Juvenile Monkeys Research Articles

Developmental trajectory of unconventional T cells of the cynomolgus macaque thymus

As nonhuman primates are immunologically the closest model to humans, a comprehensive understanding of T-cell development in these species is crucial. However, the differentiation pathways in which thymocytes participate, along with their heterogeneity, remain poorly characterized. Using single-cell RNA sequencing, we thoroughly profiled the development of various T-cell lineages in the juvenile cynomolgus monkey thymus, identifying and characterizing 12 distinct thymic cell states or types. Interestingly, we identified two unexpected cell types, an agonist-selected and a memory-like cell population. The agonist-selected cell population expressed genes associated with strong TCR signaling, such as PDCD1, CD5, NFKBID, NFATC1, BCL2L11, and NR4A1 but exhibiting significantly higher PDCD1 expression compared with cells following the conventional developmental pathway. Additionally, we identified a substantial number of memory-like cell populations characterized by high CXCR3 and EOMES expression. Notably, this population also highly expressed the effector-associated markers, GZMK, NKG7, and GNLY, as well as the innate cell-associated markers, ZBTB16, TYROBP, KLRB1, KLRC1, and NCR3. The EOMES + memory-like cell population expressed highly PDCD1, indicating the presence of an agonist-selection footprint. Our findings provide insights into the agonist-selection pathway that allows self-reactive thymocytes to survive thymic selections and differentiate into various unconventional T-cell lineages.

Detection of Mycobacterium bovis in Free-Ranging Sapajus nigritus, Argentina.

Mycobacterium bovis and Mycobacterium tuberculosis are the most relevant among pathogenic mycobacteria, both belonging to the M. tuberculosis complex (MTC). Samples of blood, liver, spleen, kidneys, lungs and caseous tubercles were collected from a free-ranging juvenile black capuchin monkey (Sapajus nigritus) showing non-specific signs of illness. Macroscopic findings included emaciation, a caseous lesion in a tooth and gingiva, disseminated nodules in both lungs and left kidney parenchyma and caseous nodules on the pleura and mesentery. The lesions suggested MTC infection, a diagnosis subsequently supported in the lung by bacilloscopy, immunochromatography and PCR. A multiplex PCR further validated the presence of M. bovis genes. Cases of tuberculosis in platyrrhine primates have only been reported in animals maintained in captivity. We describe for the first time the pathological and molecular findings of M. bovis infection in a free-ranging platyrrhine monkey within an area of intense human-wildlife interaction, which has important implications from a One Health perspective.

Early blood immune molecular alterations in cynomolgus monkeys with a PSEN1 mutation causing familial Alzheimer's disease.

More robust non-human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD. We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3' and 5' intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non-human primate model. We observed early changes of AD-related pathological proteins (cerebrospinal fluid Aβ42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1-ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1-ΔE9 cynomolgus monkeys. PSEN1 mutant cynomolgus monkeys recapitulate AD-related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD-associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions. A dual-guide CRISPR/Cas9 system successfully mimics AD PSEN1-ΔE9 mutation by genomic excision of exon 9. PSEN1 mutant cynomolgus monkey-derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aβ secretion. Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys. Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD-related pathological proteins (increased Aβ42 and phosphorylated tau).

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.

Male juvenile golden snub-nosed monkeys acting as the mountee to receive grooming in their same-sex mounts

