Development and assessment of a stair ascension challenge as a measure of aging and physical function in nonhuman primates.

Nonhuman primates (NHPs) are valuable models for studying healthspan, including frailty development. Frailty metrics in people centers on functional measures, including usual gait speed which can be predictive of all-cause mortality. This concept that physical competencies are able to prognosticate an individual's health trajectory over chronologic aging is well-accepted and has led to refinements in how physical function is evaluated, and include measures of strength and power along with walking speed. NHP studies of aging require evaluation of physical function, which can be difficult in field and research settings. We compared stair climb velocity to usual walking speed in 28 peri-geriatric to geriatric NHPs, as incorporating a climbing obstacle integrates multiple components of physical function: isolated leg and back strength, proprioception, balance, and range of motion. We find that stair climbing speed was reliable between observers, and whether timing was in-person take from video capture. The stair climb rates were 50% more associated with chronological age than walking speed (R = -0.68 vs. -0.45) and only stair climbing speeds were retained as predictive of age when walking speed and bodyweight were included in multivariate models (overall R2 = 0.44; p < 0.0001). When comparing young (10-16 years) versus geriatric (16-29 years) stair climbing speed was significantly different (p < 0.001), while walking speeds only tended to be slower (p = 0.12) suggesting that the additional challenge of a stair climb better unmasks subclinical frailty development that usual walking speed.

Efficiency of whole-exome sequencing in old world and new world primates using human capture reagents.

BACKGROUND: Whole-exome sequencing (WES) can expedite research on genetic variation in non-human primate (NHP) models of human diseases. However, NHP-specific reagents for exome capture are not available. This study reports the use of human-specific capture reagents in WES for olive baboons, marmosets, and vervet monkeys. METHODS: Exome capture was carried out using the SureSelect Human All Exon V6 panel from Agilent Technologies, followed by high-throughput sequencing. Capture of protein-coding genes and detection of single nucleotide variants were evaluated. RESULTS: Exome capture and sequencing results showed that more than 97% of old world and 93% of new world monkey protein coding genes were detected. Single nucleotide variants were detected across the genomes and missense variants were found in genes associated with human diseases. CONCLUSIONS: A cost-effective approach based on commercial, human-specific reagents can be used to perform WES for the discovery of genetic variants in these NHP species.

Modeling variation in the growth of wild and captive juvenile vervet monkeys in relation to diet and resource availability.

OBJECTIVES: To compare longitudinal weight gain in captive and wild juvenile vervet monkeys and conduct an empirical assessment of different mechanistic growth models. METHODS: Weights were collected from two groups of captive monkeys and two consecutive cohorts of wild monkeys until the end of the juvenile period (~800 days). The captive groups were each fed different diets, while the wild groups experienced different ecological conditions. Three different growth curve models were compared. RESULTS: By 800 days, the wild juveniles were lighter, with a slower maximum growth rate, and reached asymptote earlier than their captive counterparts. There were overall differences in weight and growth rate across the two wild cohorts. This corresponded to differences in resource availability. There was considerable overlap in growth rate and predicted adult weight of male and females in the first, but not the second, wild cohort. Maternal parity was not influential. While the von Bertalanffy curve provided the best fit to the data sets modeled together, the Logistic curve best described growth in the wild cohorts when considered separately. CONCLUSIONS: The growth curves of the two captive cohorts are likely to lie near the maximum attainable by juvenile vervets. It may be helpful to include deviations from these rates when assessing the performance of wild vervet monkeys. The comparison of wild and captive juveniles confirmed the value of comparing different growth curve models, and an appreciation that the best models may well differ for different populations. Choice of mechanistic growth model can, therefore, be empirically justified, rather than theoretically predetermined.

In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates.

