Juvenile Macaques Research Articles

Comparative assessment of the transduction efficiency and safety associated with the delivery of AAV9-GFP vector via lumbar puncture route to juvenile Cynomolgus Macaques with and without anti-AAV9 pre-existing antibodies

Comparative assessment of the transduction efficiency and safety associated with the delivery of AAV9-GFP vector via lumbar puncture route to juvenile Cynomolgus Macaques with and without anti-AAV9 pre-existing antibodies

Transiently boosting Vγ9+Vδ2+ γδ T cells early in Mtb coinfection of SIV-infected juvenile macaques does not improve Mtb host resistance.

Children living with HIV have a higher risk of developing tuberculosis (TB), a disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Gamma delta (γδ) T cells in the context of HIV/Mtb coinfection have been understudied in children despite in vitro evidence suggesting γδ T cells assist with Mtb control. We investigated whether boosting a specific subset of γδ T cells, phosphoantigen-reactive Vγ9+Vδ2+ cells, could improve TB outcome using a nonhuman primate model of pediatric HIV/Mtb coinfection. Juvenile Mauritian cynomolgus macaques (MCM), equivalent to 4- to 8-year-old children, were infected intravenously (i.v.) with SIV. After 6 months, MCM were coinfected with a low dose of Mtb and then randomized to receive zoledronate (ZOL), a drug that increases phosphoantigen levels, (n = 5; i.v.) at 3 and 17 days after Mtb accompanied by recombinant human IL-2 (s.c.) for 5 days following each ZOL injection. A similarly coinfected MCM group (n = 5) was injected with saline as a control. Vγ9+Vδ2+ γδ T cell frequencies spiked in the blood, but not airways, of ZOL+IL-2-treated MCM following the first dose, however, were refractory to the second dose. At necropsy 8 weeks after Mtb, ZOL+IL-2 treatment did not reduce pathology or bacterial burden. γδ T cell subset frequencies in granulomas did not differ between treatment groups. These data show that transiently boosting peripheral γδ T cells with ZOL+IL-2 soon after Mtb coinfection of SIV-infected MCM did not improve Mtb host defense.

Evaluating the Effect of a Probiotic on Prevention of Diarrhea, Stress Response, and Social Interactions in a Colony of Macaca fascicularis

Background: Social housing changes are associated with diarrhea in macaques, presumably due to stress. Objective: Since probiotics are utilized in humans for diarrhea, we tested the effectiveness of a species- specific probiotic, SDPro™ (composition: ~2 billion CFU each of live Lactobacillus reuteri and Saccharomyces boulardii), to prevent relocation-associated diarrhea. Assessments of the gutmicrobiome and diarrhea severity were made. Behavioral observations and cortisol levels were examined after relocation to test the effects of the probiotic treatment. Methods: The probiotic was administered to 60 juvenile macaques of both sexes (Probiotic +) and outcomes were compared to 60 control (Probiotic -) macaques. The effects on gut microbiome composition were analyzed via 16s microbiome analysis in half the animals from both groups. Social behaviors were monitored twice-weekly in the morning and afternoon for five weeks following 10- days of SDPro™ administration in 56 subjects and hair cortisol was assayed. Results: Probiotic administration altered beta, but not alpha, diversity, and caused changes in taxa abundance at the phylum, genus, and species levels. The Probiotic + group was enriched in Firmicutes, Clostridium, and Lactobacillus and diminished in Bacteriodies (p’s < 0.05) compared to controls. Although SDPro™ did not alter diarrhea incidence following relocation, it reduced diarrhea severity in males only. Males also exhibited higher cortisol levels than females but there was no probiotic effect. Probiotic treatment had minor behavioral effects; the typical reduction in locomotion seen in the afternoon was eliminated. Conclusion: The results suggest that SDPro™ may be a viable tool to prevent relocation-induced diarrhea in juvenile male macaques.

Transiently boosting Vγ9+Vδ2+ γδ T cells early in Mtb coinfection of SIV-infected juvenile macaques does not improve Mtb host resistance.

