequent due to a strong reliance on aggression to establish and maintain hierarchical relationships. we studied six captive groups of rhesus macaques (macaca mulatta) that underwent a variety of social perturbations and ex ...201931787789
intervention for early diabetic nephropathy by mesenchymal stem cells in a preclinical nonhuman primate model.diabetic nephropathy (dn) is one of the most severe chronic diabetic complications and the main cause of end-stage renal disease. chronic inflammation plays a key role in the development of dn. however, few treatment strategies are available; therefore, new and effective strategies to ameliorate dn at the early stage must be identified.201931791397
impact of analytical treatment interruption on the central nervous system in a simian-hiv model.analytical treatment interruption (ati) studies are often used to evaluate potential hiv cure strategies. this study was conducted to determine the impact of ati on simian-hiv (shiv) infection in the central nervous system.201931789818
alveolar bone repair of rhesus monkeys by using bmp-2 gene and mesenchymal stem cells loaded three-dimensional printed bioglass scaffold.over the past years, the study about bone tissue engineering in the field of regenerative medicine has been a main research topic. using three-dimensional (3d) porous degradable scaffold complexed with mesenchymal stem cells (mscs) and growth factor gene to improve bone tissue repair and regeneration has raised much interest. this study mainly evaluated the osteogenesis of alveolar bone defects of animal in the following experimental groups: sham-operated (so), 3d printed bioglass (3d-bg), 3d-bg ...201931796797
impact of q-griffithsin anti-hiv microbicide gel in non-human primates: in situ analyses of epithelial and immune cell markers in rectal mucosa.natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. we here assessed the effect of rectal application of an anti-hiv lectin-based microbicide q-griffithsin (q-grft) in rectal tissue samples from rhesus macaques. e-cadherin+ cells, cd4+ cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. variations in cell numbers between baseline ...201931792342
trio deep-sequencing does not reveal unexpected off-target and on-target mutations in cas9-edited rhesus monkeys.crispr-cas9 is a widely-used genome editing tool, but its off-target effect and on-target complex mutations remain a concern, especially in view of future clinical applications. non-human primates (nhps) share close genetic and physiological similarities with humans, making them an ideal preclinical model for developing cas9-based therapies. however, to our knowledge no comprehensive in vivo off-target and on-target assessment has been conducted in nhps. here, we perform whole genome trio sequen ...201931797925
igg fc-binding motif-conjugated hiv-1 fusion inhibitor exhibits improved potency and in vivo half-life: potential application in combination with broad neutralizing antibodies.the clinical application of conventional peptide drugs, such as the hiv-1 fusion inhibitor enfuvirtide, is limited by their short half-life in vivo. to overcome this limitation, we developed a new strategy to extend the in vivo half-life of a short hiv-1 fusion inhibitory peptide, cp24, by fusing it with the human igg fc-binding peptide (ibp). the newly engineered peptide ibp-cp24 exhibited potent and broad anti-hiv-1 activity with ic50 values ranging from 0.2 to 173.7 nm for inhibiting a broad ...201931805154
comparing the efficacy of an anti-human vegf-a neutralizing antibody versus bevacizumab on a laser-induced choroidal neovascularization (cnv) rhesus monkey model.to evaluate the efficacy of a therapy on improving characteristics of laser-induced choroidal neovascularization (cnv) via single intravitreal injection of a humanized anti-human vegf monoclonal antibody (pro-169) versus bevacizumab in a rhesus monkey model.201931806932
deconstructing sociality: the types of social connections that predict longevity in a group-living primate.many species use social interactions to cope with challenges in their environment and a growing number of studies show that individuals which are well-connected to their group have higher fitness than socially isolated individuals. however, there are many ways to be 'well-connected' and it is unclear which aspects of sociality drive fitness benefits. being well-connected can be conceptualized in four main ways: individuals can be socially integrated by engaging in a high rate of social behaviour ...201931822256
rectal microbiome composition correlates with humoral immunity to hiv-1 in vaccinated rhesus macaques.the microbiome is an integral and dynamic component of the host and is emerging as a critical determinant of immune responses; however, its influence on vaccine immunogenicity is largely not well understood. here, we examined the pivotal relationship between the mucosal microbiome and vaccine-induced immune responses by assessing longitudinal changes in vaginal and rectal microbiome profiles after intradermal immunization with a human immunodeficiency virus type 1 (hiv-1) dna vaccine in adult rh ...201931826975
mrsa strains in nepalese rhesus macaques (macaca mulatta) and their environment.this study looked at 227 saliva samples from rhesus macaques (macaca mulatta) and 218 samples from the surrounding environments. from these samples, mrsa isolates were collected from rhesus saliva samples (n = 13) and environmental samples (n = 19) near temple areas in kathmandu, nepal. for comparison, selected mrsa isolates (n = 5) were obtained from patients with wound infections from a kathmandu hospital. all isolates were characterized using abbott staphytype® dna microarrays. eighteen isola ...201931827462
bioinformatic analysis of peripheral blood rna-sequencing sensitively detects the cause of late graft loss following overt hyperglycemia in pig-to-nonhuman primate islet xenotransplantation.clinical islet transplantation has recently been a promising treatment option for intractable type 1 diabetes patients. although early graft loss has been well studied and controlled, the mechanisms of late graft loss largely remains obscure. since long-term islet graft survival had not been achieved in islet xenotransplantation, it has been impossible to explore the mechanism of late islet graft loss. fortunately, recent advances where consistent long-term survival (≥6 months) of adult porcine ...201931827198
alzheimer's-like pathology in aging rhesus macaques: unique opportunity to study the etiology and treatment of alzheimer's disease.although mouse models of alzheimer's disease (ad) have provided tremendous breakthroughs, the etiology of later onset ad remains unknown. in particular, tau pathology in the association cortex is poorly replicated in mouse models. aging rhesus monkeys naturally develop cognitive deficits, amyloid plaques, and the same qualitative pattern and sequence of tau pathology as humans, with tangles in the oldest animals. thus, aging rhesus monkeys can play a key role in ad research. for example, aging m ...201931871209
