Using ecological niche modelling to prioritise areas for conservation of the critically endangered Buffy-Headed marmoset (Callithrix flaviceps).

Endemic to the Atlantic Forest in Southeastern Brazil, the critically endangered Buffy-Headed marmoset (Callithrix flaviceps) is lacking the required attention for effective conservation. We modelled its ecological niche with the main objectives of (1) defining suitable habitat and (2) prioritising areas for conservation and/or restoration. The current geographical range of Callithrix flaviceps in the Atlantic Forest of Southeast Brazil. We used Ensemble Species Distribution Modelling to define current habitat suitability considering four climate and two landscape variables. To identify areas to prioritise for conservation and/or restoration, we predicted future habitat suitability considering the intermediate (RCP4.5) and extreme (RCP8.5) climate change scenarios for the years 2050 and 2070. Among the variables included to predict current species distribution, tree canopy cover, precipitation seasonality and temperature seasonality were the most important whereas digital elevation model and precipitation during the wettest month were the least important. Callithrix flaviceps was most likely to occur in areas with tree canopy cover >80%, high precipitation seasonality and temperature seasonality between 21 and 23°C. From the future suitability prediction maps, the Caparaó National Park stands out as a likely key area for the preservation of the species. Furthermore, high climatic suitability but low landscape suitability suggests that habitat restoration in 'Serra das Torres' (South of the current distribution area) might be a useful strategy. However, creating ecological corridors on the west side of Caparaó would be necessary to improve connectivity. More surveys within and beyond the current geographical range are required to define more precisely the distribution of the species. Our results support the notion that seasonality is important for Callithrix flaviceps and that as a montane species, it prefers colder environments and higher altitudes. Within both climate change scenarios, Caparaó National Park was predicted to be highly suitable, with a high probability of presence.

Development and characterization of a non-human primate model of disseminated synucleinopathy.

Introduction: The presence of a widespread cortical synucleinopathy is the main neuropathological hallmark underlying clinical entities such as Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). There currently is a pressing need for the development of non-human primate (NHPs) models of PDD and DLB to further overcome existing limitations in drug discovery. Methods: Here we took advantage of a retrogradely-spreading adeno-associated viral vector serotype 9 coding for the alpha-synuclein A53T mutated gene (AAV9-SynA53T) to induce a widespread synucleinopathy of cortical and subcortical territories innervating the putamen. Four weeks post-AAV deliveries animals were sacrificed and a comprehensive biodistribution study was conducted, comprising the quantification of neurons expressing alpha-synuclein, rostrocaudal distribution and their specific location. Results: Intraputaminal deliveries of AAV9-SynA53T lead to a disseminated synucleinopathy throughout ipsi- and contralateral cerebral cortices, together with transduced neurons located in the ipsilateral caudal intralaminar nuclei and in the substantia nigra pars compacta (leading to thalamostriatal and nigrostriatal projections, respectively). Cortical afferent systems were found to be the main contributors to putaminal afferents (superior frontal and precentral gyri in particular). Discussion: Obtained data extends current models of synucleinopathies in NHPs, providing a reproducible platform enabling the adequate implementation of end-stage preclinical screening of new drugs targeting alpha-synuclein.

