Primates Research Articles

Normative Profile of Retinal Nerve Fiber Layer Thickness and Lamina Cribrosa-Related Parameters in a Healthy Non-Glaucoma Cynomolgus Monkey Colony.

The purpose of this study was to investigate the normal range of ophthalmic parameters and the correlations between systematic and ocular parameters and retinal nerve fiber layer (RNFL) thickness among a healthy non-glaucoma cynomolgus monkey colony. All included monkeys were given detailed ophthalmic examinations, including anterior and posterior segments. Furthermore, univariate and multivariate linear regression models were conducted to estimate the relationship between systemic and ophthalmic parameters and global RNFL thickness. A total of 349 non-glaucoma monkeys (18.69 ± 2.88 years old) were collected. The global RNFL thickness was 94.61 ± 10.13 µm, and sex-specific differences existed in all sectors. The decreasing trend of RNFL is as follows: inferotemporal, superotemporal, inferonasal, superonasal, temporal, and nasal. For lamina cribrosa (LC)-related parameters, cup depth (P < 0.01), LC thickness (P = 0.014), and Bruch's membrane opening (BMO) - minimum rim width 2 (P = 0.002) were greater in the male group. However, LC depth (P = 0.02), anterior laminar insertion depth-1 (P = 0.009), and mean anterior laminar insertion depth (P = 0.029) of female monkeys were greater than those of male monkeys. In multivariate linear regression, only older age was significantly related to reduced global RNFL thickness (P < 0.001). Our findings suggest the differences in RNFL thickness distribution and sex between non-glaucoma cynomolgus monkeys and humans. Therefore, the impact of this difference on outcomes should be fully considered in laboratory animal studies. Our findings are also significant in terms of developing a normative optical coherence tomography (OCT) database in nonhuman primates (NHPs). We found that the differences in RNFL thickness distribution and sex between non-glaucoma cynomolgus monkey colonies and humans should be thoroughly taken into account in laboratory animal studies.

Imaging the immune sequelae of infection with SARS-CoV-2 in nonhuman primates by using two nanobody PET-tracers.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacts multiple anatomical sites. Whether this is due to the virus itself or is a secondary effect caused by the influx and activation of immune cells is not known. Positron emission tomography (PET) with immunoglobulins can provide insights into which sites and cells are activated in a living animal. Our aim is to use two nanobodies as tools to monitor (1) the distribution of antigen presenting cells (APC) by virtue of their Mafa-DR expression profile, (2) virus-infected cells and viral particles using a nanobody against the SARS-CoV-2 spike protein. Two [89Zr]-labeled nanobodies that target the SARS-CoV-2 spike protein and major histocompatability complex (MHC) class II antigens (Mafa-DR), respectively, are used to monitor their distribution during an experimental SARS-CoV-2 infection in a nonhuman primate model. Scans are obtained before infection and on Day 3 and 10 post infection (pi) in two macaques each. The [89Zr]anti-SARS-CoV-2 spike nanobody localized to SARS-CoV-2-associated lung lesions and the nasal mucosa, while the [89Zr]anti-human leukocyte antigen (HLA)-DR nanobody was predominantly found in non-affected lung tissue after infection. We also detected, pi, upregulation of the Mafa-DR signal, indicative of recruitment of professional APCs, in the superior sagittal sinus. [89Zr]-labeled nanobodies show recruitment of macrophages/monocytes in non-lesional lung tissue in cynomolgus macaques after experimental infection with SARS-CoV-2, as well as accumulation of the spike protein in both lung lesions and the nasal mucosa during infection. These results show the possibility of in vivo monitoring the quality and quantity of immune responses during the initial stages of an infection.

6 Oral: ZW220, a NaPi2b-directed topoisomerase I inhibitor Antibody-Drug Conjugate, demonstrates compelling preclinical activity in NSCLC, ovarian and uterine cancer models, with a favorable toxicology profile in non-human primates

6 Oral: ZW220, a NaPi2b-directed topoisomerase I inhibitor Antibody-Drug Conjugate, demonstrates compelling preclinical activity in NSCLC, ovarian and uterine cancer models, with a favorable toxicology profile in non-human primates

Developing an erythrocyte‒MHC-I conjugate for cancer treatment.