Children living with HIV have a higher risk of developing tuberculosis (TB), a disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Gamma delta (γδ) T cells in the context of HIV/Mtb coinfection have been understudied in children, despite in vitro evidence suggesting γδ T cells assist with Mtb control. We investigated whether boosting a specific subset of γδ T cells, phosphoantigen-reactive Vγ9+Vδ2+ cells, could improve TB outcome using a nonhuman primate model of pediatric HIV/Mtb coinfection. Juvenile Mauritian cynomolgus macaques (MCM), equivalent to 4-8-year-old children, were infected intravenously (i.v.) with SIV. After 6 months, MCM were coinfected with a low dose of Mtb and then randomized to receive zoledronate (ZOL), a drug that increases phosphoantigen levels, (n=5; i.v.) at 3- and 17- days after Mtb accompanied by recombinant human IL-2 (s.c.) for 5 days following each ZOL injection. A similarly coinfected MCM group (n=5) was injected with saline as a control. Vγ9+Vδ2+ γδ T cell frequencies spiked in the blood, but not airways, of ZOL+IL-2-treated MCM following the first dose, however, were refractory to the second dose. At necropsy eight weeks after Mtb, ZOL+IL-2 treatment did not reduce pathology or bacterial burden. γδ T cell subset frequencies in granulomas did not differ between treatment groups. These data show that transiently boosting peripheral γδ T cells with ZOL+IL-2 soon after Mtb coinfection of SIV-infected MCM did not improve Mtb host defense.

Visual Preference for Socially Relevant Spatial Relations in Humans and Monkeys.

As a powerful social signal, a body, face, or gaze facing toward oneself holds an individual's attention. We asked whether, going beyond an egocentric stance, facingness between others has a similar effect and why. In a preferential-looking time paradigm, human adults showed spontaneous preference to look at two bodies facing toward (vs. away from) each other (Experiment 1a, N = 24). Moreover, facing dyads were rated higher on social semantic dimensions, showing that facingness adds social value to stimuli (Experiment 1b, N = 138). The same visual preference was found in juvenile macaque monkeys (Experiment 2, N = 21). Finally, on the human development timescale, this preference emerged by 5 years, although young infants by 7 months of age already discriminate visual scenes on the basis of body positioning (Experiment 3, N = 120). We discuss how the preference for facing dyads-shared by human adults, young children, and macaques-can signal a new milestone in social cognition development, supporting processing and learning from third-party social interactions.

Bioactivity and efficacy of a hyperimmune bovine colostrum product- Travelan, against shigellosis in a non-Human primate model (Macaca mulatta)

Infectious diarrhea is a World Health Organization public health priority area due to the lack of effective vaccines and an accelerating global antimicrobial resistance crisis. New strategies are urgently needed such as immunoprophylactic for prevention of diarrheal diseases. Hyperimmune bovine colostrum (HBC) is an established and effective prophylactic for infectious diarrhea. The commercial HBC product, Travelan® (Immuron Ltd, Australia) targets multiple strains of enterotoxigenic Escherichia coli (ETEC) is highly effective in preventing diarrhea in human clinical studies. Although Travelan® targets ETEC, preliminary studies suggested cross-reactivity with other Gram-negative enteric pathogens including Shigella and Salmonella species. For this study we selected an invasive diarrheal/dysentery-causing enteric pathogen, Shigella, to evaluate the effectiveness of Travelan®, both in vitro and in vivo. Here we demonstrate broad cross-reactivity of Travelan® with all four Shigella spp. (S. flexneri, S. sonnei, S. dysenteriae and S. boydii) and important virulence factor Shigella antigens. Naïve juvenile rhesus macaques (NJRM) were randomized, 8 dosed with Travelan® and 4 with a placebo intragastrically twice daily over 6 days. All NJRM were challenged with S. flexneri 2a strain 2457T on the 4th day of treatment and monitored for diarrheal symptoms. All placebo-treated NJRM displayed acute dysentery symptoms within 24–36 hours of challenge. Two Travelan®-treated NJRM displayed dysentery symptoms and six animals remained healthy and symptom-free post challenge; resulting in 75% efficacy of prevention of shigellosis (p = 0.014). These results strongly indicate that Travelan® is functionally cross-reactive and an effective prophylactic for shigellosis. This has positive implications for the prophylactic use of Travelan® for protection against both ETEC and Shigella spp. diarrheal infections. Future refinement and expansion of pathogens recognized by HBC including Travelan® could revolutionize current management of gastrointestinal infections and outbreaks in travelers’ including military, peacekeepers, humanitarian workers and in populations living in endemic regions of the world.