PURPOSE: 5-HT2AR exists in high and low affinity states. Agonist PET tracers measure binding to the active high affinity site and thus provide a functionally relevant measure of the receptor. Limited in vivo data have been reported so far for a comparison of agonist versus antagonist tracers for 5-HT2AR used as a proof of principle for measurement of high and low affinity states of this receptor. We compared the in vivo binding of [11C]CIMBI-5, a 5-HT2AR agonist, and of the antagonist [11C]M100907, in monkeys and baboons. METHODS: [11C]CIMBI-5 and [11C]M100907 baseline PET scans were performed in anesthetized male baboons (n=2) and male vervet monkeys (n=2) with an ECAT EXACT HR+ and GE 64-slice PET/CT Discovery VCT scanners. Blocking studies were performed in vervet monkeys by pretreatment with MDL100907 (0.5 mg/kg, i.v.) 60 minutes prior to the scan. Regional distribution volumes and binding potentials were calculated for each ROI using the likelihood estimation in graphical analysis and Logan plot, with either plasma input function or reference region as input, and simplified reference tissue model approaches. RESULTS: PET imaging of [11C]CIMBI-5 in baboons and monkeys showed the highest binding in 5-HT2AR-rich cortical regions, while the lowest binding was observed in cerebellum, consistent with the expected distribution of 5-HT2AR. Very low free fractions and rapid metabolism were observed for [11C]CIMBI-5 in baboon plasma. Binding potential values for [11C]CIMBI-5 were 25-33% lower than those for [11C]MDL100907 in the considered brain regions. CONCLUSION: The lower binding potential of [11C]CIMBI-5 in comparison to [11C]MDL100907 is likely due to the preferential binding of the former to the high affinity site in vivo in contrast to the antagonist,  [11C]MDL100907, which binds to both high and low affinity sites.

Composition and stability of the vervet monkey milk microbiome.

The human milk microbiome is vertically transmitted to offspring during the postnatal period and has emerged as a critical driver of infant immune and metabolic development. Despite this importance in humans, the milk microbiome of nonhuman primates remains largely unexplored. This dearth of comparative work precludes our ability to understand how species-specific differences in the milk microbiome may differentially drive maternal effects and limits how translational models can be used to understand the role of vertically transmitted milk microbes in human development. Here, we present the first culture-independent data on the milk microbiome of a nonhuman primate. We collected milk and matched fecal microbiome samples at early and late lactation from a cohort of captive lactating vervet monkeys (N = 15). We found that, similar to humans, the vervet monkey milk microbiome comprises a shared community of taxa that are universally present across individuals. However, unlike in humans, this shared community is dominated by the genera Lactobacillus, Bacteroides, and Prevotella. We also found that, in contrast to previous culture-dependent studies in humans, the vervet milk microbiome exhibits greater alpha-diversity than the gut microbiome across lactation. Finally, we did not find support for the translocation of microbes from the gut to the mammary gland within females (i.e., "entero-mammary pathway"). Taken together, our results show that the vervet monkey milk microbiome is taxonomically diverse, distinct from the gut microbiome, and largely stable. These findings demonstrate that the milk microbiome is a unique substrate that may selectively favor the establishment and persistence of particular microbes across lactation and highlights the need for future experimental studies on the origin of microbes in milk.

A nonhuman primate model of early Alzheimer's disease pathologic change: Implications for disease pathogenesis.

INTRODUCTION: Nonhuman primates may serve as excellent models of sporadic age-associated brain ß-amyloid deposition and Alzheimer's disease pathologic changes. We examined whether a vervet nonhuman primate model recapitulated pathologic, physiologic, and behavioral features of early Alzheimer's disease. METHODS: Nine middle-aged (mean = 11.2 years) and nine aged (mean = 21.7 years) female vervet/African green monkeys underwent cerebrospinal fluid collection, gait speed measurement, and neuroimaging before neuropathologic assessment. RESULTS: ß-amyloid plaques were identified in all aged vervets and paired helical filament tau immunoreactivity was observed in all animals. Cerebrospinal fluid ß-amyloid42 and gait speed correlated negatively with age and plaque density. Greater plaque and paired helical filament tau burden predicted reduced volumes and CMRg in several brain regions. DISCUSSION: We observed a coordinated set of relationships among neuropathologic, cerebrospinal fluid, imaging, and behavioral modalities consistent with early Alzheimer's disease. Our results support future use of the vervet model to explore disease mechanisms, biomarkers, and novel therapeutic strategies.

