Development In Nonhuman Primates Research Articles

Comparative study of pancreatic vessels and mesopancreas of rhesus monkeys and humans.

With the introduction of the concept of mesopancreas defining the perineural structures that includes neurovascular bundle and lymph nodes extending from the posterior surface of the pancreatic head to behind the mesenteric vessels,Total Mesopancreas Excision (TMpE) based on this theory has facilitated the development of pancreatic cancer surgery in clinical practice in recent years. However, the existence of so called mesopancreas in the human body is still in debate and the comparative study of mesopancreas of rhesus monkey and human have not been well investigated. The aim of our study is to compare the pancreatic vessels and fascia of human and rhesus monkeys in anatomical and embryological perspectives and to support the utilization of rhesus monkey as animal model. In this study, 20 rhesus monkey cadavers were dissected and their mesopancreas location, relationships and arterial distribution were analyzed. We compared the location and developmental patterns of mesopancreas in macaques and humans. The results showed that the distribution of pancreatic arteries in rhesus monkeys was the same as that in humans, which is consistent with phylogenetic similarities. However, the morphological features of the mesopancreas and greater omentum is anatomically different from that of humans, including (1) the greater omentum is not connected to the transverse colon in monkeys. (2) The presence of the dorsal mesopancreas of the rhesus monkey suggests that it be an intraperitoneal organ. Comparative anatomical studies of mesopancreas and arteries in macaques and humans showed characteristic patterns of mesopancreas and similarities in pancreatic artery development in nonhuman primates, consistent with phylogenetic differentiation.

Resting-State fMRI-Based Screening of Deschloroclozapine in Rhesus Macaques Predicts Dosage-Dependent Behavioral Effects.

Chemogenetic techniques, such as designer receptors exclusively activated by designer drugs (DREADDs), enable transient, reversible, and minimally invasive manipulation of neural activity in vivo Their development in nonhuman primates is essential for uncovering neural circuits contributing to cognitive functions and their translation to humans. One key issue that has delayed the development of chemogenetic techniques in primates is the lack of an accessible drug-screening method. Here, we use resting-state fMRI, a noninvasive neuroimaging tool, to assess the impact of deschloroclozapine (DCZ) on brainwide resting-state functional connectivity in 7 rhesus macaques (6 males and 1 female) without DREADDs. We found that systemic administration of 0.1 mg/kg DCZ did not alter the resting-state functional connectivity. Conversely, 0.3 mg/kg of DCZ was associated with a prominent increase in functional connectivity that was mainly confined to the connections of frontal regions. Additional behavioral tests confirmed a negligible impact of 0.1 mg/kg DCZ on socio-emotional behaviors as well as on reaction time in a probabilistic learning task; 0.3 mg/kg DCZ did, however, slow responses in the probabilistic learning task, suggesting attentional or motivational deficits associated with hyperconnectivity in fronto-temporo-parietal networks. Our study highlights both the excellent selectivity of DCZ as a DREADD actuator, and the side effects of its excess dosage. The results demonstrate the translational value of resting-state fMRI as a drug-screening tool to accelerate the development of chemogenetics in primates.SIGNIFICANCE STATEMENT Chemogenetics, such as designer receptors exclusively activated by designer drugs (DREADDs), can afford control over neural activity with unprecedented spatiotemporal resolution. Accelerating the translation of chemogenetic neuromodulation from rodents to primates requires an approach to screen novel DREADD actuators in vivo Here, we assessed brainwide activity in response to a DREADD actuator deschloroclozapine (DCZ) using resting-state fMRI in macaque monkeys. We demonstrated that low-dose DCZ (0.1 mg/kg) did not change whole-brain functional connectivity or affective behaviors, while a higher dose (0.3 mg/kg) altered frontal functional connectivity and slowed response in a learning task. Our study highlights the excellent selectivity of DCZ at proper dosing, and demonstrates the utility of resting-state fMRI to screen novel chemogenetic actuators in primates.

Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring.

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.

Bringing up baby: Maternal responsiveness, secondary attachments, and the development of infant social competence in wild olive baboons (Papio anubis).