Pharmacokinetics of cannabidiol-/cannabidiolic acid-rich hemp oil in juvenile cynomolgus macaques (Macaca fascicularis)

IntroductionCannabinoids are increasingly popular in human and veterinary medicine and have been studied as an alternative treatment for a wide range of disorders. The goal of this study was to perform a pharmacokinetic analysis of oral cannabidiol (CBD)-/cannabidiolic acid (CBDA)-rich hemp oil (CBD/ArHO) in juvenile cynomolgus macaques (Macaca fascicularis).MethodsAfter a 2 mg/kg CBD/ArHO pilot study, 4 and 8 mg/kg direct-to-mouth CBD/ArHO were administered (n = 4 per dose) once daily for 14 days and blood was collected at 0-, 0.5-, 1-, 2-, 4-, 8-, 12-, and 24-h, and on Days 7 and 14, to quantify serum cannabinoid concentrations by high-performance liquid chromatography–tandem mass spectrometry. Serum biochemistries and complete blood counts were performed on Days 0, 1, and 14.ResultsThe maximum mean serum concentration (Cmax) of CBDA was 28.6–36.2 times that of CBD at 4 and 8 mg/kg. At 8 mg/kg, the Cmax of CBD was 1.4 times higher (p = 0.0721), and CBDA was significantly 1.8 times higher (p = 0.0361), than at 4 mg/kg. The maximum mean serum concentration of ∆9-tetrahydrocannabinol (THC) was 4.80 ng/mL at 8 mg/kg. Changes in serum biochemistries and complete blood counts over time were not clinically significant.DiscussionGiven the low serum CBD concentrations, the doses and frequency used in this study may be insufficient for a therapeutic effect of CBD in particular; therefore, clinical studies are needed to determine the therapeutic dose of CBD and CBDA for macaques, which may differ based on the disorder targeted.

Conjugation of HIV-1 envelope to hepatitis B surface antigen alters vaccine responses in rhesus macaques

An effective HIV-1 vaccine remains a critical unmet need for ending the AIDS epidemic. Vaccine trials conducted to date have suggested the need to increase the durability and functionality of vaccine-elicited antibodies to improve efficacy. We hypothesized that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T cell help and improve antibody production against HIV-1. To test this, we developed an innovative conjugate vaccine regimen that used a modified vaccinia virus Ankara (MVA) co-expressing HIV-1 envelope (Env) and the hepatitis B virus surface antigen (HBsAg) as a prime, followed by two Env–HBsAg conjugate protein boosts. We compared the immunogenicity of this conjugate regimen to matched HIV-1 Env-only vaccines in two groups of 5 juvenile rhesus macaques previously immunized with hepatitis B vaccines in infancy. We found expansion of both HIV-1 and HBsAg-specific circulating T follicular helper cells and elevated serum levels of CXCL13, a marker for germinal center activity, after boosting with HBsAg–Env conjugate antigens in comparison to Env alone. The conjugate vaccine elicited higher levels of antibodies binding to select HIV Env antigens, but we did not observe significant improvement in antibody functionality, durability, maturation, or B cell clonal expansion. These data suggests that conjugate vaccination can engage both HIV-1 Env and HBsAg specific T cell help and modify antibody responses at early time points, but more research is needed to understand how to leverage this strategy to improve the durability and efficacy of next-generation HIV vaccines.

Prenatal Zika virus exposure is associated with lateral geniculate nucleus abnormalities in juvenile rhesus macaques.

Zika virus' neural tropism causes significant neural pathology, particularly in developing fetuses. One of the consistent findings from humans and animal models is that prenatal exposure to Zika virus (ZIKV) causes pathology in the eyes and visual pathways of the brain, although the extent to which this pathology persists over development is not clear. In the present report, we build upon our previous work which demonstrated that full-term rhesus monkey ( Macaca mulatta ) fetuses who were exposed to ZIKV early in gestation had significant pathological abnormalities to the organization of the lateral geniculate nucleus (LGN), a major hub of the visual network. The objective of the present work was to replicate those LGN findings and determine whether such pathology persisted across childhood development. We carried out histological analyses of the LGNs of two juvenile rhesus monkeys who were prenatally exposed to ZIKV and two age-matched controls. Pregnant rhesus monkeys were infected with ZIKV via the intravenous and intra-amniotic routes and tracked across development. Following sacrifice and perfusion, brains were subjected to quantitative neuroanatomical analyses with a focus on the size and structure of the LGN and its composite layers. Early fetal ZIKV exposure resulted in developmental abnormalities within the brains' visual pathway: specifically disorganization, blending of layers, laminar discontinuities, and regions of low cell density within the LGN. These abnormalities were not observed in the control animals. Our findings demonstrate that the ZIKV's damage to the LGN that occurs during fetal development persists into childhood.