Abstract Same-sex mounts provide male juvenile golden snub-nosed monkeys (Rhinopithecus roxellana) with opportunities to practice heterosexual copulatory skills and are often followed by grooming (post-mounting grooming, PMG). We hypothesized that juveniles acted as the mountee and provided mounting opportunities to receive grooming from their peer mounter. Here, we observed same-sex mounts among male juveniles (N = 5) in a captive group of R. roxellana in Shanghai Wild Animal Park, China, from November 2014 to June 2015. Among 1,044 mounts recorded, 45.40% were accompanied by PMG initiated by the mounter and only 3.74% were followed by PMG initiated by the mountee. Mountees were more likely to receive PMG when they performed a mounting solicitation than when they did not, or when they were mounted for a longer time (even if they did not solicit). Over a long timeframe (1 month), mountee’s tended to choose partners who groomed them more often than others after mounting, regardless of how long the grooming lasted. However, whether the mounter groomed the mountee did not predict the mounting direction in their subsequent mount. Our results suggest that, in the context of same-sex mounts, juveniles provide mounting opportunities to receive grooming from peers on a long-term, rather than on a short-term basis. This study provides the first evidence that juveniles’ same-sex mounting strategy may be associated with the grooming market in nonhuman primates, which necessitates further investigation with large free-ranging groups due to the limited sample size of individuals and the captive setting of the current study.

Ocular examination findings and selected ophthalmic diagnostic tests in African green monkeys (Chlorocebus aethiops sabaeus).

To document ocular lesions and establish ophthalmic diagnostic test reference values in a colony of African green monkeys (Chlorocebus aethiops sabaeus). Fifty one geriatric (GAGM, 19-30 years old), 10 adult (AAGM, 5-9 years old) and 10 juvenile (JAGM, <2 years old) African green monkeys housed in a single Caribbean research colony. Ocular biomicroscopy, indirect fundoscopy, Schirmer tear test (STT), rebound tonometry (TonoVet®) and corneal fluorescein staining were performed. Mixed ANCOVA tests were performed to compare STT and IOP between groups. Common ocular lesions in GAGM included vitreal degeneration (27/51, 51/102 eyes) and cataracts (21/51, 32/102 eyes). Vitreal degeneration was also common in AAGM (8/10, 16/20 eyes) and infrequent in JAGM (3/10, 6/20 eyes). Cataracts were not present in any JAGM or AAGM. All eyes in all three groups had perilimbal corneal pigmentation and faint lace-like anterior corneal stromal opacification. Median (range) STT values were 16.0 (18) mm/min in GAGM. Mean (SD) STT values were 14.2 (4.6) mm/min in AAGM, and 8.9 (3.4) mm/min in JAGM. Median (range) IOP values were 16.5 (27) mmHg in GAGM. Mean (SD) IOP values were 18.0 (2.8) mmHg in AAGM, and 14.1 (2.2) mmHg in JAGM. JAGM had significantly lower STT and IOP values compared to AAGM (p = .0449, .0057, respectively) and GAGM (p = .0002, .0130, respectively). Spontaneous ocular lesions were common in geriatric monkeys in this research colony. IOP and STT values were lower in juvenile African green monkeys relative to adult or geriatric animals.

Strong ties formation, composition and processes at play during the developmental period of juvenile vervet monkeys

Understanding the development of social relationships can provide insights into the processes by which social network structures emerge and vary across species. Here we extend a previous analysis (Vilette et al., 2022, Animal Behaviour, 194, 205–223) that tested Kohn's (2019, Animal Behaviour, 154, 1–6) model of social relationship formation in three groups of wild juvenile vervet monkeys, Chlorocebus pygerythrus. This previous analysis showed that, although developmental patterns did not conform to the exploration, pruning and consolidation phases identified by Kohn (2019), juveniles formed a core of strong social ties (a social ‘bubble’) across development. Here, we use a novel approach to objectively extract strong ties and ask whether Kohn's (2019) phases are more appropriately evaluated with reference to the subset of strong ties that constitute social bubbles. We investigate social bubble formation and composition, as well as the role of maternal behaviour in the development of these bubbles. As before, spatial and grooming social bubbles did not develop according to Kohn's (2019) framework. On the one hand, spatial bubbles were composed mainly of juveniles and showed increased association rates for family members during the annual birth season. Juvenile grooming bubbles, on the other hand, were stable over time and restricted solely to their mothers. Resulting from this, we found that juveniles did not simply groom their closest spatial associates but distributed their grooming towards specific partners. Finally, we found that a mother's grooming ties and her offspring's grooming weak ties remained mostly different as juveniles developed. This finding supports a previous analysis on our population (Jarrett et al., 2018, Proceedings of the Royal Society B: Biological Sciences, 285(1876), Article 20172668), where juveniles had to develop connections with nonmaternal associates in order to replicate the overall grooming network. These results indicate that the structure and composition of social bubbles in our sample reflect both the behaviour under consideration (grooming or spatial proximity) and group demography.