Caregiver responsiveness and presence of secondary attachments play a crucial role in children's socio-cognitive and emotional development, but little is known of their effect on the development of non-human primates. Here we present the results of a 16-month behavioral study conducted on 22 wild infant olive baboons (Papio anubis) at the Uaso Ngiro Baboon Project, Kenya. This is the first study to examine the effects of maternal responsiveness and secondary attachments on the development of infant social behavior in a wild primate species that does not breed cooperatively. The data track maternal responsiveness and the rates of two behavioral indicators of infant social competence-orienting toward interactions and social play-over the course of the first year of life. Maternal responsiveness decreased as infants grew older, while infant orientation toward interactions and play behavior increased. Infants with poorly responsive mothers were more likely to have secondary attachments, and infants with secondary attachments to siblings oriented more frequently to social interactions than those with secondary attachments to adult/subadult males or with no secondary attachments. These findings indicate that variation in maternal responsiveness and presence of secondary attachments can influence the development of social competence in olive baboon infants.

Rational Vaccine Design in the Time of COVID-19

As scientists consider SARS-CoV-2 vaccine design, we discuss problems that may be encountered and how to tackle them by what we term “rational vaccine design.” We further discuss approaches to pan-coronavirus vaccines. We draw on experiences from recent research on several viruses including HIV and influenza, as well as coronaviruses.

Yearbook of Physical Anthropology Preface.

Yearbook of Physical Anthropology Preface.

Resources for functional genomic studies of health and development in nonhuman primates.

Primates display a wide range of phenotypic variation underlaid by complex genetically regulated mechanisms. The links among DNA sequence, gene function, and phenotype have been of interest from an evolutionary perspective, to understand functional genome evolution and its phenotypic consequences, and from a biomedical perspective to understand the shared and human-specific roots of health and disease. Progress in methods for characterizing genetic, transcriptomic, and DNA methylation (DNAm) variation is driving the rapid development of extensive omics resources, which are now increasingly available from humans as well as a growing number of nonhuman primates (NHPs). The fast growth of large-scale genomic data is driving the emergence of integrated tools and databases, thus facilitating studies of gene functionality across primates. This review describes NHP genomic resources that can aid in exploration of how genes shape primate phenotypes. It focuses on the gene expression trajectories across development in different tissues, the identification of functional genetic variation (including variants deleterious for protein function and regulatory variants modulating gene expression), and DNAm profiles as an emerging tool to understand the process of aging. These resources enable comparative functional genomics approaches to identify species-specific and primate-shared gene functionalities associated with health and development.

Studying human and nonhuman primate evolutionary biology with powerful in vitro and in vivo functional genomics tools.

In recent years, tools for functional genomic studies have become increasingly feasible for use by evolutionary anthropologists. In this review, we provide brief overviews of several exciting in vitro techniques that can be paired with "-omics" approaches (e.g., genomics, epigenomics, transcriptomics, proteomics, and metabolomics) for potentially powerful evolutionary insights. These in vitro techniques include ancestral protein resurrection, cell line experiments using primary, immortalized, and induced pluripotent stem cells, and CRISPR-Cas9 genetic manipulation. We also discuss how several of these methods can be used in vivo, for transgenic organism studies of human and nonhuman primate evolution. Throughout this review, we highlight example studies in which these approaches have already been used to inform our understanding of the evolutionary biology of modern and archaic humans and other primates while simultaneously identifying future opportunities for anthropologists to use this toolkit to help answer additional outstanding questions in evolutionary anthropology.