Evaluation of tissue-engineered human acellular vessels as a Blalock–Taussig–Thomas shunt in a juvenile primate model

ObjectivesPalliative treatment of cyanotic congenital heart disease (CCHD) uses systemic-to-pulmonary conduits, often a modified Blalock–Taussig–Thomas shunt (mBTTs). Expanded polytetrafluoroethylene (ePTFE) mBTTs have associated risks for thrombosis and infection. The Human Acellular Vessel (HAV) (Humacyte, Inc) is a decellularized tissue-engineered blood vessel currently in clinical trials in adults for vascular trauma, peripheral artery disease, and end-stage renal disease requiring hemodialysis. In addition to restoring blood flow, the engineered HAV demonstrates the capacity for host cellular remodeling into native-like vasculature. Here we report preclinical evaluation of a small-diameter (3.5 mm) HAV as a mBTTs in a non-human primate model. MethodsWe implanted 3.5 mm HAVs as right subclavian artery to pulmonary artery mBTTs in non-immunosuppressed juvenile rhesus macaques (n = 5). HAV patency, structure, and blood flow were assessed by postoperative imaging from 1 week to 6 months. Histology of HAVs and surrounding tissues was performed. ResultsSurgical procedures were well tolerated, with satisfactory anastomoses, showing feasibility of using the 3.5 mm HAV as a mBTTs. All macaques had some immunological reactivity to the human extracellular matrix, as expected in this xenogeneic model. HAV mBTTs remained patent for up to 6 months in animals, exhibiting mild immunoreactivity. Two macaques displaying more severe immunoreactivity to the human HAV material developed midgraft dilatation without bleeding or rupture. HAV repopulation by host cells expressing smooth muscle and endothelial markers was observed in all animals. ConclusionsThese findings may support use of 3.5 mm HAVs as mBTTs in CCHD and potentially other pediatric vascular indications.

The long-term gut bacterial signature of a wild primate is associated with a timing effect of pre- and postnatal maternal glucocorticoid levels

BackgroundDuring development, elevated levels of maternal glucocorticoids (GCs) can have detrimental effects on offspring morphology, cognition, and behavior as well as physiology and metabolism. Depending on the timing of exposure, such effects may vary in strength or even reverse in direction, may alleviate with age, or may concern more stable and long-term programming of phenotypic traits. Maternal effects on gut bacterial diversity, composition, and function, and the persistence of such effects into adulthood of long-lived model species in the natural habitats remain underexplored.ResultsIn a cross-sectional sample of infant, juvenile, and adult Assamese macaques, the timing of exposure to elevated maternal GCs during ontogeny was associated with the gut bacterial community of the offspring. Specifically, naturally varying maternal GC levels during early but not late gestation or lactation were associated with reduced bacterial richness. The overall effect of maternal GCs during early gestation on the gut bacterial composition and function exacerbated with offspring age and was 10 times stronger than the effect associated with exposure during late prenatal or postnatal periods. Instead, variation in maternal GCs during the late prenatal or postnatal period had less pronounced or less stable statistical effects and therefore a weaker effect on the entire bacterial community composition, particularly in adult individuals. Finally, higher early prenatal GCs were associated with an increase in the relative abundance of several potential pro-inflammatory bacteria and a decrease in the abundance of Bifidobacterium and other anti-inflammatory taxa, an effect that exacerbated with age.ConclusionsIn primates, the gut microbiota can be shaped by developmental effects with strong timing effects on plasticity and potentially detrimental consequences for adult health. Together with results on other macaque species, this study suggests potential detrimental developmental effects similar to rapid inflammaging, suggesting that prenatal exposure to high maternal GC concentrations is a common cause underlying both phenomena. Our findings await confirmation by metagenomic functional and causal analyses and by longitudinal studies of long-lived, ecologically flexible primates in their natural habitat, including developmental effects that originate before birth.3d25Wu_1Je2mxjb-DcHdXZVideo