A measles-vectored vaccine candidate expressing prefusion-stabilized SARS-CoV-2 spike protein brought to phase I/II clinical trials: protection of African green monkeys from COVID-19 disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is responsible for the largest human pandemic in 100 years. Thirty-four vaccines are currently approved for use worldwide, and approximately 67% of the world population has received a complete primary series of one, yet countries are dealing with new waves of infections, variant viruses continue to emerge, and breakthrough infections are frequent secondary to waning immunity. Here, we evaluate a measles virus (MV)-vectored vaccine expressing a stabilized prefusion SARS-CoV-2 spike (S) protein (MV-ATU3-S2PΔF2A; V591) with demonstrated immunogenicity in mouse models (see companion article [J. Brunet, Z. Choucha, M. Gransagne, H. Tabbal, M.-W. Ku et al., J Virol 98:e01693-23, 2024, https://doi.org/10.1128/jvi.01693-23]) in an established African green monkey model of disease. Animals were vaccinated with V591 or the control vaccine (an equivalent MV-vectored vaccine with an irrelevant antigen) intramuscularly using a prime/boost schedule, followed by challenge with an early pandemic isolate of SARS-CoV-2 at 56 days post-vaccination. Pre-challenge, only V591-vaccinated animals developed S-specific antibodies that had virus-neutralizing activity as well as S-specific T cells. Following the challenge, V591-vaccinated animals had lower infectious virus and viral (v) RNA loads in mucosal secretions and stopped shedding virus in these secretions earlier. vRNA loads were lower in these animals in respiratory and gastrointestinal tract tissues at necropsy. This correlated with a lower disease burden in the lungs as quantified by PET/CT at early and late time points post-challenge and by pathological analysis at necropsy.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the largest human pandemic in 100 years. Even though vaccines are currently available, countries are dealing with new waves of infections, variant viruses continue to emerge, breakthrough infections are frequent, and vaccine hesitancy persists. This study uses a safe and effective measles vaccine as a platform for vaccination against SARS-CoV-2. The candidate vaccine was used to vaccinate African green monkeys (AGMs). All vaccinated AGMs developed robust antigen-specific immune responses. After challenge, these AGMs produced less virus in mucosal secretions, for a shorter period, and had a reduced disease burden in the lungs compared to control animals. At necropsy, lower levels of viral RNA were detected in tissue samples from vaccinated animals, and the lungs of these animals lacked the histologic hallmarks of SARS-CoV-2 disease observed exclusively in the control AGMs.

Why did humans surpass all other primates? Are our brains so different? Part 2.

The second part of this review is an attempt to explain why only Homo sapiens developed language. It should be remarked that this review is based on the opinion of a clinical neurologist and does not intend to go beyond an overview of this complex topic. The progressive development of language was probably due to the expansion of the prefrontal cortex (PFC) and its networks. PFC is the largest area of the human cerebral cortex and is much more expanded in humans than in other primates. To achieve language, several other functions should have been attained, including abstraction, reasoning, expanded working memory, and executive functions. All these functions are strongly related to PFC and language had a profound retroactive impact on them all. Language and culture produce anatomic and physiological modifications in the brain. Learning to read is presented as an example of how culture modifies the brain.

A segunda parte desta revisão é uma tentativa de explicar por que apenas o Homo sapiens desenvolveu a linguagem. Ressalta-se que esta revisão é baseada na opinião de um neurologista clínico e não pretende ir além de uma visão geral deste tema complexo. O desenvolvimento progressivo da linguagem provavelmente se deveu à expansão do córtex pré-frontal (PFC) e de suas conexões. O PFC é a maior área do córtex cerebral humano e é muito maior em seres humanos do que em outros primatas. Para adquirir a linguagem, diversas outras funções precisavam ter sido alcançadas, incluindo abstração, raciocínio, expansão da memória de trabalho e funções executivas. Todas essas funções estão fortemente relacionadas com o PFC e a linguagem teve um profundo impacto retroativo em todas elas. A linguagem e a cultura produzem modificações anatômicas e fisiológicas no cérebro. Aprender a ler é apresentado como um exemplo de como a cultura modifica o cérebro.

Why did humans surpass all other primates? Are our brains so different? Part 1.

This review is based on a conference presented in June 2023. Its main objective is to explain the cognitive differences between humans and non-human primates (NHPs) focusing on characteristics of their brains. It is based on the opinion of a clinical neurologist and does not intend to go beyond an overview of this complex topic. As language is the main characteristic differentiating humans from NHPs, this review is targeted at their brain networks related to language. NHPs have rudimentary forms of language, including primitive lexical/semantic signs. Humans have a much broader lexical/semantic repertory, but syntax is the most important characteristic, which is probably unique to Homo sapiens. Angular gyrus, Broca's area, temporopolar areas, and arcuate fascicle, are much more developed in humans. These differences may explain why NHPs did not develop a similar language to ours. Language had a profound influence on all other higher nervous activities.