Pharmacokinetic and Target Engagement Measures of ANX007, an Anti-C1q Antibody Fragment, Following Intravitreal Administration in Nonhuman Primates.

C1q and the classical complement cascade are key regulators of synaptic pruning, and their aberrant activation has been implicated in neurodegenerative ophthalmic diseases including geographic atrophy and glaucoma. The antigen-binding fragment antibody ANX007 specifically recognizes globular head groups of C1q to block substrate binding and functionally inhibit classical complement cascade activation. ANX007 was assessed in nonclinical studies of biodistribution and C1q target engagement in the eye following intravitreal (IVT) administration in cynomolgus monkeys. Female juvenile cynomolgus monkeys (n = 12) received a single bilateral dose of 1 or 5 mg ANX007/eye, with vitreous and non-perfused tissue samples collected approximately 4 weeks later. In a separate study, male (n = 6/5) and female (n = 6/5) animals received repeat bilateral dosing of 1, 2.5, or 5 mg ANX007/eye on days 1 and 29, with aqueous and vitreous collections on day 44 or day 59. Tissues from the 5 mg/eye repeat-dose group were perfused, and retina, choroid, and optic nerve samples were collected approximately 2 and 4 weeks post-last dose. Following a single dose of ANX007, vitreous levels of free drug were measurable through 4 weeks at both the 1 and 5 mg dose levels, with approximately 3-day half-life. With repeat dose of 5 mg/eye, free-ANX007 was measurable 4 weeks post-last dose in perfused retina and choroid and up to approximately 2 weeks post-last dose in optic nerve. There was a strong correlation between C1q target engagement and free drug levels in aqueous and vitreous humors and retinal tissue. Following IVT administration, ANX007 distributes to sites within the retina that are relevant to neurodegenerative ophthalmic disease with clear evidence of C1q target engagement. Based on its mechanism of action inhibiting C1q and its downstream activity, ANX007 is predicted to mitigate tissue damage driven by classical complement activation in the retina. These data support further clinical evaluation of ANX007.

Juvenile toxicity study of PF-07256472/recifercept, a recombinant human soluble fibroblast growth factor receptor 3, in 2-3-month-old cynomolgus monkeys.

Achondroplasia is an autosomal disorder caused by point mutation in the gene encoding fibroblast growth factor receptor 3 (FGFR3) and resulting in gain of function. Recifercept is a potential disease modifying treatment for achondroplasia and functions as a decoy protein that competes for ligands of the mutated FGFR3. Recifercept is intended to restore normal bone growth by preventing the mutated FGFR3 from negative inhibitory signaling in pediatric patients with achondroplasia. Here we evaluated the potential effects of twice weekly administration of recifercept to juvenile cynomolgus monkeys (approximately 3-months of age at the initiation of dosing) for 6-months. No adverse effects were noted in this study, identifying the high dose as the no-observed-adverse-effect-level and supporting the use of recifercept in pediatric patients from birth. Considering that juvenile toxicity studies in nonhuman primates are not frequently conducted, and when they are conducted they typically utilize animals ≥9months of age, this study demonstrates the feasibility of executing a juvenile toxicity study in very young monkeys prior to weaning.