An R848 adjuvanted influenza vaccine promotes early activation of B cells in the draining lymph nodes of non-human primate neonates.

Impaired immune responsiveness is a significant barrier to vaccination of neonates. By way of example, the low seroconversion observed following influenza vaccination has led to restriction of its use to infants over 6 months of age, leaving younger infants vulnerable to infection. Our previous studies using a non-human primate neonate model demonstrated that the immune response elicited following vaccination with inactivated influenza virus could be robustly increased by inclusion of the Toll-like receptor agonist flagellin or R848, either delivered individually or in combination. When delivered individually, R848 was found to be the more effective of the two. To gain insights into the mechanism through which these adjuvants functioned in vivo, we assessed the initiation of the immune response, i.e. at 24 hr, in the draining lymph node of neonate non-human primates. Significant up-regulation of co-stimulatory molecules on dendritic cells could be detected, but only when both adjuvants were present. In contrast, R848 alone could increase the number of cells in the lymph node, presumably through enhanced recruitment, as well as B-cell activation at this early time-point. These changes were not observed with flagellin and the dual adjuvanted vaccine did not promote increases beyond those observed with R848 alone. In vitro studies showed that R848 could promote B-cell activation, supporting a model wherein a direct effect on neonate B-cell activation is an important component of the in vivo potency of R848 in neonates.

The genome of the vervet (Chlorocebus aethiops sabaeus).

We describe a genome reference of the African green monkey or vervet (Chlorocebus aethiops). This member of the Old World monkey (OWM) superfamily is uniquely valuable for genetic investigations of simian immunodeficiency virus (SIV), for which it is the most abundant natural host species, and of a wide range of health-related phenotypes assessed in Caribbean vervets (C. a. sabaeus), whose numbers have expanded dramatically since Europeans introduced small numbers of their ancestors from West Africa during the colonial era. We use the reference to characterize the genomic relationship between vervets and other primates, the intra-generic phylogeny of vervet subspecies, and genome-wide structural variations of a pedigreed C. a. sabaeus population. Through comparative analyses with human and rhesus macaque, we characterize at high resolution the unique chromosomal fission events that differentiate the vervets and their close relatives from most other catarrhine primates, in whom karyotype is highly conserved. We also provide a summary of transposable elements and contrast these with the rhesus macaque and human. Analysis of sequenced genomes representing each of the main vervet subspecies supports previously hypothesized relationships between these populations, which range across most of sub-Saharan Africa, while uncovering high levels of genetic diversity within each. Sequence-based analyses of major histocompatibility complex (MHC) polymorphisms reveal extremely low diversity in Caribbean C. a. sabaeus vervets, compared to vervets from putatively ancestral West African regions. In the C. a. sabaeus research population, we discover the first structural variations that are, in some cases, predicted to have a deleterious effect; future studies will determine the phenotypic impact of these variations.

Human Striatal Dopaminergic and Regional Serotonergic Synaptic Degeneration with Lewy Body Disease and Inheritance of APOE ε4.

Cognitive impairment in older individuals is a complex trait that in population-based studies most commonly derives from an individually varying mixture of Alzheimer disease, Lewy body disease, and vascular brain injury. We investigated the molecular composition of synaptic particles from three sources: consecutive rapid autopsy brains from the Adult Changes in Thought Study, a population-based cohort; four aged nonhuman primate brains optimally processed for molecular investigation; and targeted replacement transgenic mice homozygous for APOE ε4. Our major goal was to characterize the molecular composition of human synaptic particles in regions of striatum and prefrontal cortex. We performed flow cytometry to measure six markers of synaptic subtypes, as well as amyloid ß 42 and paired helical filament tau. Our results showed selective degeneration of dopaminergic terminals throughout the striatum in individuals with Lewy body disease, and serotonergic degeneration in human ventromedial caudate nucleus from individuals with an APOE ε4 allele. Similar results were seen in mouse caudate nucleus homozygous for APOE ε4 via targeted replacement. Together, extension of these clinical, pathologic, and genetic associations from tissue to the synaptic compartment of cerebral cortex and striatum strongly supports our approach for accurately observing the molecular composition of human synapses by flow cytometry.