Esta revisão baseia-se numa conferência apresentada em junho de 2023. O seu principal objetivo é explicar as diferenças cognitivas entre humanos e primatas não humanos (PNH) com base nas características dos seus cérebros. Baseia se na opinião de um neurologista clínico e não pretende ir além de uma visão geral deste tema complexo. Como a linguagem é a principal característica que diferencia os humanos dos PNH, esta revisão concentra-se nas redes cerebrais relacionadas à linguagem. Os PNH têm formas rudimentares de linguagem, incluindo sinais lexicais/semânticos primitivos. Os humanos têm um repertório léxico/semântico muito mais amplo, mas a sintaxe é a característica mais importante e única do Homo sapiens. O giro angular, a área de Broca, as áreas temporopolares e o fascículo arqueado são muito mais desenvolvidos em humanos. Essas diferenças podem explicar por que os PNH não desenvolveram uma linguagem semelhante à nossa. A linguagem teve influência profunda em todas as outras atividades nervosas superiores.

Exploring the One Health Paradigm in Male Breast Cancer.

How cancer patterns in humans compare to those of other species remains largely unknown and there is an even bigger knowledge gap for rare cancers like male breast cancer. One Health is a convergence of human and animal healthcare that encourages cross-pollination of medical research uniting human and veterinary medicine. Recognising that breast cancer occurs spontaneously in other male species (e.g. primates, canines, felines), and knowing that no laboratory models exist for male breast cancer, which limits our ability to perform functional studies, we explored the feasibility of applying One Health to breast cancer in men by conducting a narrative review of the topic. Spontaneous development of breast cancer was reported in captive male primates and in companion canines and felines. Some parallels in tumour biology of human male breast cancer with canines and primates were found. The age distribution, pattern of biomarker expression and metastasis were similar, with mammary tumours typically detected after two-thirds of average lifespan. However, instances of triple negative and inflammatory breast cancer, which are rarely observed in human male breast cancer, were found in canines and histological classification was inconsistent between species. These disparities need redressing to enable full exploration of the One Health paradigm in rare cancers.

In vitro characterization of [125I]HY-3-24, a selective ligand for the dopamine D3 receptor.

Introduction: Dopamine D3 receptor (D3R) ligands have been studied for the possible treatment of neurological and neuropsychiatric disorders. However, selective D3R radioligands for in vitro binding studies have been challenging to identify due to the high structural similarity between the D2R and D3R. In a prior study, we reported a new conformationally-flexible benzamide scaffold having a high affinity for D3R and excellent selectivity vs. D2R. In the current study, we characterized the in vitro binding properties of a new radioiodinated ligand, [125I]HY-3-24. Methods: In vitro binding studies were conducted in cell lines expressing D3 receptors, rat striatal homogenates, and rat and non-human primate (NHP) brain tissues to measure regional brain distribution of this radioligand. Results: HY-3-24 showed high potency at D3R (Ki = 0.67 ± 0.11 nM, IC50 = 1.5 ± 0.58 nM) compared to other D2-like dopamine receptor subtypes (D2R Ki = 86.7 ± 11.9 nM and D4R Ki > 1,000). The Kd (0.34 ± 0.22 nM) and Bmax (38.91 ± 2.39 fmol/mg) values of [125I]HY-3-24 were determined. In vitro binding studies in rat striatal homogenates using selective D2R and D3R antagonists confirmed the D3R selectivity of [125I]HY-3-24. Autoradiography results demonstrated that [125I]HY-3-24 specifically binds to D3Rs in the nucleus accumbens, islands of Calleja, and caudate putamen in rat and NHP brain sections. Conclusion: These results suggest that [125I]HY-3-24 appears to be a novel radioligand that exhibits high affinity binding at D3R, with low binding to other D2-like dopamine receptors. It is anticipated that [125I]HY-3-24 can be used as the specific D3R radioligand.

Genetic characterization of a captive marmoset (Callithrix jacchus) colony using genotype-by-sequencing.

The marmoset is a fundamental nonhuman primate model for the study of aging, neurobiology, and many other topics. Genetic management of captive marmoset colonies is complicated by frequent chimerism in the blood and other tissues, a lack of tools to enable cost-effective, genome-wide interrogation of variation, and historic mergers and migrations of animals between colonies. We implemented genotype-by-sequencing (GBS) of hair follicle derived DNA (a minimally chimeric DNA source) of 82 marmosets housed at the Southwest National Primate Research Center (SNPRC). Our primary goals were the genetic characterization of our marmoset population for pedigree verification and colony management and to inform the scientific community of the functional genetic makeup of this valuable resource. We used the GBS data to reconstruct the genetic legacy of recent mergers between colonies, to identify genetically related animals whose relationships were previously unknown due to incomplete pedigree information, and to show that animals in the SNPRC colony appear to exhibit low levels of inbreeding. Of the >99,000 single-nucleotide variants (SNVs) that we characterized, >9800 are located within gene regions known to harbor pathogenic variants of clinical significance in humans. Overall, we show the combination of low-resolution (sparse) genotyping using hair follicle DNA is a powerful strategy for the genetic management of captive marmoset colonies and for identifying potential SNVs for the development of biomedical research models.