Network formation during social integration in juvenile vervet monkeys

Understanding the development of social relationships, or the process of socialization, can provide insights into the processes by which social network structures emerge and vary across species. In this analysis, we investigated the process of network formation from a developmental perspective using data from three groups of wild vervet monkeys, Chlorocebus pygerythrus . We used a dynamic social network approach that allowed us to capture patterns of social change over time. Specifically, we considered the temporal dynamics of two separate interaction networks, spatial and grooming associations, and investigated these patterns between the sexes. We used these data to test predictions derived from a developmental framework on relationship formation put forward by Kohn (2019, Animal Behaviour , 154 , 1–6). We found that females and males differed in their grooming patterns but were similar in their spatial associations. Furthermore, spatial proximity ego-networks showed seasonal patterns, whereas grooming ego-networks did not. When all relevant centrality measures were considered in concert, we found evidence to suggest that a distinctive network structure forms across the course of development, with ego-networks composed of few strong ties and many weak ties, regardless of behaviour and sex. However, these networks were not produced according to the processes described by Kohn (2019), perhaps because Kohn's framework is concerned mainly with network composition and not structure. Overall, our results provide evidence for social niche construction across development, with the formation of a core social ‘bubble’ of strong ties that can provide a consistent and predictable immediate social environment. More broadly, these patterns suggest that network formation is a process of ongoing adjustment to the social environment, and not an attempt to meet an optimal end goal. • We examined sociality in vervets following Kohn (2019, Animal Behaviour , 154 , 1–6). • Vervet monkeys did not develop following Kohn's three socialization phases. • Spatial ego-networks were seasonal; male and female grooming ego-networks differed. • Spatial and grooming ego-networks had few strong ties and many weak ties. • Social integration involves continual adjustments via social niche construction.

Treating Thyroid Associated Ophthalmopathy in Pediatric Patients.

Thyroid associated ophthalmopathy (TAO) is a common extra-thyroid clinical manifestation of Graves’ disease. It is an inflammatory disease of the eye and orbital tissues. Up to one-third of pediatric Graves’ disease patients could be diagnosed with TAO. The symptoms can be variable with remissions and exacerbations of pediatric Graves’ disease, which has negative effects on the quality of life in children. Teprotumumab is a fully human IgG1κ type monoclonal antibody targeting insulin-like growth factor-1 receptor (IGF-1R), and was approved for the treatment of TAO as a “breakthrough therapy” by the FDA in 2020. Nevertheless, the safety and effectiveness have not been established in pediatric patients. IGF-1R plays an important role in human development, which raises concerns of developmental toxicity. As presented in the pharmacology review report, juvenile monkeys were tested in two separate repeated-dose toxicity studies and no NOAEL was identified. Teprotumumab affected the growth, thymus, spleen and decreased the bone growth. Younger animals seemed to be more sensitive to the effects on normal growth and normal thymus. Hearing impairment posed additional risk to the potential pediatric use, especially for school-age children. Considering the nature of the target, Teprotumumab should not be used empirically in children. More efforts would be made for the further development of teprotumumab for pediatric use.

First survey on seroprevalence of Japanese encephalitis in long-tailed macaques (Macaca fascicularis) in Bali, Indonesia.

Background and Aim:Japanese encephalitis (JE) is a zoonotic infectious inflammatory brain disease caused by the JE virus (JEV). Considerable research into the seroprevalence of JE in domestic animals has been conducted, but there have been no reports of its occurrence in wild animals, including long-tailed macaques (Macaca fascicularis). This study aimed to estimate the seroprevalence of JEV infection and its determinants in long-tailed macaques in Bali and the prevalence of mosquito vectors.Materials and Methods:Blood samples (3 mL) were collected from a population of M. fascicularis (92 heads) inhabiting a small forest with irrigated rice field nearby (wetland area) in Ubud, Gianyar, and from two populations in dryland areas with no wet rice field (Uluwatu, Badung, and Nusa Penida, Bali Province, Indonesia). The collected sera were tested for antibodies against JEV using a commercially available enzyme-linked immunosorbent assay kit (qualitative monkey JE Immunoglobulin G antibody kit). The seropositivity of the antibodies was then compared based on different variables, namely, habitat type, age, and sex.Results:The seroprevalence of the JEV antibodies in all the samples tested was found to be 41.3%. The seropositivity of the monkey serum samples collected from the wetland area was 46.4%, which was higher than the seropositivity of the sera samples collected from the dried field areas (1.25%). Monkey sera collected from the wetland areas were 6.1 times (odds ratio [OR]: 6.1; 95% confidence interval [CI]: 0.71-51.5, p>0.05) more likely to be seropositive compared to the monkey sera collected from the dried field areas. Meanwhile, female monkeys were 1.79 times (OR: 1.79; 95% CI: 0.76-4.21; p>0.05) more likely to be seropositive to JEV than males. Similarly, juvenile monkeys were 2.38 times (OR: 2.38; 95% CI: 0.98-5.79); p>0.05) more likely to be seropositive against the JEV than adult monkeys. However, none of these differences achieved statistical significance. Regarding the JEV mosquito vector collection, more Culex mosquitoes were found in the samples from the wetland areas than from the dried field areas.Conclusion:The study confirms the existence of JEV infection in long-tailed macaques in Bali. There were patterned seropositivity differences based on habitat, age, and sex of the monkeys, but these were not significant. The possibility of monkeys as a JEV reservoir and the presence of the mosquitoes as the JEV vector are suggested but require more study to confirm.