A Novel R848-Conjugated Inactivated Influenza Virus Vaccine Is Efficacious and Safe in a Neonate Nonhuman Primate Model.

Influenza virus infection of neonates poses a major health concern, often resulting in severe disease and hospitalization. At present, vaccines for this at-risk population are lacking. Thus, development of an effective vaccine is an urgent need. In this study, we have used an innovative nonhuman primate neonate challenge model to test the efficacy of a novel TLR 7/8 agonist R848-conjugated influenza virus vaccine. The use of the intact virus represents a step forward in conjugate vaccine design because it provides multiple antigenic targets allowing for elicitation of a broad immune response. Our results show that this vaccine induces high-level virus-specific Ab- and cell-mediated responses in neonates that result in increased virus clearance and reduced lung pathology postchallenge compared with the nonadjuvanted virus vaccine. Surprisingly, the addition of a second TLR agonist (flagellin) did not enhance vaccine protection, suggesting that combinations of TLR that provide increased efficacy must be determined empirically. These data support further exploration of this new conjugate influenza vaccine approach as a platform for use in the at-risk neonate population.

In vivo evaluation of [18F]FECIMBI-36, an agonist 5-HT2A/2C receptor PET radioligand in nonhuman primate.

We recently reported the radiosynthesis and in vitro evaluation of [18F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([18F]FECIMBI-36) or ([18F]1), an agonist radioligand for 5HT2A/2C receptors in postmortem samples of human brain. Herein we describe the in vivo evaluation of [18F]FECIMBI-36 in vervet/African green monkeys by PET imaging. PET images show that [18F]FECIMBI-36 penetrates the blood-brain barrier and a low retention of radioactivity is observed in monkey brain. Although the time activity curves indicate a somehow heterogeneous distribution of the radioligand in the brain, the low level of [18F]FECIMBI-36 in brain may limit the use of this tracer for quantification of 5-HT2A/2C receptors by PET.

Pair housing of Vervets/African Green Monkeys for biomedical research.

Vervets, also known as African green monkeys, are a nonhuman primate species widely used in biomedical research. However, there are currently few references available describing techniques and rates of success for pair-housing this species. We present data from four cohorts of vervets from three different facilities: (i) the Wake Forest Vervet Research Colony (VRC; n = 72 female pairs, n= 52 male pairs), (ii) the University of Louisiana at Lafayette-New Iberia Research Center (UL-NIRC; n = 57 female pairs, n = 54 male pairs), (iii) the Tulane National Primate Research Center (TNRPC; n = 18 male pairs), and (iv) a cohort of imported males (n = 18 pairs) at Wake Forest. Compatibility was measured at 14, 30, and 60 days following introduction. Success rates for pair-housing at 14 days ranged from 96% to 98% for females and 96% to 100% for males at the VRC and UL-NIRC but were lower in the smaller imported male cohorts (TNPRC: 50%; WF: 28%). Among the UL-NIRC cohort and VRC male cohort, most of the pair separations after 14 days were due to reasons unrelated to social incompatibility. In contrast, a large proportion of TNPRC and imported male pairs successful at 14 days required separation within 60 days due to incompatibility. Multiple logistic regressions were performed using cohort, mean age of pair and weight difference between pair-mates as potential predictors of compatibility at 14 days. All three predicted the 14-day outcome in males but not females. A separate analysis in the VRC cohort found no evidence that prior familiarity in a group setting influenced outcomes. Variations in success rates across cohorts may have been influenced by introduction methodology. Behavioral differences between vervets and macaques, coupled with our findings, lead us to theorize that the gradual introduction techniques commonly implemented to pair house macaques may not be beneficial or suitable for this species. Am. J. Primatol. 79:e22501, 2017. © 2015 Wiley Periodicals, Inc.

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates.