oligomeric aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging.as the average age of the population continues to rise, the number of individuals affected with age-related cognitive decline and alzheimer's disease (ad) has increased and is projected to cost more than $290 billion in the united states in 2019. despite significant investment in research over the last decades, there is no effective treatment to prevent or delay ad progression. there is a translational gap in ad research, with promising drugs based on work in rodent models failing in clinical tr ...201931871145
infant rhesus macaque (macaca mulatta) personality and subjective well-being.infant temperament is theorized to lay the foundation for adult personality; however, many questions remain regarding personality in infancy, including the number of dimensions, extent to which they are adult-like, and their relation to other outcomes, such as mental and physical health. here we tested whether adult-like personality dimensions are already present in infancy in a nonhuman primate species. we measured personality and subjective well-being in 7-month-old rhesus macaques (n = 55) us ...201931856210
inferring synaptic inputs from spikes with a conductance-based neural encoding model.descriptive statistical models of neural responses generally aim to characterize the mapping from stimuli to spike responses while ignoring biophysical details of the encoding process. here, we introduce an alternative approach, the conductance-based encoding model (cbem), which describes a mapping from stimuli to excitatory and inhibitory synaptic conductances governing the dynamics of sub-threshold membrane potential. remarkably, we show that the cbem can be fit to extracellular spike train da ...201931850846
characterization of a live-attenuated hcmv-based vaccine platform.vaccines based on cytomegalovirus (cmv) demonstrate protection in animal models of infectious disease and cancer. vaccine efficacy is associated with the ability of cmv to elicit and indefinitely maintain high frequencies of circulating effector memory t cells (tem) providing continuous, life-long anti-pathogen immune activity. to allow for the clinical testing of human cmv (hcmv)-based vaccines we constructed and characterized as a vector backbone the recombinant molecular clone tr3 representin ...201931848362
male morphological traits are heritable but do not predict reproductive success in a sexually-dimorphic primate.sexual selection favours traits that increase reproductive success via increased competitive ability, attractiveness, or both. male rhesus macaque (macaca mulatta) morphological traits are likely to reflect the effects of multiple sexual selection pressures. here, we use a quantitative genetic approach to investigate the production and maintenance of variation in male rhesus macaque morphometric traits which may be subject to sexual selection. we collected measurements of body size, canine lengt ...201931874959
[investigation of metabolism of hn-1 isolated from millettia pachyloba in vivo and in vitro].ultra-fast performance liquid chromatography-mass spectrometry( uflc-ms/ms) was used to study the anti-inflammatory active ingredient of millettia pachyloba,6-methoxy-8,8-dimethyl-3-( 2,4,5-trimethoxyphenyl)-4 h,8 h-pyrano[2,3-f]chromen-4-one( hn-1),in liver microsomes of rats,mice,rhesus monkeys,beagle dogs and humans metabolic stability,and compare the metabolic differences between different species. the metabolic phenotype in human liver microsomes was determined by chemical inhibitor method. ...201931872642
statin treatment prevents the development of pulmonary arterial hypertension in a nonhuman primate model of hiv-associated pah.pulmonary arterial hypertension (pah) is a life-threatening disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure, and right heart failure. human immunodeficiency virus (hiv)-infected individuals have a higher incidence of pah than the non-hiv infected population and evidence suggests a role for systemic and pulmonary inflammation in the pathogenesis of hiv-associated pah. due to their pleiotropic effects, including immune-modulatory and anti-inflammatory e ...201931882598
estrogen activates alzheimer's disease genes.women are at increased risk for alzheimer's disease (ad), but the reason why remains unknown. one hypothesis is that low estrogen levels at menopause increases vulnerability to ad, but this remains unproven.201931890855
outlining key inflammation-associated parameters during early phase of an experimental gram-negative sepsis model in rhesus macaques (macaca mulatta).the aim of this study was to identify inflammation-associated markers during the early phase of sepsis in rhesus macaque. four rhesus macaques were given an intravenous dose of 1010 cfu/kg of e. coli. blood samples were collected before, or 30 minutes, 2, 4, 6 and 8 hours after e. coli infusion. physiological parameters, bacteremia, endotoxemia, c-reactive protein (crp), procalcitonin (pct), and plasma cytokines/chemokines were determined for each animal. bacteremia was present in all animals fr ...201931942564
a practical method for creating targeted focal ischemic stroke in the cortex of nonhuman primates.ischemic stroke is a major cause of disability among adults worldwide. despite its prevalence, few effective treatment options exist to alleviate sensory and motor dysfunctions that result from stroke. in the past, rodent models of stroke have been the primary experimental models used to develop stroke therapies. however, positive results in these studies have failed to replicate in human clinical trials, highlighting the importance of nonhuman primate (nhp) models as a preclinical step. althoug ...201931946636
the role of protein and free amino acids on intake, metabolism, and gut microbiome: a comparison between breast-fed and formula-fed rhesus monkey infants.background: compared to breast-fed (bf), formula-fed (ff) infants exhibit more rapid weight gain, a different fecal microbial profile, as well as elevated serum insulin, insulin growth factor 1 (igf-1), and branched chain amino acids (bcaas). since infant formula contains more protein and lower free amino acids than breast milk, it is thought that protein and/or free amino acids may be key factors that explain phenotypic differences between bf and ff infants. methods: newborn rhesus monkeys (mac ...201932039120
peripherally administered kp-10 prevents development of insulin-induced hypoglycemic shock in diabetic rhesus monkeys.this study investigated whether kisspeptin-10 (kp-10) prevents diabetic rhesus monkeys from insulin-induced hypoglycemic shock.201931896266