Putative white-naped mangabey (Cercocebus lunulatus) × olive baboon (Papio anubis) hybrids from Comoé National Park in Côte d’Ivoire

Abstract We report the presence of at least one putative hybrid monkey, white-naped mangabey (Cercocebus lunulatus) × olive baboon (Papio anubis), at Comoé National Park (CNP) in north-eastern Côte d’Ivoire. C. lunulatus and P. anubis belong to two separate clades within the African Papionini (Papionina), which is known to display a complex pattern of evolutionary history involving ancient and recent hybridization. CNP is a bushy savanna-dominated protected area home to 12–13 primate species. Only about 9–11 % of the land cover is forest. C. lunulatus is an Endangered species while P. anubis is a Least Concern species. While conducting a reconnaissance survey on June 23, 2019, the first author observed and photographed a mangabey-baboon hybrid-like juvenile male monkey (2019A). At the same area where 2019A was photographed, a camera trap (CT) captured a video of a hybrid-like juvenile male monkey (2021B) on January 14, 2021, and another nearby CT captured a video of a slightly older hybrid-like juvenile male monkey (2021C) on May 23, 2021. Because there are reported cases of hybrids in captivity that occurred between the members of the two separate clades of the Papionini, the discovery of such intergeneric hybrids in the wild would not be surprising. We examine the idiosyncratic features of the putative hybrids and discuss the implication for conservation and future directions for research, considering the potential interacting factors that may lead to intergeneric hybridization. Specifically, to assess genetic population structure within C. lunulatus and P. anubis and to clarify the degree of gene flow among the two species, collecting biological matter from the putative hybrids, mangabeys, and baboons is necessary. Also, to elucidate the circumstances that might have stimulated hybridization, examining changes that might have occurred in the two species’ ecology and demography is essential.

Robust locomotor performance of squirrel monkeys (Saimiri boliviensis) in response to simulated changes in support diameter and compliance.

Arboreal environments require overcoming navigational challenges not typically encountered in other terrestrial habitats. Supports are unevenly distributed and vary in diameter, orientation, and compliance. To better understand the strategies that arboreal animals use to maintain stability in this environment, laboratory researchers must endeavor to mimic those conditions. Here, we evaluate how squirrel monkeys (Saimiri boliviensis) adjust their locomotor mechanics in response to variation in support diameter and compliance. We used high-speed cameras to film two juvenile female monkeys as they walked across poles of varying diameters (5, 2.5, and 1.25 cm). Poles were mounted on either a stiff wooden base ("stable" condition) or foam blocks ("compliant" condition). Six force transducers embedded within the pole trackway recorded substrate reaction forces during locomotion. We predicted that squirrel monkeys would walk more slowly on narrow and compliant supports and adopt more "compliant" gait mechanics, increasing stride lengths, duty factors, and an average number of limbs gripping the support, while the decreasing center of mass height, stride frequencies, and peak forces. We observed few significant adjustments to squirrel monkey locomotor kinematics in response to changes in either support diameter or compliance, and the changes we did observe were often tempered by interactions with locomotor speed. These results differ from a similar study of common marmosets (i.e., Callithrix jacchus, with relatively poor grasping abilities), where variation in diameter and compliance substantially impacted gait kinematics. Squirrel monkeys' strong grasping apparatus, long and mobile tails, and other adaptations for arboreal travel likely facilitate robust locomotor performance despite substrate precarity.