An evolutionary perspective on the development of primate sociality

It is now well established that sociality plays a crucial role in primates. For example, among non-human primates, individuals with strong social bonds significantly increase their fecundity, reproductive success, offspring survival and longevity. Also in humans, social integration positively affects psychological stress, health and survival. However, despite the evidence that sociality is a fundamental fitness trait, relatively little is known about how sociality develops. Previous studies are mainly limited to the development of human sociality in Western cultures. Hence, to increase our knowledge about important human developmental milestones, an inter-specific and inter-cultural approach is needed. In particular, to understand the evolutionary roots of human sociality, studies on non-human primates are of large importance. The present Topical Collection is divided into four parts addressing (i) the effect of main bonding partners (mothers, siblings, peers) on social development in non-human primates; (ii) other factors affecting social development, such as sex differences, genetic constraints and personality; (iii) how social cognition and multimodal communication develop through early life in non-human primates and (iv) how human sociality develops through ontogeny, with a special focus on cross-cultural differences. In this paper, we introduce the development of sociality from an evolutionary perspective, briefly summarise each contribution of this Topical Collection and close with possible future directions. We aim to summarise the current state of research on the development of primate sociality, stimulate inter-disciplinary research and provide insight into the outstanding variability in social development across non-human primate species and human cultures. This paper opens a Topical Collection on the development of primate sociality. Here, we introduce the topic, summarise contributions to this collection and outline future directions. To understand the evolutionary roots of human sociality, we consider the social development across different non-human primate species and human cultures.

Immune System Promiscuity in Human and Nonhuman Primate Evolution

Many genes that respond to infection have functions outside of immunity and have been found to be under natural selection. Pathogens may therefore incidentally alter nonimmune physiology through engagement with immune system genes. This raises a logical question of how genetically promiscuous the immune system is, here defijined as how heavily cross-referenced the immune system is into other physiological systems. This work examined immune gene promiscuity across physiological systems in primates by assessing the baseline (unperturbed) expression of key tissue and cell types for diffferences, and primate genomes for signatures of selection. These effforts revealed “immune” gene expression to be cross-referenced extensively in other physiological systems in primates. When immune and nonimmune tissues diverge in expression, the diffferentially expressed genes at baseline are enriched for cell biological activities not immediately identifijiable as immune function based. Individual comparisons of immune and nonimmune tissues in primates revealed low divergence in gene expression between tissues, with the exception of whole blood. Immune gene promiscuity increases over evolutionary time, with hominoids exhibiting the most cross-referencing of such genes among primates. An assessment of genetic sequences also found positive selection in the coding regions of diffferentially expressed genes between tissues functionally associated with immunity. This suggests that, with increasing promiscuity, divergent gene expression between the immune system and other physiological systems tends to be adaptive and enriched for immune functions in hominoids.

Biological Anthropology in 2018: Grounded in Theory, Questioning Contexts, Embracing Innovation

ABSTRACTBiological anthropology in 2018 encapsulated what past scholars envisioned for its future: a multidisciplinary approach to understanding human and nonhuman primate evolution and diversity using the most innovative techniques and rigorous standards available. This year also built on a tradition of introspection about what biological anthropology encompasses and by whom and how it is conducted. This review highlights research and movements in the field that reflect both of these pursuits. Studies drew on evolutionary theory to generate novel insights into human and nonhuman primate biology, behavior, and organization. Studies on hominin evolution and human biology have upended previous understandings by revealing more dynamic and context‐dependent processes in our ancestry and phenotypic expressions. Across subdisciplines, biological anthropologists have advanced the use of new technologies and analytical techniques and begun to promote open, transparent, and reproducible science among a more diverse community of researchers. [year in review, evolutionary anthropology, context and variation, emerging technologies, transparent methods, researcher diversity]

OR08-5 The Effect of Short-Term Western-Style Diet Consumption on Primate Ovarian Follicle, Oocyte, and Embryo Development