quantification of viral rna and dna positive cells in tissues from simian immunodeficiency virus/simian human immunodeficiency virus infected controller and progressor rhesus macaques.eradication of human immunodeficiency virus 1 (hiv-1) from an infected individual cannot be achieved using current antiretroviral therapy (art) regimens. viral reservoirs established in early infection remain unaffected by art and are able to replenish systemic infection upon treatment interruption. simian immunodeficiency virus (siv) infected macaque models are useful for studying hiv pathogenesis, treatments, and persistent viral reservoirs. here, we used the siv macaque model to examine and q ...201931921088
reelin immunoreactivity in the adult spinal cord: a comparative study in rodents, carnivores, and non-human primates.reelin is a large extracellular matrix (ecm) glycoprotein secreted by several neuronal populations in a specific manner in both the developing and the adult central nervous system. the extent of reelin protein distribution and its functional role in the adult neocortex is well documented in different mammal models. however, its role in the adult spinal cord has not been well characterized and its distribution in the rodent spinal cord is fragmentary and has not been investigated in carnivores or ...201931969808
overexpression of cd6 and pd-1 identifies dysfunctional cd8+ t-cells during chronic siv infection of rhesus macaques.effective cd8+ t-cell responses play an important role in determining the course of siv/hiv viral infection. here we identified a unique population of dysfunctional cd8+ t-cells in lymphoid tissues and bronchoalveolar lavage (bal) of rhesus macaques with chronic siv infection characterized by co-expression of cd6 and pd-1. the frequency of cd6 and pd-1 co-expressing cd8+ t-cells was significantly increased in lymphoid tissues and bal during chronic siv infection compared to pre-infection levels. ...201931998302
analysis of carboxylesterase 2 transcript variants in cynomolgus macaque liver.carboxylesterase (ces) is important for the detoxification of a wide range of drugs and xenobiotics. in this study, the hepatic level of ces2 mrna was examined in cynomolgus macaques used widely in preclinical studies for drug metabolism. three ces2 mrnas were present in cynomolgus macaque liver. the mrna level was highest for cynomolgus ces2a (formerly ces2v3), much lower for cynomolgus ces2b (formerly ces2v1) and extremely low for cynomolgus ces2c (formerly ces2v2). most various transcript var ...201929384423
functional mait cells are associated with reduced simian-human immunodeficiency virus infection.mucosa-associated invariant t (mait) cells are recently characterized as a novel subset of innate-like t cells that recognize microbial metabolites as presented by the mhc-1b-related protein mr1. the significance of mait cells in anti-bacterial defense is well-understood but not clear in viral infections such as siv/hiv infection. here we studied the phenotype, distribution, and function of mait cells and their association with plasma viral levels during chronic shiv infection in rhesus macaques ...201932010135
network models predict that pyramidal neuron hyperexcitability and synapse loss in the dlpfc lead to age-related spatial working memory impairment in rhesus monkeys.behavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. persistent activity of layer 3 pyramidal dorsolateral prefrontal cortex (dlpfc) neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. in vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial w ...201932009920
refining the ecological brain: strong relation between the ventromedial prefrontal cortex and feeding ecology in five primate species.to survive in complex and seasonal environments, primates are thought to rely upon cognitive capacities such as decision-making and episodic memory, which enable them to plan their daily foraging path. according to the ecological brain hypothesis, feeding ecology has driven the expansion of the brain to support the corresponding development of cognitive skills. recent works in cognitive neurosciences indicate that cognitive operations such as decision-making or subjective evaluation (which are c ...201931030897
frontal eye field inactivation reduces saccade preparation in the superior colliculus but does not alter how preparatory activity relates to saccades of a given latency.a neural correlate for saccadic reaction times (srts) in the gap saccade task is the level of low-frequency activity in the intermediate layers of the superior colliculus (isc) just before visual target onset: greater levels of such preparatory isc low-frequency activity precede shorter srts. the frontal eye fields (fefs) are one likely source of isc preparatory activity, since fef preparatory activity is also inversely related to srt. to better understand the fef's role in saccade preparation, ...201929766038
uncoupling the widespread occurrence of anti-nmdar1 autoantibodies from neuropsychiatric disease in a novel autoimmune model.autoantibodies of the igg class against n-methyl-d-aspartate-receptor subunit-nr1 (nmdar1-ab) were considered pathognomonic for anti-nmdar encephalitis. this view has been challenged by the age-dependent seroprevalence (up to >20%) of functional nmdar1-ab of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. these findings question a merely encephalitogenic role of nmdar1-ab. here, we show that nmdar1-ab belong to the normal autoimmune repertoire of ...201929426955
porcine endothelial grafts could survive for a long term without using systemic immunosuppressors: an investigation of feasibility and efficacy of xeno-descemet's stripping automated endothelial keratoplasty from wzs-pig to rhesus monkey.in current non-human primate models, full-thickness porcine grafts could not achieve long-term survival without using potent systemic immunosuppressors. moreover, the thickness disparity in xeno-pkp proved to be hard to manipulate and may cause several complications which also could prevent the grafts from long survival. considering the advantages of descemet's stripping automated endothelial keratoplasty (dsaek) derived from its ultrathin graft and lower rejection rate, we hypothesize xeno-dsae ...201929932259
an exploration of the relationships among facial dimensions, age, sex, dominance status, and personality in rhesus macaques (macaca mulatta).aspects of personality in nonhuman primates have been linked to health, social relationships, and life history outcomes. in humans as well as nonhuman primates, facial morphology is associated with assertiveness, aggression, and measures of dominance status. in this study we aimed to examine the relationship among facial morphology, age, sex, dominance status, and ratings on the personality dimensions confidence, openness, assertiveness, friendliness, activity, and anxiety in rhesus macaques (ma ...201932747846