UNLABELLED: Influenza virus can cause life-threatening infections in neonates and young infants. Although vaccination is a major countermeasure against influenza, current vaccines are not approved for use in infants less than 6 months of age, in part due to the weak immune response following vaccination. Thus, there is a strong need to develop new vaccines with improved efficacy for this vulnerable population. To address this issue, we established a neonatal African green monkey (AGM) nonhuman primate model that could be used to identify effective influenza vaccine approaches for use in young infants. We assessed the ability of flagellin, a Toll-like receptor 5 (TLR5) agonist, to serve as an effective adjuvant in this at-risk population. Four- to 6-day-old AGMs were primed and boosted with inactivated PR8 influenza virus (IPR8) adjuvanted with either wild-type flagellin or inactive flagellin with a mutation at position 229 (m229), the latter of which is incapable of signaling through TLR5. Increased IgG responses were observed following a boost, as well as at early times after challenge, in infants vaccinated with flagellin-adjuvanted IPR8. Inclusion of flagellin during vaccination also resulted in a significantly increased number of influenza virus-specific T cells following challenge compared to the number in infants vaccinated with the m229 adjuvant. Finally, following challenge infants vaccinated with IPR8 plus flagellin exhibited a reduced pathology in the lungs compared to that in infants that received IPR8 plus m229. This study provides the first evidence of flagellin-mediated enhancement of vaccine responses in nonhuman primate neonates. IMPORTANCE: Young infants are particularly susceptible to severe disease as a result of influenza virus infection. Compounding this is the lack of effective vaccines for use in this vulnerable population. Here we describe a vaccine approach that results in improved immune responses and protection in young infants. Incorporation of flagellin during vaccination resulted in increased antibody and T cell responses together with reduced disease following virus infection. These results suggest that flagellin may serve as an effective adjuvant for vaccines targeted to this vulnerable population.

Vitamin D heritability and effect of pregnancy status in Vervet monkeys (Chlorocebus aethiops sabaeus) under conditions of modest and high dietary supplementation.

OBJECTIVES: The two objectives of the current study were to: 1) investigate the genetic contributions to variations in serum vitamin D concentrations under two dietary conditions (a standard monkey biscuit diet vs. a diet designed to model typical American consumption); and 2) explore the interaction of vitamin D with pregnancy status using a cohort of pedigreed female vervet/African green monkeys. METHODS: This study includes 185 female (≥3.5 years) vervet/African green monkeys (Chlorocebus aethiops sabaeus) from a multi-generational, pedigreed breeding colony. The 25(OH)D3 concentrations were first measured seven to eight weeks after consuming a "typical American" diet (TAD), deriving 37, 18, and 45% of calories from fat, protein sources, and carbohydrates, and supplemented with vitamin D to a human equivalent of 1,000 IU/day. Vitamin D concentrations were assessed again when animals were switched to a low-fat, standard biscuit diet (LabDiet 5038) for 8 months, which provided a human equivalent of approximately 4,000 IU/day of vitamin D. All statistical analyses were implemented in SOLAR. RESULTS: Pregnancy was associated with reduced 25(OH)D3 concentrations. Heritability analyses indicated a significant genetic contribution to 25(OH)D3 concentrations in the same monkeys consuming the biscuit diet (h(2) =0.66, P=0.0004) and TAD (h(2) =0.67, P=0.0078) diets, with higher 25(OH)D3 concentrations in animals consuming the biscuit diet. Additionally, there was a significant genotype-by-pregnancy status interaction on 25(OH)D3 concentrations (P<0.05) only among animals consuming the TAD diet. DISCUSSION: These results support the existence of a genetic contribution to differences in serum 25(OH)D3 concentrations by pregnancy status and emphasize the role of diet (including vitamin D supplementation) in modifying genetic signals as well as vitamin D concentrations.

Sequencing strategies and characterization of 721 vervet monkey genomes for future genetic analyses of medically relevant traits.