A maternal high-fat diet is associated with reduced oocyte quality, fertilization, as well as altered preimplantation embryo development. It is unclear, especially in women, if these effects are due to the diet itself or the subsequent development of metabolic dysfunction. Thus, a longitudinal study was performed using the clinically relevant rhesus macaque model to test the hypothesis that short-term exposure to a high-fat Western Style Diet (WSD) negatively impacts primate ovarian follicle, oocyte, and preimplantation embryo development. Oocytes were collected from regularly cycling female rhesus macaques (N=10; ages 5-6yrs) after undergoing a controlled ovarian stimulation protocol (COS1) while consuming a Standard Chow Diet (SCD; 13% fat). Animals were then switched to WSD (35% fat) for 6-8 months prior to going through a second COS protocol (COS2). Follicular fluid (FF) was collected from 4 individual follicles per female per COS and pooled for subsequent steroid and cytokine analysis by mass spectrometry and a multiplex assay system (Luminex), respectively. Individually isolated oocytes and oocytes aspirated from the remaining follicles were then assessed for reinitiation of meiosis, in vitro fertilization (IVF) and subsequent blastocyst formation rates. Time-lapse monitoring (TLM) was performed post-IVF to study initial mitotic division kinetics, as well as cellular fragmentation and multipolar divisions. Weight gain by the female macaques post-WSD intake recorded at COS2 was significant (P=0.0001), but insulin resistance (HOMA-IR) at the time of COS2 was not significantly different from COS1. Of the 10 females, 2 were resistant to weight gain and another 2 did not respond to COS2. Excluding the 2 non-responsive females, FF interleukin (IL)-1 receptor antagonist (IL-1RA; P=0.009) and IL-2 (P=0.004) levels decreased post-WSD intake. The levels of cortisone, an inactive metabolite of the biologically active glucocorticoid cortisol, were 18% higher, while mean cortisol levels were 22% lower, in the FF collected from COS2 relative to COS1. This resulted in a reduced cortisol:cortisone ratio post-WSD intake (P=0.028) and negatively correlated with the resident oocyte’s ability to form a blastocyst following IVF (R=-0.66; P<0.05). While 138 blastocysts were obtained from COS1, the total number blastocysts collected from COS significantly decreased to 77 (P=0.036) post-WSD intake (COS2). Lastly, a higher occurrence of multipolar divisions was observed with fertilized oocytes collected post-WSD diet consumption (COS2) compared to fertilized oocytes collected from animals receiving SCD (COS1). These results demonstrate that WSD consumption alters the intrafollicular microenvironment as well as oocyte and preimplantation embryo development in non-human primates even in the absence of large-scale metabolic changes. Funding: NIH P51 OD011092, NCTRI P50 HD071836

Research progress of adaptive evolution of non-human primates based on genomics

Genomics research of non-human primates can not only explore its molecular mechanisms of evolution and adaptation, but also improve the exploration and utilization of its genetic resources. Recently, the development of genome sequencing methods and its related technologies have made a great contribution to the genomic studies of non-human primates, especially in their adaptation and evolution. Therefore, we summarized the trends of genomics research of non-human primates, analyzed and discussed the research progress of adaptative evolution and biomedical research about non-human primates. This review provides an outlook of the genomics and evolutionary biology of non-human primates in this review, aiming to give a valuable guideline for the future genomic study and sustainable exploitation and utilization of non-human primate resource.

A recombinant vesicular stomatitis-based Lassa fever vaccine elicits rapid and long-term protection from lethal Lassa virus infection in guinea pigs

The World Health Organization has identified Lassa virus (LASV) as one of the top five pathogens to cause a severe outbreak in the near future. This study assesses the ability of a leading vaccine candidate, recombinant Vesicular stomatitis virus expressing LASV glycoprotein (VSVΔG/LASVGPC), and its ability to induce rapid and long-term immunity to lethal guinea pig-adapted LASV (GPA-LASV). Outbred guinea pigs were vaccinated with a single dose of VSVΔG/LASVGPC followed by a lethal challenge of GPA-LASV at 7, 14, 25, 189, and 355 days post-vaccination. Statistically significant rapid and long-term protection was achieved at all time points with 100% protection at days 7 and 14 post-vaccination. While 83 and 87% protection were achieved at 25 days and 6 months post-vaccination, respectively. When guinea pigs were challenged one year after vaccination 71% protection was achieved. Notable infectious virus was isolated from the serum and tissues of some but not all animals. Total LASVGPC-specific IgG titers were also measured on a monthly basis leading up to LASV challenge however, it is unclear if antibody alone correlates with short and long term survival. These studies confirm that a single dose of VSVΔG/LASVGPC can induce rapid and long-term protection from LASV infection in an aggressive outbred model of infection, and supports further development in non-human primates.