[stimulation of cognitive abilities in aged macaques by moderate hypobaric hypoxia.]the importance of studying neurological and mental changes in aged non-human primates, in particular rhesus macaques (macaca mulatta), is due to their genetic and physiological similarity with humans, which in preclinical studies of age-dependent cognitive decline correction makes them preferable to rodents. in this paper we study the behavior of three older monkeys in solving conditioned-reflex task of image differentiation. the obtained values of several cognitive characteristics were compared ...201930877829
immunochemical analysis of the expression of sv2c in mouse, macaque and human brain.the synaptic vesicle glycoprotein 2c (sv2c) is an undercharacterized protein with enriched expression in phylogenetically old brain regions. its precise role within the brain is unclear, though various lines of evidence suggest that sv2c is involved in the function of synaptic vesicles through the regulation of vesicular trafficking, calcium-induced exocytosis, or synaptotagmin function. sv2c has been linked to multiple neurological disorders, including parkinson's disease and psychiatric condit ...201929274878
transformation of visual representations across ventral stream body-selective patches.although the neural processing of visual images of bodies is critical for survival, it is much less well understood than face processing. functional imaging studies demonstrated body selective regions in primate inferior temporal cortex. to advance our understanding of how the visual brain represents bodies, we compared the representation of animate and inanimate objects in two such body patches with fmri-guided single unit recordings in rhesus monkeys. we found that the middle superior temporal ...201929186363
a trivalent hcv vaccine elicits broad and synergistic polyclonal antibody response in mice and rhesus monkey.despite the development of highly effective direct-acting antivirals, a prophylactic vaccine is needed for eradicating hcv. a major hurdle of hcv vaccine development is to induce immunity against hcv with high genome diversity. we previously demonstrated that a soluble e2 (se2) expressed from insect cells induces broadly neutralising antibodies (nabs) and prevents hcv infection. the objective of this study is to develop a multivalent hcv vaccine to increase the antigenic coverage.201929180585
lifespan trajectories of white matter changes in rhesus monkeys.progress in neurodevelopmental brain research has been achieved through the use of animal models. such models not only help understanding biological changes that govern brain development, maturation and aging, but are also essential for identifying possible mechanisms of neurodevelopmental and age-related chronic disorders, and to evaluate possible interventions with potential relevance to human disease. genetic relationship of rhesus monkeys to humans makes those animals a great candidate for s ...201929701751
microglia: an intrinsic component of the proliferative zones in the fetal rhesus monkey (macaca mulatta) cerebral cortex.microglial cells are increasingly recognized as modulators of brain development. we previously showed that microglia colonize the cortical proliferative zones in the prenatal brain and regulate the number of precursor cells through phagocytosis. to better define cellular interactions between microglia and proliferative cells, we performed lentiviral vector-mediated intraventricular gene transfer to induce enhanced green fluorescent protein expression in fetal cerebrocortical cells. tissues were ...201929992243
gdnf revisited: a novel mammalian cell-derived variant form of gdnf increases dopamine turnover and improves brain biodistribution.parkinson's disease (pd) is a disorder affecting dopamine neurons for which there is no cure. glial cell line-derived neurotrophic factor (gdnf) and the closely related protein neurturin are two trophic factors with demonstrated neuroprotective and neurorestorative properties on dopamine neurons in multiple animal species. however, gdnf and neurturin phase-2 clinical trials have failed to demonstrate a significant level of improvement over placebo controls. insufficient drug distribution in the ...201929857941
neuronal connections of direct and indirect pathways for stable value memory in caudal basal ganglia.direct and indirect pathways in the basal ganglia work together for controlling behavior. however, it is still a controversial topic whether these pathways are segregated or merged with each other. to address this issue, we studied the connections of these two pathways in the caudal parts of the basal ganglia of rhesus monkeys using anatomical tracers. our previous studies showed that the caudal basal ganglia control saccades by conveying long-term values (stable values) of many visual objects t ...201929737578
social status predicts response to dietary cycling in female rhesus monkeys.with the prevalence of obesity among women the united states surpassing 40%, it is critical to understand how environmental factors influence appetite, body fat accumulation, and the ability to lose weight and maintain weight loss. psychosocial stress exposure is a risk factor for increased consumption of calorically dense diets (cdd), which are high in fat and sugars and promote both increased food intake and weight gain. however, it remains unclear how appetite is affected by psychosocial fact ...201930032952
in vitro and in vivo models of hiv latency.latently infected cells are very infrequent in cd4+ t cells from antiretroviral (arv) treated individuals, with only approximately one in a million infected cd4+ t cells in blood. given the low frequency of infected cells in vivo, multiple in vitro latency models have been developed to facilitate investigations into mechanisms of hiv latency, as well as to enable the evaluation of pharmacological and immunological interventions aimed at depleting latently infected cells. these in vitro models in ...201930030796
monkey models and hiv vaccine research.since the discovery of acquired immunodeficiency syndrome (aids) in 1981, it has been extremely difficult to develop an effective vaccine or a therapeutic cure despite over 36 years of global efforts. one of the major reasons is due to the lack of an immune-competent animal model that supports live human immunodeficiency virus (hiv) infection and disease progression such that vaccine-induced correlates of protection and efficacy can be determined clearly before human trials. nevertheless, rhesus ...201930030791