BACKGROUND: We report here the first genome-wide high-resolution polymorphism resource for non-human primate (NHP) association and linkage studies, constructed for the Caribbean-origin vervet monkey, or African green monkey (Chlorocebus aethiops sabaeus), one of the most widely used NHPs in biomedical research. We generated this resource by whole genome sequencing (WGS) of monkeys from the Vervet Research Colony (VRC), an NIH-supported research resource for which extensive phenotypic data are available. RESULTS: We identified genome-wide single nucleotide polymorphisms (SNPs) by WGS of 721 members of an extended pedigree from the VRC. From high-depth WGS data we identified more than 4 million polymorphic unequivocal segregating sites; by pruning these SNPs based on heterozygosity, quality control filters, and the degree of linkage disequilibrium (LD) between SNPs, we constructed genome-wide panels suitable for genetic association (about 500,000 SNPs) and linkage analysis (about 150,000 SNPs). To further enhance the utility of these resources for linkage analysis, we used a further pruned subset of the linkage panel to generate multipoint identity by descent matrices. CONCLUSIONS: The genetic and phenotypic resources now available for the VRC and other Caribbean-origin vervets enable their use for genetic investigation of traits relevant to human diseases.

Executive function mediates age-related variation in social integration in female vervet monkeys (Chlorocebus sabaeus).

In humans, social participation and integration wane with advanced age, a pattern hypothesized to stem from cognitive or physical decrements. Similar age-related decreases in social participation have been observed in several nonhuman primate species. Here, we investigated cross-sectional age-related associations between social interactions, activity patterns, and cognitive function in 25 group-living female vervets (a.k.a. African green monkeys, Chlorocebus sabaeus) aged 8-29 years. Time spent in affiliative behavior decreased with age, and time spent alone correspondingly increased. Furthermore, time spent grooming others decreased with age, but the amount of grooming received did not. The number of social partners to whom individuals directed grooming also decreased with age. Grooming patterns mirrored physical activity levels, which also decreased with age. The relationship between age and grooming time was mediated, in part, by cognitive performance. Specifically, executive function significantly mediated age's effect on time spent in grooming interactions. In contrast, we did not find evidence that physical performance mediated age-related variation in social participation. Taken together, our results suggest that aging female vervets were not socially excluded but decreasingly engaged in social behavior, and that cognitive deficits may underlie this relationship.

Significant genotype by diet (G × D) interaction effects on cardiometabolic responses to a pedigree-wide, dietary challenge in vervet monkeys (Chlorocebus aethiops sabaeus).

Nutrient composition of a diet (D) has been shown to interact with genetic predispositions (G) to affect various lipid phenotypes. Our aim in this study was to confirm G × D interaction and determine whether the interaction extends to other cardiometabolic risk factors such as glycemic measures and body weight. Subjects were vervet monkeys (Chlorocebus aethiops sabaeus; n = 309) from a multigenerational pedigreed colony initially fed with a plant-based diet, standard primate diet (18% calories from protein, 13% from fat, and 69% from carbohydrates), and subsequently challenged for 8 weeks with a diet modeled on the typical American diet (18% calories from protein, 35% from fat, and 47% from carbohydrates). Our results showed that although exposure to the challenge diet did not result in significant changes in weight, most lipid and glycemic biomarkers moved in an adverse direction (P < 0.01). Quantitative genetic analyses showed that cardiometabolic phenotypes were significantly heritable under both dietary conditions (P < 0.05), and there was significant evidence of G × D interaction for these phenotypes. We observed significant differences in the additive genetic variances for most lipid phenotypes (P < 10(-4) ), indicating that the magnitude of genetic effects varies by diet. Furthermore, genetic correlations between diets differed significantly from 1 with respect to insulin, body weight, and some lipid phenotypes (P < 0.01). This implied that distinct genetic effects are involved in the regulation of these phenotypes under the two dietary conditions. These G × D effects confirm and extend previous observations in baboons (Papio sp.) and suggest that mimicking the typical human nutritional environment can reveal genetic influences that might not be observed in animals consuming standard, plant-based diets.

Age-related degenerative functional, radiographic, and histological changes of the shoulder in nonhuman primates.