Pilot Study on Food-processing Behaviour by Males Long-tailed Macaques on Tinjil Island, Indonesia

Non-Human Primates (NHP) have a slow life history compared to other mammals due to their complex brain growth. Brain complexity correlates with behaviour complexity, especially feeding behaviour, which enables primates to have the capability in leaf processing step, tool use, or even food washing. Macaca fascicularis on Tinjil Island is one of the NHP species conducting food-cleaning behaviour. Thus, this study aims to figure out the food-cleaning behaviour differences across the age classes of juvenile and male long-tailed macaques (LTM). The feeding behaviour of two age classes of male LTM through 3 different types of food processing was analysed using focal animal sampling and instantaneous recording methods. Then, the data were statistically analysed using Mann-Whitney and Kruskal-Wallis. We found that both age classes used Step 1 of the processing food type more than other types. Analysis within each age class showed different results that juvenile male LTM had a higher frequency of Step 0 and lower frequency of Step 1 than adult male LTM and vice versa. The result indicates no significant differences in the three food type processing between juvenile and adult male LTM.

Transcriptomic changes in the hypothalamus of rhesus monkeys with bone marrow mesenchymal stem cells treatment

Background: It is acknowledged that the hypothalamus plays an important role in the regulation of aging, and bone marrow mesenchymal stem cells (BMSCs) possess an anti-aging effect, this study was therefore designed to investigate transcriptomic changes in the hypothalamus of aged rhesus monkeys with BMSCs-treatment to explore the underlying molecular mechanism for the anti-aging effect of BMSCs. Methods: Transcriptome profiling sequencing was conducted on the juvenile rhesus macaques (YN), adult rhesus macaques (QN), aged rhesus macaques (LN) and BMSCs-treated aged rhesus macaques (ZL). Then, differentially expressed genes (DEG) analysis was performed between YN and QN, QN and LN, LN and ZL, respectively. After the intersection of DEGs from these three pairs of comparisons, screened intersecting genes were subject to GO (Gene Ontology) enrichment analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and PPI (protein-protein interaction) analysis to explore their interactions and underlying mechanism of BMSCs for retarding aging. Lastly, according to the results of PPI and the most enriched GO term, we further integrated and screened genes, which were regarded as aging-related genes in the hypothalamus. Results: According to obtained transcriptome profiling data, 671 differentially expressed genes were screened between QN and YN, 1315 genes between LN and QN, and 1345 genes between ZL and LN. After intersecting, 53 genes were screened out. GO analysis showed that most genes were mainly enriched in intercellular adhesion, sphingosinol biosynthesis, ceramide biosynthesis in BP, while in the cell membrane group and Golgi membrane in CC. PPI suggested that SPTLC2, ASAH2, FA2H and other genes had higher core degrees, indicating these hub genes may be involved in the process of aging by lipid metabolism. After the final screening, a total of 28 genes with significant differences were screened out, among which GPR68, LOC706331, STRA6 and PDE7B were up-regulated in QN and ZL compared with YN and LN respectively, while down-regulated in LN compared with QN. The other 24 genes were down-regulated in QN and ZL compared with YN and LN respectively, while up-regulated in LN compared with QN. Conclusion: A total of 28 genes were recognized as aging-related genes in the hypothalamus, and BMSCs treatment for retarding aging may be involved in these gene targets.

Metformin Disrupts Signaling and Metabolism in Fetal Hepatocytes.

The major metformin uptake transporter OCT1 is expressed in the fetal liver, and fetal hepatic uptake of metformin is observed invivo. Metformin activates AMPK, reduces glucose production, and decreases oxygen consumption in fetal hepatocytes, demonstrating similar effects as in juvenile hepatocytes. Unique to fetal hepatocytes, metformin activates metabolic stress pathways and alters the expression of secreted growth factors and hepatokines. Disruption of signaling and metabolism with increased stress pathways and reduced anabolic pathways by metformin in the fetal liver may underlie reduced growth in fetuses exposed to metformin.