Low color temperature artificial lighting can slow myopia development: Long-term study using juvenile monkeys

The incidence of myopia has increased rapidly in recent decades, suggesting that environmental factors, such as light, may be an important cause. Correlated color temperature (CCT) is a commonly used index to quantify the spectral composition of light. Here, we used 32 juvenile monkeys (16 females and 16 males) and selected four kinds of light with typical but different CCTs to study the relationship between CCT and ocular axial elongation. After 365 days of observation, ocular axial elongation under low-CCT light was smaller than that under high-CCT light and this effect was robust and stable over the entire observation period. As excessive axial elongation is the main cause of juvenile myopia, these results provide a new approach for the prevention of juvenile myopia.

Immune Cell and Adipose Gene Expression Reprogramming in Juvenile Monkeys Born to Health and Weight-Diverse Mothers

Over 93 million Americans are obese and 66 million suffer from metabolic disease. Roughly 40% of obese people do not have metabolic abnormalities (metabolically health obese [MHO]), while approximately 15% of lean do (metabolically unhealthy lean [MUL]). African green monkeys (AGMs) demonstrate naturally occurring obesity and metabolic syndrome (MetS) without diet manipulation, and MetS criteria are heritable. Age-matched maternal AGMs were classified by adjusted MetS criteria ([n=44]; waist >40cm, fasting glucose (FG) >100 mg/dL, SBP/DBP >135/85mmHg, and HDL-c <50mg/dL) and classified as metabolically healthy lean (MHL), MHO, MUL or metabolically unhealthy obese (MUO). Age, weight and sex-matched pre-pubertal juvenile offspring from these mothers were additionally selected (n=9-11/group; ages=1.1-3.4years) for evaluation. We assessed monocyte subtypes by flow cytometry, and subcutaneous adipose gene expression patterns by RNAseq. Non-classical monocytes were increased in obese and unhealthy mothers (MHO p=0.02, MUL p=0.003, MUO p=0.00002) compared to MHL. MUL and MUO juvenile offspring also had more non-classical monocytes compared to MHL (p=0.05 and p=0.07). Monocyte chemoattractant protein-1 (MCP)-1 was measured in plasma and found to be elevated in MUO juveniles (p=0.02). Patterns of increased cytokine and extracellular matrix gene expression were seen in MUL and MUO juveniles’ adipose (6-7/group), mirroring obese and unhealthy mothers’ adipose gene expression patterns. Maternal health and obesity influence offspring immune cells and adipose gene expression prior to weight gain and metabolic disease onset. Our data underscore maternal monocyte and adipose profiles as inherited phenotypes that present prior to adipose expansion and may be targets to improve intergenerational health trajectories.

Serum- and Feeder-Free Culture of Juvenile Monkey Female Germline Stem Cells and Testosterone Regulation of their Self-Renewal.

Female germline stem cells (FGSCs) have been found in mouse, rat, pig, sheep and human ovaries. However, there is no information on the isolation or long-term culture of FGSCs from non-human primates. Here, we identified the presence of FGSCs in the ovaries of juvenile (3-4-year-old) cynomolgus monkeys using DDX4 and Ki67 double immunofluorescence. Then, a long-term serum- and cell feeder-free culture system for these FGSCs was used to establish a cell line, and its biological characteristics were analyzed. We found that testosterone promoted self-renewal of the cells. This study confirmed for the first time the presence of FGSCs in the ovary of non-human primates. This culture system and cell line will be of great significance for research in medicine and reproductive biology.

Parentally deprived juvenile Owl monkeys suffer from long-term high infection rates but not from altered hair cortisol concentrations nor from stereotypic behaviours.