Mature erythrocytes are known to lack major histocompatibility complex (MHC) proteins. However, the presence of MHC molecules on erythrocytes has been occasionally reported, though without a defined function. In this study, we designed erythrocyte conjugated solely with a fusion protein consisting of an antigenic peptide linked to MHC class I (MHC-I) protein, termed MHC-I‒Ery. The modified erythrocyte, decorated with the peptide derived from human papillomavirus (HPV) 16 oncoprotein E6/E7, effectively activated antigen-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from HPV16+ cervical cancer patients. Additionally, MHC-I‒Ery monotherapy was shown to inhibit antigen-positive tumor growth in mice. This treatment immediately activated CD8+ T cells and reduced suppressive myeloid cells in the spleen, leading to systemic anti-tumor activity. Safety and tolerability evaluations of MHC-I‒Ery in non-human primates further supported its clinical potential. Our results first demonstrated that erythrocytes equipped solely with antigen peptide‒MHC-I complexes can robustly stimulate the immune system, suggesting a novel and promising approach for advancing cancer immunotherapy.

In search of problems

With early training in physics, my career was marked by continuous learning and searching for interesting problems in biology. Here, I recount some key events that influenced my choices of research topics. The diversity of topics could be attributed to my own lack of a particular focus and the interests of students and postdocs who happened to join my laboratory. My scientific and educational ventures led to my extensive involvement in Chinese neuroscience and various studies in non-human primates.

A Precision Engineered Interleukin-2 for Bolstering CD8+ T- and NK-cell Activity without Eosinophilia and Vascular Leak Syndrome in Nonhuman Primates.

SAR-444245 (SAR'245, pegenzileukin) is an extended half-life IL-2 that targets effector CD8+ T and NK cells, with little effect on regulatory T cells. We show that in the nonhuman primate model that closely approximates human immune function and response to IL-2, SAR'245 selectively activates CD8+ T and NK effectors without significant serious side effects (vascular leak syndrome or cytokine release syndrome), suggesting its potential for the treatment of solid tumors in humans.

Pre-clinical and clinical trials for anesthesia in neonates: gaps and future directions.

Literature examining possible deleterious effects of anesthesia exposure on the developing brain has increased substantially over the past 30years. Initial concerning findings in animal models, both rodents and non-human primates, prompted increasingly thorough examinations in humans, including randomized controlled trials. This review will provide a concise overview of what we know about anesthesia and the developing brain: the background in animal studies, the most robust results we have in humans, and the work yet to be done. This is particularly relevant to a pediatric radiology audience because we have the unique opportunity to modify anesthesia exposure during imaging through innovation.

Kidney-Targeted Delivery of Nonviral Nucleic Acids Using Noninvasive Transcutaneous Ultrasound Enables Safe, Re-dosable, Titratable, and Durable Gene Expression in Mice and Nonhuman Primates

Kidney-Targeted Delivery of Nonviral Nucleic Acids Using Noninvasive Transcutaneous Ultrasound Enables Safe, Re-dosable, Titratable, and Durable Gene Expression in Mice and Nonhuman Primates

Laparoscopic sigmoid colectomy with primary anastomosis for experimental modeling in the nonhuman primate

Laparoscopic sigmoid colectomy with primary anastomosis for experimental modeling in the nonhuman primate

The Integration of Veterinary Medicine and Behavioral Management in the Care of Captive Pigtail Macaques (Macaca nemestrina)

The Washington National Primate Research Center (WaNPRC) maintains the largest domestic breeding colony of pigtail macaques (Macaca nemestrina) in the United States, with animals housed in small to medium-sized social groups. As part of the animal care plan, a programmatic framework is utilized, which integrates clinical care with socialization considerations for nonhuman primates (NHPs). This framework encompasses the following areas: (1) socialization in the clinical setting; (2) positive reinforcement training (PRT); (3) measures to ensure proper identification and medication distribution; and (4) in-group treatments. The success of this framework is demonstrated by the high socialization rate for hospitalized animals (99.5% social pairing success), with the majority of clinical cases (95%) being treated in social groups. Ultimately, this framework seeks to buffer stressors when animals require clinical care or husbandry manipulations. Taken together, the above components foster an environment that provides a comprehensive approach to NHP medical and behavioral management.

Assessment of the Depiction of Superficial White Matter Using Ultra-High-Resolution Diffusion MRI.