Age and social affinity effects on contact call interactions in free-ranging spider monkeys

Nonhuman primates’ vocal repertoire has shown little plasticity, with immatures producing adult-like acoustic structures. Yet, the use of different call types shows a degree of socially dependent flexibility during development. In several nonhuman primate species, group members exchange contact calls respecting a set of social and temporal rules that may be learned (e.g., overlap avoidance, turn-taking, social selection of interacting partners, and call type matching). Here, we study the use of contact calls in free-living adult and immature (old and young) spider monkeys (Ateles geoffroyi). We focused our study in two contact call types of the species’ repertoire: whinnies and high-whinnies. Our results suggest that individuals in all age classes produced both call types, with immatures producing less frequently the whinny call type. Immature individuals exchanged calls less often than adults, although their contribution increased with age. Conversely, mature individuals regulated their emissions by (1) exchanging more calls with their preferred affiliative partner and (2) matching the call type, while immatures did not. Our results show that contact call usage changes during development and suggest that adult rules might be learned. We argue that call matching is a “conversational rule” that young individuals acquire with apparent call-type-dependent variations during development. Our findings support the idea that social factors influence vocal development in nonhuman primates. We studied the social rules underlying vocal interaction patterns in free-ranging spider monkeys. We found that, while both immature (old and young) and mature individuals were able to produce the two species contact call types, they differed strongly in the way they used them. Matures called more often and exchanged more, while the vocal response rates of immature individuals increased with age. Also, mature individuals exchanged preferentially with their close associates and matched their call types while immatures did not. As in other species, we predict that these exchange patterns serve as a social rule to maintain and strengthen social bonds between individuals. We discuss our findings in light of the probable role of social learning during acquisition of the appropriate context of calling and of the response to others’ calls. These findings support the idea that social influences guide vocal development in nonhuman primates.

Population genetics of the ABO locus within the rhesus (Macaca mulatta) and cynomolgus (M.fascicularis) macaque hybrid zone.

Knowledge of the macaque ABO blood group system has been critical in the development of nonhuman primates (NHPs) as a translational model. Serving not only as a useful homologue of the disease-linked ABO system in humans, macaque ABO blood groups must be typed in colonies prior to performing experimental procedures requiring blood transfusion or transplantation. While the rates of blood type incompatibility and the distributions of A, B and AB blood groups are known in large samples of rhesus (Macaca mulatta) and cynomolgus (M.fascicularis) macaques, there is a dearth of blood type data from macaque populations occupying the rhesus-cynomolgus hybrid zone in Southeast Asia. Using molecular phenotyping, we profiled ABO blood group distributions of 232 macaques from 10 populations in the hybrid zone and compared them to pure blood populations of the two species. We found that while these distributions are significantly different in most populations, there was a lack of differentiation between the hybrid and cynomolgus macaques as well as between the Thai and neighbouring populations. This supports a more expansive model of hybridization between rhesus and cynomolgus macaques than often proposed and highlights the increased need for consideration of population genetic structure in biomedical studies that employ macaques as animal models. Additionally, we report an enrichment of indeterminate blood types in the hybrid populations.

SIRT6 deficiency results in developmental retardation in cynomolgus monkeys.

SIRT6 acts as a longevity protein in rodents1,2. However, its biological function in primates remains largely unknown. Here we generate a SIRT6-null cynomolgus monkey (Macaca fascicularis) model using a CRISPR-Cas9-based approach. SIRT6-deficient monkeys die hours after birth and exhibit severe prenatal developmental retardation. SIRT6 loss delays neuronal differentiation by transcriptionally activating the long non-coding RNA H19 (a developmental repressor), and we were able to recapitulate this process in a human neural progenitor cell differentiation system. SIRT6 deficiency results in histone hyperacetylation at the imprinting control region of H19, CTCF recruitment and upregulation of H19. Our results suggest that SIRT6 is involved in regulating development in non-human primates, and may provide mechanistic insight into human perinatal lethality syndrome.