new minipromoter ple345 (nefl) drives strong and specific expression in retinal ganglion cells of mouse and primate retina.retinal gene therapy is leading the neurological gene therapy field, with 32 ongoing clinical trials of recombinant adeno-associated virus (raav)-based therapies. importantly, over 50% of those trials are using restricted promoters from human genes. promoters that restrict expression have demonstrated increased efficacy and can limit the therapeutic to the target cells thereby reducing unwanted off-target effects. retinal ganglion cells are a critical target in ocular gene therapy; they are invo ...201930062914
nonnavigational spatial memory performance is unaffected by hippocampal damage in monkeys.evidence that the hippocampus is critical for spatial memory in nonnavigational tests is mixed. a recent study reported that temporary hippocampal inactivation impaired spatial memory in the nonnavigational hamilton search task in monkeys. however, several studies have documented no impairment on other nonnavigational spatial memory tests following permanent hippocampal lesions. it was hypothesized that transient, but not permanent, hippocampal disruption produces deficits because monkeys underg ...201930069946
age-related seroprevalence of antibodies against aav-lk03 in a uk population cohort.recombinant adeno-associated virus (raav) vectors are a promising platform for in vivo gene therapy. the presence of neutralizing antibodies (nab) against aav capsids decreases cell transduction efficiency and is a common exclusion criterion for participation in clinical trials. novel engineered capsids are being generated to improve gene delivery to the target cells and facilitate success of clinical trials; however, the prevalence of antibodies against such capsids remains largely unknown. we ...201930027761
macaque parvocellular mediodorsal thalamus: dissociable contributions to learning and adaptive decision-making.distributed brain networks govern adaptive decision-making, new learning and rapid updating of information. however, the functional contribution of the rhesus macaque monkey parvocellular nucleus of the mediodorsal thalamus (mdpc) in these key higher cognitive processes remains unknown. this study investigated the impact of mdpc damage in cognition. preoperatively, animals were trained on an object-in-place scene discrimination task that assesses rapid learning of novel information within each s ...201930022540
behavioral impact of long-term chronic implantation of neural recording devices in the rhesus macaque.ensemble recording methods are pervasive in basic and clinical neuroscience research. invasive neural implants are used in patients with drug resistant epilepsy to localize seizure origin, in neuropsychiatric or parkinson's patients to alleviate symptoms via deep brain stimulation, and with animal models to conduct basic research. studies addressing the brain's physiological response to chronic electrode implants demonstrate that the mechanical trauma of insertion is followed by an acute inflamm ...201930016006
convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei of nonhuman primates.muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function.201929931364
haplodeletion of follistatin-like 1 attenuates radiation-induced pulmonary fibrosis in mice.radiation-induced pulmonary fibrosis (ripf) is a severe and life-threatening complication of radiation therapy in patients with thoracic cancer; however, the exact molecular mechanisms remain unknown, and there is no effective treatment method in clinic. here, we assessed the role of follistatin-like 1 (fstl1) in ripf.201930171878
interindividual differences in neonatal sociality and emotionality predict juvenile social status in rhesus monkeys.in humans, socioeconomic status (ses) has profound outcomes on socio-emotional development and health. however, while much is known about the consequences of ses, little research has examined the predictors of ses due to the longitudinal nature of such studies. we sought to explore whether interindividual differences in neonatal sociality, temperament, and early social experiences predicted juvenile social status in rhesus monkeys (macaca mulatta), as a proxy for ses in humans. we performed neon ...201930171780
evaluation of a pet radioligand to image o-glcnacase in brain and periphery of rhesus monkey and knock-out mouse.accumulation of hyperphosphorylated tau, a microtubule-associated protein, plays an important role in the progression of alzheimer disease. animal studies suggest that one strategy for treating alzheimer disease and related tauopathies may be inhibition of o-glcnacase (oga), which may subsequently decrease pathologic tau phosphorylation. here, we report the pharmacokinetics of a novel pet radioligand, 18f-lsn3316612, which binds with high affinity and selectivity to oga. methods: pet imaging was ...201930213846
the effects of breastfeeding versus formula-feeding on cerebral cortex maturation in infant rhesus macaques.breastfeeding is positively associated with several outcomes reflecting early brain development and cognitive functioning. brain neuroimaging studies have shown that exclusively breastfed children have increased white matter and subcortical gray matter volume compared to formula-fed children. however, it is difficult to disentangle the effects of nutrition in breast milk from other confounding factors that affect brain development, particularly in studies of human subjects. among the nutrients p ...201930201462
ascites formation accompanied by portal vein thrombosis after porcine islet xenotransplantation via the portal vein in rhesus macaque (macaca mulatta).pig-to-nonhuman primate (nhp) islet transplantation has been widely conducted as a preclinical xenotransplantation model prior to human clinical trial. portal vein thrombosis is one of the complications associated with islet infusion through the portal vein into the liver. here, we briefly report severe case of ascites formation accompanied by portal vein thrombi after pig-to-nhp islet xenotransplantation in a rhesus monkey. meticulous prophylactic treatment such as continuous heparin infusion s ...201930194788
effects of long-term high-fat food or methamphetamine intake and serotonin 2c receptors on reversal learning in female rhesus macaques.perseverative behavior has been highly implicated in addiction. activation of serotonin 2c receptors (5-ht2crs) attenuates cocaine and high caloric food intake, but whether a 5-ht2cr agonist can reduce high caloric diet (hcd) or methamphetamine (meth) intake and response perseveration remains unknown. clarifying the role of 5-ht2crs in these behaviors will improve knowledge of neurochemical processes that regulate flexible decision-making and whether improvements in decision-making are accompani ...201930188516