In captive colonies, owl monkeys' mothers sometimes reject their newborns.To prevent, mortality infants are manually raised by veterinarians. Both parental separation and rejection are stressful experiences, associated with elevated stress, physical, and behavioural disorders. The effect ofparental deprivation in IVITA's owl monkeys stress profiles and health is unknown. We comparedstress biomarkers such as hair cortisol (using cortisol ELISA), stereotypic behaviours (with infrared cameras), and infection histories in juveniles separated from parents soon after birth (n = 14, ~17months) and controls (n = 11, ~17months). Parentally deprivedowlmonkeys show higher infection rates than controls (p = .001).However, they display no higher incidence of biomarkers of stress: Neither stereotypic behaviour nor cortisol in hair was different between cohorts. Irrespective of deprivation status, rates of infection, and concentration of cortisol in hair were positively associated (R2 = .29, p = .005). Early parental deprivation and natural high levels of cortisol secretion are associated with elevated infection levels in the IVITA owl monkey juveniles detectable up to 17months post separation.

Safety and efficacy of an engineered hepatotropic AAV gene therapy for ornithine transcarbamylase deficiency in cynomolgus monkeys

X-linked inherited ornithine transcarbamylase deficiency (OTCD) is the most common disorder affecting the liver-based urea cycle, a pathway enabling detoxification of nitrogen waste and endogenous arginine biosynthesis. Patients develop acute hyperammonemia leading to neurological sequelae or death despite the best-accepted therapy based on ammonia scavengers and protein-restricted diet. Liver transplantation is curative but associated with procedure-related complications and lifelong immunosuppression. Adeno-associated viral (AAV) vectors have demonstrated safety and clinical benefits in a rapidly growing number of clinical trials for inherited metabolic liver diseases. Engineered AAV capsids have shown promising enhanced liver tropism. Here, we conducted a good-laboratory practice-compliant investigational new drug-enabling study to assess the safety of intravenous liver-tropic AAVLK03 gene transfer of a human codon-optimized OTC gene. Juvenile cynomolgus monkeys received vehicle and a low and high dose of vector (2 × 1012 and 2 × 1013 vector genome (vg)/kg, respectively) and were monitored for 26 weeks for in-life safety with sequential liver biopsies at 1 and 13 weeks post-vector administration. Upon completion of monitoring, animals were euthanized to study vector biodistribution, immune responses, and histopathology. The product was well tolerated with no adverse clinical events, predominant hepatic biodistribution, and sustained supra-physiological OTC overexpression. This study supports the clinical deployment of intravenous AAVLK03 for severe OTCD.

Gut Microbial and Metabolic Profiling Reveal the Lingering Effects of Infantile Iron Deficiency Unless Treated with Iron.

Iron deficiency (ID) compromises the health of infants worldwide. Although readily treated with iron, concerns remain about the persistence of some effects. Metabolic and gut microbial consequences of infantile ID were investigated in juvenile monkeys after natural recovery (pID) from iron deficiency or post-treatment with iron dextran and B vitamins (pID+Fe). Metabolomic profiling of urine and plasma is conducted with 1 H nuclear magnetic resonance (NMR) spectroscopy. Gut microbiota are characterized from rectal swabs by amplicon sequencing of the 16S rRNA gene. Urinary metabolic profiles of pID monkeys significantly differed from pID+Fe and continuously iron-sufficient controls (IS) with higher maltose and lower amounts of microbial-derived metabolites. Persistent differences in energy metabolism are apparent from the plasma metabolic phenotypes with greater reliance on anaerobic glycolysis in pID monkeys. Microbial profiling indicated higher abundances of Methanobrevibacter, Lachnobacterium, and Ruminococcus in pID monkeys and any history of ID resulted in a lower Prevotella abundance compared to the IS controls. Lingering metabolic and microbial effects are found after natural recovery from ID. These long-term biochemical derangements are not present in the pID+Fe animals emphasizing the importance of the early detection and treatment of early-life ID to ameliorate its chronic metabolic effects.