No food left behind: foraging route choices among free-ranging Japanese macaques (Macaca fuscata) in a multi-destination array at the Awajishima Monkey Center, Japan.

Animals must make route choices every day when moving through their habitat while foraging. Choosing an optimal route can be cognitively costly, and primates and other animals have been shown to use simple heuristics, "rules of thumb", to make foraging route choices. We investigated the potential use of heuristics among foraging free-ranging Japanese monkeys (Macaca fuscata) during solitary foraging trials. We also investigated the potential influence of individual variables (age and sex) and social variables (presence in the central group, presence of potential inter- and intraspecific competitors), on the use of heuristics, route length and trial time. We used a multi-destination foraging experiment with 6 platforms in a (4m×8m) Z-array, completed by 29 Japanese macaques in 155 runs at the Awajishima Monkey Center in Japan. Our results showed that the macaques chose routes consistent with heuristics (e.g. nearest neighbour heuristic 19.4%, convex hull heuristic 4.5%) and selected optimal routes (shortest path in 23.9% of the trials). We also identified a potential new heuristic that was used most frequently, that we termed the "sweep heuristic" (27.1% of trials), which we interpreted as a strategy to deal with competitive foraging trade-offs - choosing routes to prioritize not leaving isolated food pieces behind. Age was significantly related to trial time; juvenile macaques were faster than adults and young adults, using speed to gain access to resources. Solitary trials with conspecifics present took significantly longerroutes. Our results suggest that contextual factors led to variation in Japanese macaque decision-making, and we suggest that the preferential use of a sweep heuristic may have been a response to high intragroup competition.

The Pharmacokinetics of Subcutaneous Methylnaltrexone Bromide in Rhesus Macaques (Macaca mulatta).

Opioids are an integral component of pain management for nonhuman primates. These potent analgesics also adverse gastrointestinal (GI) effects that include constipation, bloating, and delayed gastric emptying. Methylnaltrexone bromide (MNTX) is a selective, peripherally acting μ- and κ-opioid receptor antagonist that can be used to mitigate the GI effects associated with opioid administration. Unlike naltrexone, a similar drug in this class, MNTX possesses an N-methyl-quaternary amine group that prevents it from crossing the blood brain barrier. This blockage allows inhibition of peripheral GI opioid receptors without affecting opioid-mediated analgesia in the central nervous system. We conducted a pharmacokinetic analysis of MNTX in serum and CSF of 6 healthy juvenile male rhesus macaques after subcutaneous administration of a 0.15-mg/kg dose. We hypothesized that the macaques would demonstrate a Tmax of 0.5 h, similar to that of humans, and that no MNTX would be detected in the CSF. This treatment resulted in a peak serum concentration of 114 ± 44 ng/mL at 0.25 ± 0.00 h; peak CSF at concentrations were 0.34 ± 0.07 ng/mL at the Tmax. These data show that subcutaneous administration of MNTX to rhesus macaques may block peripheral adverse effects of opioids without interfering with their central analgesic effects.

Host Immunity to Mycobacterium tuberculosis Infection Is Similar in Simian Immunodeficiency Virus (SIV)-Infected, Antiretroviral Therapy-Treated and SIV-Naïve Juvenile Macaques.

Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV. The immunologic mechanisms involved in TB progression in both HIV-naive and HIV-infected children have not been explored. Much of our current understanding is based on human studies in adults and adult animal models. In this study, we sought to model childhood HIV/Mycobacterium tuberculosis (Mtb) coinfection in the setting of ART and characterize T cells during TB progression. Macaques equivalent to 4 to 8 year-old children were intravenously infected with SIVmac239M, treated with ART 3 months later, and coinfected with Mtb 3 months after initiating ART. SIV-naive macaques were similarly infected with Mtb alone. TB pathology and total Mtb burden did not differ between SIV-infected, ART-treated and SIV-naive macaques, although lung Mtb burden was lower in SIV-infected, ART-treated macaques. No major differences in frequencies of CD4+ and CD8+ T cells and unconventional T cell subsets (Vγ9+ γδ T cells, MAIT cells, and NKT cells) in airways were observed between SIV-infected, ART-treated and SIV-naive macaques over the course of Mtb infection, with the exception of CCR5+ CD4+ and CD8+ T cells which were slightly lower. CD4+ and CD8+ T cell frequencies did not differ in the lung granulomas. Immune checkpoint marker levels were similar, although ki-67 levels in CD8+ T cells were elevated. Thus, ART treatment of juvenile macaques, 3 months after SIV infection, resulted in similar progression of Mtb and T cell responses compared to Mtb in SIV-naive macaques.