joint representation of connectome-scale structural and functional profiles for identification of consistent cortical landmarks in macaque brain.discovery and representation of common structural and functional cortical architectures has been a significant yet challenging problem for years. due to the remarkable variability of structural and functional cortical architectures in human brain, it is challenging to jointly represent a common cortical architecture which can comprehensively encode both structure and function characteristics. in order to better understand this challenge and considering that macaque monkey brain has much less var ...201930178424
uteroplacental and fetal 4d flow mri in the pregnant rhesus macaque.pregnancy complications are often associated with poor uteroplacental vascular adaptation and standard diagnostics are unable to reliably quantify flow in all uteroplacental vessels and have poor sensitivity early in gestation.201930102431
low cognitive flexibility as a risk for heavy alcohol drinking in non-human primates.chronic alcohol abuse is frequently considered a habitual or inflexible behavior; however, measures of pre-existing cognitive flexibility prior to initiation of alcohol use are usually not available. this study used rhesus monkeys and an attentional set-shifting task to investigate whether pre-existing cognitive flexibility would predict increased risk for heavy alcohol drinking. as previously reported, monkeys were given 30 daily set-shifting sessions prior to alcohol access. these sessions con ...201930097387
exploring the neuromechanism of chronic ephedrine addiction in rhesus monkeys: a behavioural and brain resting-state fmri study.ephedrine is thought to exert behavioural effects primarily through actions on the central nervous system. however, the neuromechanism underlying the effects of ephedrine addiction still remains unclear. our study aimed to establish chronic ephedrine addiction models in rhesus monkeys and to investigate the neuromechanism of chronic ephedrine addiction using the behavioural methods combined with resting-state blood oxygenation level dependent-functional magnetic resonance imaging (bold-fmri). mo ...201930059694
plasmodium 18s rrna of intravenously administered sporozoites does not persist in peripheral blood.plasmodium 18s rrna is a biomarker used to monitor blood-stage infections in malaria clinical trials. plasmodium sporozoites also express this biomarker, and there is conflicting evidence about how long sporozoite-derived 18s rrna persists in peripheral blood. if present in blood for an extended timeframe, sporozoite-derived 18s rrna could complicate use as a blood-stage biomarker.201830053881
radiolabel validation of cortisol in the hair of rhesus monkeys.analysis of cortisol in hair has become a widespread tool for assessment of hypothalamic-pituitary-adrenal (hpa) axis activity because of its ease of collection and its ability to provide cumulative data over a period of months. in order to meaningfully interpret hair cortisol, however a direct validation by radio-metabolism is required to understand cortisol incorporation into hair. tritiated [3h]-cortisol was iv administered to adult rhesus monkeys to determine 1) if [3h] is found in the hair ...201830053699
human polyclonal antibodies produced by transchromosomal cattle provide partial protection against lethal zaire ebolavirus challenge in rhesus macaques.antibody therapy has been used to treat a variety of diseases and the success of zmapp and other monoclonal antibody-based therapies during the 2014-2016 west african ebola outbreak has shown this countermeasure can be a successful therapy for ebola hemorrhagic fever. this study utilized transchromosomal bovines (tcb) vaccinated with a dna plasmid encoding ebola virus glycoprotein sequence to produce human polyclonal antibodies directed against ebola virus glycoprotein. when administered 1 day p ...201830053153
new insights into marburg virus disease pathogenesis in the rhesus macaque model.previously, several studies have been performed to delineate the development and progression of marburg virus infection in nonhuman primates (nhps), primarily to clarify the mechanisms of severe (fatal) disease. after the 2013-2016 ebola virus disease (evd) epidemic in western africa, there has been a reassessment of the available filovirus animal models and the utility of these to faithfully recapitulate human disease. the high lethality of the nhp models has raised doubts as to their ability t ...201830053050
focal optogenetic suppression in macaque area mt biases direction discrimination and decision confidence, but only transiently.insights from causal manipulations of brain activity depend on targeting the spatial and temporal scales most relevant for behavior. using a sensitive perceptual decision task in monkeys, we examined the effects of rapid, reversible inactivation on a spatial scale previously achieved only with electrical microstimulation. inactivating groups of similarly tuned neurons in area mt produced systematic effects on choice and confidence. behavioral effects were attenuated over the course of each sessi ...201830051817
beneficial effects of human anti-interleukin-15 antibody in gluten-sensitive rhesus macaques with celiac disease.overexpression of interleukin-15 (il-15) is linked with immunopathology of several autoimmune disorders including celiac disease. here, we utilized an anti-human il-15 antibody 04h04 (anti-il-15) to reverse immunopathogenesis of celiac disease. anti-il-15 was administered to six gluten-sensitive rhesus macaques with celiac disease characteristics including gluten-sensitive enteropathy (gse), and the following celiac-related metrics were evaluated: morphology (villous height/crypt depth ratio) of ...201830050538
the rhesus monkey hippocampus critically contributes to scene memory retrieval, but not new learning.humans can recall a large number of memories years after the initial events. patients with amnesia often have lesions to the hippocampus, but human lesions are imprecise, making it difficult to identify the anatomy underlying memory impairments. rodent studies enable great precision in hippocampal manipulations, but not investigation of many interleaved memories. thus it is not known how lesions restricted to the hippocampus affect the retrieval of multiple sequentially encoded memories. further ...201830049888
xenoantigen deletion and chemical immunosuppression can prolong renal xenograft survival.xenotransplantation using pig organs could end the donor organ shortage for transplantation, but humans have xenoreactive antibodies that cause early graft rejection. genome editing can eliminate xenoantigens in donor pigs to minimize the impact of these xenoantibodies. here we determine whether an improved cross-match and chemical immunosuppression could result in prolonged kidney xenograft survival in a pig-to-rhesus preclinical model.201830048323