BACKGROUND: Nonhuman primates have similar shoulder anatomy and physiology compared to humans, and may represent a previously underutilized model for shoulder research. This study sought to identify naturally occurring bony and muscular degeneration in the shoulder of nonhuman primates and to assess relationships between structural and functional aspects of the shoulder and measures of physical function of the animals. We hypothesized that age-related degenerative changes in the shoulders of nonhuman primates would resemble those observed in aging humans. METHODS: Middle-aged (n = 5; ages 9.4-11.8 years) and elderly (n = 6; ages 19.8-26.4 years) female vervet monkeys were studied for changes in mobility and shoulder function, and radiographic and histologic signs of age-related degeneration. RESULTS: Four out of 6 (4/6) elderly animals had degenerative changes of the glenoid compared to 0/5 of the middle-aged animals (P = .005). Elderly animals had glenoid retroversion, decreased joint space, walked slower, and spent less time climbing and hanging than middle-aged vervets (P < .05). Physical mobility and shoulder function correlated with glenoid version angle (P < .05). Supraspinatus muscles of elderly animals were less dense (P = .001), had decreased fiber cross-sectional area (P < .001), but similar amounts of nuclear material (P = .085). Degenerative rotator cuff tears were not observed in any of the eleven animals. DISCUSSION AND CONCLUSION: The vervet monkey naturally undergoes age-related functional, radiographic and histological changes of the shoulder, and may qualify as an animal model for selected translational research of shoulder osteoarthritis.

Early time-restricted feeding improves high-density lipoprotein amount and function in nonhuman primates, without effects on body composition.

OBJECTIVE: Time-restricted feeding (TRF), whereby caloric intake is limited to a <12-hour window, is a potential regimen to ameliorate metabolic syndrome and cardiovascular disease (CVD) risk co-occurring with aging and with obesity. Early TRF (eTRF; early morning feeding followed by overnight fasting) times calorie consumption with hepatic circadian gene expression rhythms. Brief TRF trials demonstrate that high-density lipoprotein (HDL) cholesterol increases similar to diet/exercise interventions, which may impart beneficial CVD effects. Using a nonhuman primate (NHP) model, the efficacy of eTRF to raise HDL and increase plasma cholesterol efflux capacity (CEC) (primarily mediated by cholesterol efflux to HDL particles, a process that is inversely associated with CVD risk) was examined. METHODS: Adult (8-16 years old, n = 25) and geriatric (≥17 years old) NHPs were randomized to ad libitum feeding or eTRF for 12 months, and relevant body composition, glycemic control, and plasma HDL cholesterol levels and CEC were measured. RESULTS: Impaired CEC was found in geriatric NHPs. eTRF induced larger-sized HDL particles, increased HDL apolipoprotein A-1 content, lowered triglyceride concentrations, and increased plasma CEC (primarily to HDL particles) in both adult and geriatric NHPs without changes in glycemic control or body composition. CONCLUSIONS: A beneficial effect of eTRF on increasing HDL CEC in NHPs was demonstrated.

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations.

G-protein-coupled receptor 119 (GPR119) has emerged as a promising target for treating type 2 diabetes mellitus. Activating GPR119 improves glucose homeostasis, while suppressing appetite and weight gain. Measuring GPR119 levels in vivo could significantly advance GPR119-based drug development strategies including target engagement, occupancy, and distribution studies. To date, no positron emission tomography (PET) ligands are available to image GPR119. In this paper, we report the synthesis, radiolabeling, and preliminary biological evaluations of a novel PET radiotracer [18F]KSS3 to image GPR119. PET imaging will provide information on GPR119 changes with diabetic glycemic loads and the efficacy of GPR119 agonists as antidiabetic drugs. Our results demonstrate [18F]KSS3's high radiochemical purity, specific activity, cellular uptake, and in vivo and ex vivo uptake in pancreas, liver, and gut regions, with high GPR119 expression. Cell pretreatment with nonradioactive KSS3, rodent PET imaging, biodistribution, and autoradiography studies showed significant blocking in the pancreas showing [18F]KSS3's high specificity.