The superficial white matter (SWM) consists of numerous short-range association fibers connecting adjacent and nearby gyri and plays an important role in brain function, development, aging, and various neurological disorders. Diffusion MRI (dMRI) tractography is an advanced imaging technique that enables in vivo mapping of the SWM. However, detailed imaging of the small, highly-curved fibers of the SWM is a challenge for current clinical and research dMRI acquisitions. This work investigates the efficacy of mapping the SWM using in vivo ultra-high-resolution dMRI data. We compare the SWM mapping performance from two dMRI acquisitions: a high-resolution 0.76-mm isotropic acquisition using the generalized slice-dithered enhanced resolution (gSlider) protocol and a lower resolution 1.25-mm isotropic acquisition obtained from the Human Connectome Project Young Adult (HCP-YA) database. Our results demonstrate significant differences in the cortico-cortical anatomical connectivity that is depicted by these two acquisitions. We perform a detailed assessment of the anatomical plausibility of these results with respect to the nonhuman primate (macaque) tract-tracing literature. We find that the high-resolution gSlider dataset is more successful at depicting a large number of true positive anatomical connections in the SWM. An additional cortical coverage analysis demonstrates significantly higher cortical coverage in the gSlider dataset for SWM streamlines under 40 mm in length. Overall, we conclude that the spatial resolution of the dMRI data is one important factor that can significantly affect the mapping of SWM. Considering the relatively long acquisition time, the application of dMRI tractography for SWM mapping in future work should consider the balance of data acquisition efforts and the efficacy of SWM depiction.

17O Schwann cell transduction and PMP22 target engagement in non-human primates supports translation of RNAi-based gene therapy for CMT1A

17O Schwann cell transduction and PMP22 target engagement in non-human primates supports translation of RNAi-based gene therapy for CMT1A

When rewards backfire: Collapsing under pressure in motor cortex

People often underperform their abilities in high-value situations, a mysterious phenomenon known as "choking under pressure." In this issue of Neuron, Smoulder etal.1 report that target-selective signals in the motor cortex of non-human primates collapse in the face of high-value opportunities.

Peptidoglycan accumulates in distinct brain regions and cell types over lifetime but is absent in newborns

Peptidoglycan (PGN) is a large complex polymer critical to structure and function of all bacterial species. Intact PGN and its fragments are inflammatory, contributing to infectious and autoimmune disease. Recent studies show that PGN physiologically contributes to immune setpoints, and importantly also to mouse brain development and behavior. However, for the human brain, it remains unknown whether PGN and its fragments differentially gain access to distinct brain regions, which cell types accumulate it, and whether PGN brain load varies with age. Therefore, we investigated human postmortem brain samples of donors with an extensive age range, from newborns to nonagenarians. We examined two monoclonal antibodies against PGN which were validated using dot blot analysis, competition assays and immunofluorescence experiments on bacteria sacculi, which jointly showed specific detection of Gram-positive PGN. As positive reference tissue, brain tissue from sepsis patients, and human liver were used, both showing the expected high PGN levels. In adult brain tissue of different age (34- to 94-year-old) and sex, we detected PGN signals in seven different brain regions, with highest loads in the occipital cortex, hippocampal formation, frontal cortex, the periventricular region and the olfactory bulb. Age-dependent increase of signals was not evident by microscopic observations and only weak correlation was found by statistical analysis in this cohort. PGN was found intracellularly in the cytoplasm surrounding the cell nucleus in astrocytes, oligodendrocytes, neurons, and endothelial cells, but not in macrophages like microglia. PGN was absent in brain tissues of three human newborns (stillbirth to four weeks old). For comparison, three brain regions from non-human primates of varying age (newborn to 21 years) were immunohistochemically stained. The highest PGN-load was observed in brain tissue from 18- to 21-year-old macaques.This first systematic evaluation of PGN in human postmortem brain suggests that PGN accumulates during lifetime until it reaches a plateau by homeostatic turnover and highlights the ubiquitous presence of PGN in human brain tissues, and their ability to participate in physiological as well as pathological processes throughout life.

Generation, expansion, gene delivery, and single-cell profiling in rhesus macaque plasma B cells.

A key step in developing engineered B cells for therapeutic purposes is evaluation in immunocompetent, large-animal models. Therefore, we developed methods to purify, expand, and differentiate non-human primate (NHP; rhesus macaque) B cells. After 7days in culture, B cells expanded 10-fold, differentiated into a plasma cell phenotype (CD38, CD138), and secreted immunoglobulin G. Using single-cell sequencing and flow cytometry, we verified the presence of plasma cell genes in differentiated NHP B cells and unearthed less-recognized markers, such as CD59 and CD79A. In contrast with human cells, we found that the immune checkpoint molecule CD274 (PD-L1) and major histocompatibility complex (MHC) class I molecules were upregulated in NHP plasma cells in the transcriptional data. Lastly, we established the conditions for efficient transduction of NHP B cells with adeno-associated virus (AAV) vectors, achieving a delivery rate of approximately 60%. We envision that this work will accelerate proof-of-concept studies using engineered B cells in NHPs.