evaluation of a mosaic hiv-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (approach) and in rhesus monkeys (nhp 13-19).more than 1·8 million new cases of hiv-1 infection were diagnosed worldwide in 2016. no licensed prophylactic hiv-1 vaccine exists. a major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. we aimed to evaluate mosaic adenovirus serotype 26 (ad26)-based hiv-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials.201830047376
figure and ground: how the visual cortex integrates local cues for global organization.inferring figure-ground organization in two-dimensional images may require different complementary strategies. for isolated objects, it has been shown that mechanisms in visual cortex exploit the overall distribution of contours, but in images of cluttered scenes where the grouping of contours is not obvious, that strategy would fail. however, natural scenes contain local features, specifically contour junctions, that may contribute to the definition of object regions. to study the role of local ...201830044171
clonal expansion of mitochondrial dna deletions is a private mechanism of aging in long-lived animals.disruption of mitochondrial metabolism and loss of mitochondrial dna (mtdna) integrity are widely considered as evolutionarily conserved (public) mechanisms of aging (lópez-otín et al., cell, 153, 2013 and 1194). human aging is associated with loss in skeletal muscle mass and function (sarcopenia), contributing significantly to morbidity and mortality. muscle aging is associated with loss of mtdna integrity. in humans, clonally expanded mtdna deletions colocalize with sites of fiber breakage and ...201830043489
in vivo imaging of inflammation and oxidative stress in a nonhuman primate model of cardiac sympathetic neurodegeneration.loss of cardiac postganglionic sympathetic innervation is a characteristic pathology of parkinson's disease (pd). it progresses over time independently of motor symptoms and is not responsive to typical anti-parkinsonian therapies. cardiac sympathetic neurodegeneration can be mimicked in animals using systemic dosing of the neurotoxin 6-hydroxydopamine (6-ohda). as in pd, 6-ohda-induced neuronal loss is associated with increased inflammation and oxidative stress. to assess the feasibility of det ...201830038956
assessment of bias in morphological identification of carnivore scats confirmed with molecular scatology in north-eastern himalayan region of pakistan.scats are often used to study ecological parameters of carnivore species. however, field identification of carnivore scats, based on their morphological characteristics, becomes difficult if many carnivore species are distributed in the same area. we assessed error rates in morphological identification of five sympatric carnivores' scats in north-eastern himalayan region of pakistan during 2013-2017. a sample of 149 scats were subjected to molecular identification using fecal dna. we used a conf ...201830038872
correlations between primary motor cortex activity with recent past and future limb motion during unperturbed reaching.many studies highlight that human movements are highly successful yet display a surprising amount of variability from trial to trial. there is a consistent pattern of variability throughout movement: initial motor errors are corrected by the end of movement, suggesting the presence of a powerful online control process. here, we analyze the trial-by-trial variability of goal-directed reaching in nonhuman primates (five male rhesus monkeys) and demonstrate that they display a similar pattern of va ...201830037832
live rubella vectors can express native hiv envelope glycoproteins targeted by broadly neutralizing antibodies and prime the immune response to an envelope protein boost.following hiv infection, most people make antibodies to gp120 and gp41, yet only a few make broadly neutralizing antibodies that target key antigenic sites on the envelope glycoproteins. the induction of broadly neutralizing antibodies by immunization remains a major challenge of hiv vaccine research. difficulties include: variable protein sequence, epitopes that depend on the native conformation, glycosylation that conceals key antigenic determinants, and the assembly of env trimers that mimic ...201830037665
tissue engineering using 3d printed nano-bioactive glass loaded with nell1 gene for repairing alveolar bone defects.the purposes of this study were to construct a novel tissue engineered bone composed of 3d-printed bioactive glass block/chitosan nanoparticles (bd/csn) composites loaded with nel-like type i molecular-1 dna (pdna-nell1) and/or bone marrow mesenchymal stem cells (bmscs), and study their osteogenic activities by repairing bone defects in rhesus monkeys. csn with nell1 gene plasmid and rhesus monkey bmscs were composited with a bd scaffold to prepare the tissue-engineered bone. four adult female r ...201830094060
transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for hiv pre-exposure prophylaxis.pre-exposure prophylaxis (prep) with antiretroviral (arv) drugs are effective at preventing human immunodeficiency virus (hiv) transmission. however, implementation of prep presents significant challenges due to poor user adherence, low accessibility to arvs and multiple routes of hiv exposure. to address these challenges, we developed the nanochannel delivery implant (ndi), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (taf) and emtricitabine ( ...201830092254
adjuvant-dependent enhancement of hiv env-specific antibody responses in infant rhesus macaques.toward the goal of developing an effective hiv vaccine that can be administered in infancy to protect against postnatal and lifelong sexual hiv transmission risks, the current pilot study was designed to compare the effect of novel adjuvants on the induction of hiv env-specific antibody responses in infant macaques. aligning our studies with the adjuvanted proteins evaluated in a prime-boost schedule with alvac in the ongoing hvtn (hiv vaccine trials network) 702 efficacy trial, we selected the ...201830089691
long-term all-optical interrogation of cortical neurons in awake-behaving nonhuman primates.whereas optogenetic techniques have proven successful in their ability to manipulate neuronal populations-with high spatial and temporal fidelity-in species ranging from insects to rodents, significant obstacles remain in their application to nonhuman primates (nhps). robust optogenetics-activated behavior and long-term monitoring of target neurons have been challenging in nhps. here, we present a method for all-optical interrogation (aoi), integrating optical stimulation and simultaneous two-ph ...201830089111