Bone Marrow Mesenchymal Stem Cells Derived from Juvenile Macaques Reversed the Serum Protein Expression Profile in Aged Macaques.

The aim of the study was to reveal the changes in serum protein composition and content in macaques during the process of ageing, and explore the effect of bone marrow mesenchymal stem cell (BMMSC) on the serum protein expression profile in elderly macaques. Naturally ageing macaques were assessed according to age. BMMSCs were intravenously infused into aged macaques. In addition, peripheral blood was collected to obtain serum for dataindependent acquisition (DIA) protein sequencing to identify aging-related indicators. One hundred eighty days after macaques received BMMSC treatment, haemoxylin and eosin (HE) staining was performed to observe the morphology and structure of aortic arches. Compared to infant and young control macaques, aged macaques showed erythema on the face, dry skin, reduced amounts of hair on the head and back, and paleness. Cultured BMMSCs from the 4th passage (P4 BMMSCs) were grown in accordance with standards used to culture mesenchymal stem cells. After BMMSC treatment, the assessed aortic arches showed no calcium salt deposition or cell necrosis, and the characteristics of the serum protein expression profile tended to be similar to that of the infant and young groups, with the expression of 41 proteins upregulated with age and that of 30 proteins downregulated with age but upregulated after BMMSC treatment. Moreover, we identified 44 significantly differentially expressed proteins between the aged model and treatment groups; 11 of the upregulated proteins were related to vascular ageing, neuronal ageing and haematopoiesis, and 33 of the downregulated proteins were associated with neuronal ageing, cardiovascular disease, and tumours. Interestingly, S100 expression in serum was significantly decreased, COMP expression was significantly increased, NKAP expression reappeared, and LCN2, CSF1R, CORO1C, CSTB and RSU-1 expression disappeared after BMMSC treatment. BMMSCs can reverse ageing-related serum protein expression.

Delineation of biomarkers and molecular pathways of residual effects of fluoxetine treatment in juvenile rhesus monkeys by proteomic profiling.

Fluoxetine (Prozac™) is the only antidepressant approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) in children. Despite its considerable efficacy as a selective serotonin reuptake inhibitor, the possible long-term effects of fluoxetine on brain development in children are poorly understood. In the current study, we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques (Macaca mulatta) one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling. We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex (DLPFC) and cingulate cortex (CC) that correlated with impulsivity in animals, suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment. Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.

Humans read emotional arousal in monkey vocalizations: evidence for evolutionary continuities in communication.

Humans and other mammalian species communicate emotions in ways that reflect evolutionary conservation and continuity, an observation first made by Darwin. One approach to testing this hypothesis has been to assess the capacity to perceive the emotional content of the vocalizations of other species. Using a binary forced choice task, we tested perception of the emotional intensity represented in coos and screams of infant and juvenile female rhesus macaques (Macaca mulatta) by 113 human listeners without, and 12 listeners with, experience (as researchers or care technicians) with this species. Each stimulus pair contained one high- and one low-arousal vocalization, as measured at the time of recording by stress hormone levels for coos and the degree of intensity of aggression for screams. For coos as well as screams, both inexperienced and experienced participants accurately identified the high-arousal vocalization at significantly above-chance rates. Experience was associated with significantly greater accuracy with scream stimuli but not coo stimuli, and with a tendency to indicate screams as reflecting greater emotional intensity than coos. Neither measures of empathy, human emotion recognition, nor attitudes toward animal welfare showed any relationship with responses. Participants were sensitive to the fundamental frequency, noisiness, and duration of vocalizations; some of these tendencies likely facilitated accurate perceptions, perhaps due to evolutionary homologies in the physiology of arousal and vocal production between humans and macaques. Overall, our findings support a view of evolutionary continuity in emotional vocal communication. We discuss hypotheses about how distinctive dimensions of human nonverbal communication, like the expansion of scream usage across a range of contexts, might influence perceptions of other species' vocalizations.