Evidence of cardiac involvement in the fetal inflammatory response syndrome: disruption of gene networks programming cardiac development in nonhuman primates

Most early preterm births are associated with intraamniotic infection and inflammation, which can lead to systemic inflammation in the fetus. The fetal inflammatory response syndrome describes elevations in the fetal interleukin-6 level, which is a marker for inflammation and fetal organ injury. An understanding of the effects of inflammation on fetal cardiac development may lead to insight into the fetal origins of adult cardiovascular disease. The purpose of this study was to determine whether the fetal inflammatory response syndrome is associated with disruptions in gene networks that program fetal cardiac development. We obtained fetal cardiac tissue after necropsy from a well-described pregnant nonhuman primate model (pigtail macaque, Macaca nemestrina) of intrauterine infection (n=5) and controls (n=5). Cases with the fetal inflammatory response syndrome (fetal plasma interleukin-6 >11 pg/mL) were induced by either choriodecidual inoculation of a hypervirulent group B streptococcus strain (n=4) or intraamniotic inoculation of Escherichia coli (n=1). RNA and protein were extracted from fetal hearts and profiled by microarray and Luminex (Millipore, Billerica, MA) for cytokine analysis, respectively. Results were validated by quantitative reverse transcriptase polymerase chain reaction. Statistical and bioinformatics analyses included single gene analysis, gene set analysis, Ingenuity Pathway Analysis (Qiagen, Valencia, CA), and Wilcoxon rank sum. Severe fetal inflammation developed in the context of intraamniotic infection and a disseminated bacterial infection in the fetus. Interleukin-6 and -8 in fetal cardiac tissues were elevated significantly in fetal inflammatory response syndrome cases vs controls (P<.05). A total of 609 probe sets were expressed differentially (>1.5-fold change, P<.05) in the fetal heart (analysis of variance). Altered expression of select genes was validated by quantitative reverse transcriptase polymerase chain reaction that included several with known functions in cardiac injury, morphogenesis, angiogenesis, and tissue remodeling (eg, angiotensin I converting enzyme 2, STEAP family member 4, natriuretic peptide A, and secreted frizzled-related protein 4; all P<.05). Multiple gene sets and pathways that are involved in cardiac morphogenesis and vasculogenesis were downregulated significantly by gene set and Ingenuity Pathway Analysis (hallmark transforming growth factor beta signaling, cellular morphogenesis during differentiation, morphology of cardiovascular system; all P<.05). Disruption of gene networks for cardiac morphogenesis and vasculogenesis occurred in the preterm fetal heart of nonhuman primates with preterm labor, intraamniotic infection, and severe fetal inflammation. Inflammatory injury to the fetal heart in utero may contribute to the development of heart disease later in life. Development of preterm labor therapeutics must also target fetal inflammation to lessen organ injury and potential long-term effects on cardiac function.

Amnion epithelial cells - a novel therapy for ischemic stroke?

Stroke is a leading cause of death and disability and new therapies are desperately needed. Given the complex nature of ischemic brain injury, it has been postulated that cell-based therapies may be useful. However, cell resources, invasive extraction procedures, immunological rejection, tumorigenesis and ethical challenges make it unlikely that many stem cell types could serve as a practical source for therapy. By contrast, these issues do not pertain to human amnion epithelial cells (hAECs), which are placenta-derived stem cells. We recently assessed the effects of systemically delivered hAECs on stroke outcome using four animal models of stroke. We demonstrated that when injected intravenously after ischemia onset, hAECs migrate preferentially to the spleen and injured brain to limit apoptosis and inflammation, and attenuate early brain infiltration of immune cells, progression of infarction and systemic immunosuppression and to ultimately ameliorate functional deficits. When administration of hAECs is delayed by 1-3 days post-stroke, long-term functional recovery can still be enhanced in young and aged mice of either sex. Moreover, our proof-of-principle findings suggest that hAECs are effective at limiting post-stroke infarct development in non-human primates. Overall, the results suggest that hAECs could be a viable clinical stroke therapy.

Animal Models for Dengue and Zika Vaccine Development.

The current status of animal models in the study of dengue and Zika are covered in this review. Mouse models deficient in IFN signaling are used to overcome the natural resistance of mice to non-encephalitic flaviviruses. Conditional IFNAR mice and non-human primates (NHP) are useful immuno-competent models. Sterile immunity after dengue vaccination is not observed in NHPs. Placental and fetal development in NHPs is similar to humans, facilitating studies on infection-mediated fetal impairment.