Bridging the Gap of Late-Gestation Human Nephrogenesis Using a Nonhuman Primate Model

Bridging the Gap of Late-Gestation Human Nephrogenesis Using a Nonhuman Primate Model

Sexual Dimorphism and Divergent Evolutionary Pathways in Primate Cranial Biomechanics: Insights From a Theoretical Morphology Framework.

The mammalian order Primates is known for widespread sexual dimorphism in size and phenotype. Despite repeated speculation that primate sexual size dimorphism either facilitates or is in part driven by functional differences in how males and females interact with their environments, few studies have directly assessed the influence of sexual dimorphism on performance traits. Here, we use a theoretical morphology framework to show that sexual dimorphism in primate crania is associated with divergent biomechanical performance traits. The degree of dimorphism is a significant covariate in biomechanical trait divergence between sexes. Males exhibit less efficient but stiffer cranial shapes and significant evolutionary allometry in biomechanical performance, whereas females maintain performance stability across their size spectrum. Evolutionary rates are elevated for efficiency in females whereas males emphasize size-dependent cranial stiffness. These findings support a hypothesis of sex-linked bifurcation in masticatory system performance: larger male crania and faster size evolution partially compensate for low efficiency and reflect a de-emphasis of mechanical leverage, whereas female crania maintain higher mechanical efficiency overall and evolve more rapidly in molar-based masticatory performance. The evolutionary checks-and-balances between size dimorphism and cranial mechanical performance may be a more important driver of primate phenotypic evolution than has been hitherto appreciated.

Deep learning detects subtle facial expressions in a multilevel society primate.

Facial expressions in nonhuman primates are complex processes involving psychological, emotional, and physiological factors, and may use subtle signals to communicate significant information. However, uncertainty surrounds the functional significance of subtle facial expressions in animals. Using artificial intelligence (AI), this study found that nonhuman primates exhibit subtle facial expressions that are undetectable by human observers. We focused on the golden snub-nosed monkeys (Rhinopithecus roxellana), a primate species with a multilevel society. We collected 3427 front-facing images of monkeys from 275 video clips captured in both wild and laboratory settings. Three deep learning models, EfficientNet, RepMLP, and Tokens-To-Token ViT, were utilized for AI recognition. To compare the accuracy of human performance, two groups were recruited: one with prior animal observation experience and one without any such experience. The results showed human observers to correctly detect facial expressions (32.1% for inexperienced humans and 45.0% for experienced humans on average with a chance level of 33%). In contrast, the AI deep learning models achieved significantly higher accuracy rates. The best-performing model achieved an accuracy of 94.5%. Our results provide evidence that golden snub-nosed monkeys exhibit subtle facial expressions. The results further our understanding of animal facial expressions and also how such modes of communication may contribute to the origin of complex primate social systems.

Performance of Human and Porcine Derived Acellular Dermal Matrices in Prepectoral Breast Reconstruction: A Long-term Clinicaland Histologic Evaluation.

Human acellular dermal matrices (ADMs) remain the most used matrices in prosthetic breast reconstruction. However, the availability and cost of ADMs limit their use in prepectoral reconstruction-which requires large amounts of ADM-and alternative matrices are therefore being explored. The aim of this study was to demonstrate the safety and efficacy of human-porcine ADM constructs via clinical outcomes and histologic evidence of graft integration. Consecutive patients undergoing tissue-expander/implant reconstructions with human-porcine ADM constructs were included. Biopsies of both ADMs were obtained at expander/implant exchange and evaluated for cellularization, vascularization, and inflammation. Postoperative complications were retrieved from patient records. Fifty-nine patients met the inclusion criteria. Mean [standard deviation] follow-up was 6.7 [0.56] years; minimum follow-up was 5 years. Any complication rate was 8.6%, including skin necrosis (6.9%), seroma (1.7%), expander/implant exposure (1.7%), and return to the operating room (2.6%). A total of 138 ADM biopsy specimens were obtained from 38 patients at expander/implant exchange. Histologic analyses revealed lower fibroblast infiltration and vascularization and higher inflammatory response in porcine vs human ADM specimens, consistent with published results in nonhuman primates. Despite these differences, there were no cases of graft rejection, capsular contracture, or expander/implant loss. Porcine ADM performs clinically in a similar manner to human ADM, albeit with minor differences in cellular ingrowth and vascularization, suggesting that it may be an alternative to human ADM in prepectoral breast reconstruction.

Efficacy of mucosal vaccines in nonhuman primates.

Efficacy of mucosal vaccines in nonhuman primates.