emg characteristics of the external anal sphincter guarding reflex and effects of a unilateral ventral root avulsion injury in rhesus macaques ( macaca mulatta).the external anal sphincter (eas) is important for the maintenance of bowel continence and may be compromised by a variety of neuropathic conditions. however, large animal models for the study of eas functions have been sparse. the eas guarding reflex was examined by electromyography (emg) in neurologically intact rhesus macaques ( n = 6) and at 4-6 wk after a unilateral eas denervation from an l6-s3 ventral root avulsion (vra) injury ( n = 6). baseline eas emg recordings were quiescent in all s ...201830089020
orientation and contrast tuning properties and temporal flicker fusion characteristics of primate superior colliculus neurons.the primate superior colliculus is traditionally studied from the perspectives of gaze control, target selection, and selective attention. however, this structure is also visually responsive, and it is the primary visual structure in several species. thus, understanding the visual tuning properties of the primate superior colliculus is important, especially given that the superior colliculus is part of an alternative visual pathway running in parallel to the predominant geniculo-cortical pathway ...201830087598
transcriptome analysis of rhesus monkey failed-to-mature oocytes: deficiencies in transcriptional regulation and cytoplasmic maturation of the oocyte mrna population.which different pathways and functions are altered in rhesus monkey oocytes that fail to mature after an ovulatory stimulus?201830085220
early antiretroviral therapy limits siv reservoir establishment to delay or prevent post-treatment viral rebound.prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (rhcmv) vectors expressing simian immunodeficiency virus (siv) antigens (rhcmv/siv) elicits immune responses that stringently control highly pathogenic siv infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. in contrast, here, we show that therapeutic rhcmv/siv vaccination of rhesus macaques previously infected with siv and given continuous combination antiretroviral therapy (cart) beginning ...201830082858
behavioral effect of chemogenetic inhibition is directly related to receptor transduction levels in rhesus monkeys.we used inhibitory dreadds (designer receptors exclusively activated by designer drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlpfc) function in male rhesus monkeys. monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine-n-oxide (cno) or vehicle. cno injections given before dreadd transduction were without effect on behavior. raav5/hsyn-hm4di-mcherry was injected bilaterally into the dlpfc of five ...201830082415
learning the meaning of new stimuli increases the cross-correlated activity of prefrontal neurons.the prefrontal cortex (pf) has a key role in learning rules and generating associations between stimuli and responses also called conditional motor learning. previous studies in pf have examined conditional motor learning at the single cell level but not the correlation of discharges between neurons at the ensemble level. in the present study, we recorded from two rhesus monkeys in the dorsolateral and the mediolateral parts of the prefrontal cortex to address the role of correlated firing of si ...201830076326
deuterium kinetic isotope effect studies of a potential in vivo metabolic trapping agent for monoamine oxidase b.visualizing the in vivo activity of monoamine oxidase b (mao-b) is a valuable tool in the ongoing investigation of astrogliosis in neurodegeneration. existing strategies for imaging changes in mao enzyme expression or activity have utilized the irreversible suicide inhibitors or high-affinity reversibly binding inhibitors as positron emission tomography (pet) ligands. as an alternative approach, we developed 4-methyl-7-[(1-[11c]methyl-1,2,3,6-tetrahydropyridin-4-yl)oxy]-2 h-chromen-2-one ([11c]c ...201830074755
an isolated limb infusion method allows for broad distribution of raavrh74.mck.galgt2 to leg skeletal muscles in the rhesus macaque.recombinant adeno-associated virus (raav)rh74.mck.galgt2 is a muscle-specific gene therapy that is being developed to treat forms of muscular dystrophy. here we report on an isolated limb infusion technique in a non-human primate model, where hindlimb blood flow is transiently isolated using balloon catheters to concentrate vector in targeted leg muscles. a bilateral dose of 2.5 × 1013 vector genomes (vg)/kg/limb was sufficient to induce galgt2-induced glycosylation in 10%-60% of skeletal myofib ...201830073180
toxicology study of intra-cisterna magna adeno-associated virus 9 expressing human alpha-l-iduronidase in rhesus macaques.mucopolysaccharidosis type i is a recessive genetic disease caused by deficiency of the lysosomal enzyme α-l-iduronidase, which leads to a neurodegenerative and systemic disease called hurler syndrome in its most severe form. several clinical trials are evaluating adeno-associated virus serotype 9 (aav9) for the treatment of neurodegenerative diseases. although these trials focus on systemic or lumbar administration, intrathecal administration via suboccipital puncture into the cisterna magna ha ...201830073179
toxicology study of intra-cisterna magna adeno-associated virus 9 expressing iduronate-2-sulfatase in rhesus macaques.hunter syndrome is an x-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase. the severe form of this progressive, systemic, and neurodegenerative disease results in loss of cognitive skills and early death. several clinical trials are evaluating adeno-associated virus 9 for the treatment of neurodegenerative diseases using systemic or intrathecal lumbar administration. in large animals, administration via suboccipital puncture gives better brain transducti ...201830073178
primary myxoid liposarcoma of the greater omentum in a rhesus macaque (macaca mulatta).we here report a spontaneous case of primary myxoid liposarcoma of the greater omentum with subsequent transperitoneal recurrence. the primary mass was incidentally found during an exploratory laparotomy for a presumed diagnosis of trichobezoar or phytobezoar and was removed surgically. histopathologic examination of the mass revealed the presence of a myxoid liposarcoma. eleven months later, recurrence with severe transperitoneal sarcomatosis of the myxoid liposarcoma was noted and confirmed by ...201830071917
rapid nicotine tolerance and cross-tolerance to varenicline in rhesus monkeys: drug discrimination.acute tolerance to effects of nicotine plays an important role in nicotine dependence, but the mechanism underlying these effects is unclear. drug discrimination was used in the current study to examine the impact of nicotine pretreatment on sensitivity to the discriminative stimulus effects of nicotine and the fda-approved smoking cessation pharmacotherapy varenicline. rhesus monkeys (n = 4) discriminated 0.032 mg/kg nicotine base iv from saline under an fr5 schedule of stimulus-shock terminati ...201830102063
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