A spontaneous hyperglycaemic cynomolgus monkey presents cognitive deficits, neurological dysfunction and cataract.

Chronic hyperglycaemia is a chief feature of diabetes mellitus and complicates with many systematic anomalies. Non-human primates (NHPs) are excellent for studying hyperglycaemia or diabetes and associated comorbidities, but lack behavioural observation. In the study, behavioural, brain imaging and histological analysis were performed in a case of spontaneously hyperglycaemic (HGM) Macaca fascicularis. The results were shown that the HGM monkey had persistent body weight loss, long-term hyperglycaemia, insulin resistance, dyslipidemia, but normal concentrations of insulin, C-peptide, insulin autoantibody, islet cell antibody and glutamic acid decarboxylase antibody. Importantly, an impaired working memory in a delayed response task and neurological dysfunctions were found in the HGM monkey. The tendency for atrophy in hippocampus was observed by magnetic resonance imaging. Lenticular opacification, lens fibres disruptions and vacuole formation also occurred to the HGM monkey. The data suggested that the spontaneous HGM monkey might present diabetes-like characteristics and associated neurobehavioral anomalies in this case. This study first reported cognitive deficits in a spontaneous hyperglycaemia NHPs, which might provide evidence to use macaque as a promising model for translational research in diabetes and neurological complications.

What we have learned from non-human primates as animal models of epilepsy.

Non-human primates (NHPs) have played a crucial role in our understanding of epilepsy, given their striking similarities with humans. Through their use, we have gained a deeper understanding of the neurophysiology and pathophysiology of epileptic seizures, and they have proven invaluable allies in developing anti-seizure therapies. This review explores the history of NHPs as natural models of epilepsy, discusses the findings obtained after exposure to various chemoconvulsant drugs and focal electrical stimulation protocols that helped uncover important mechanisms related to epilepsy, examines diverse treatments to prevent and manage epilepsy, and addresses essential ethical issues in research. In this review, we aim to emphasize the important role of NHPs in epilepsy research and summarize the benefits and challenges associated with their use as models.

Prevalence of intestinal trichomonads in captive non-human primates in China.

Trichomonads are protozoan symbionts with the capacity to infect vertebrates including humans and non-human primates (NHPs), sometimes with pathogenic effects. However, their diversity and prevalence in NHPs in China are poorly understood. A total of 533 fecal samples were collected from captive NHPs in Yunnan Province, China, of which 461 samples from Macaca fascicularis and 72 from Macaca mulatta. Trichomonadidae species were identified using PCR amplification of the ITS-1/5.8S/ITS-2 sequences. The overall prevalence of trichomonads in NHPs was determined to be 11.4% (61/533), with gender, diarrhea, and region identified as potential risk factors for the infections. Sequence alignment and phylogenetic analysis identified three species of trichomonads, i.e., Trichomitopsis minor (n = 45), Pentatrichomonas hominis (n = 11), and Tetratrichomonas sp. (n = 5). To the best of our knowledge, this is the first study to report Trichomitopsis minor infection in NHPs in China. Of note, Pentatrichomonas hominis is generally recognized as a parasitic organism affecting humans. Collectively, our results suggest that NHPs are potential sources of zoonotic trichomonad infections, highlighting the importance of surveillance and control measures to protect human and animal populations.

Title: Prévalence des Trichomonadidae intestinaux chez les primates non humains captifs en Chine. Abstract: Les Trichomonadidae sont des symbiotes protozoaires capables d'infecter les vertébrés, notamment les humains et les primates non humains (PNH), parfois avec des effets pathogènes. Cependant, leur diversité et leur prévalence chez les PNH en Chine sont mal comprises. Au total, 533 échantillons fécaux ont été collectés sur des PNH captifs dans la province du Yunnan, en Chine, dont 461 échantillons de Macaca fascicularis et 72 de Macaca mulatta. Les espèces de Trichomonadidae ont été identifiées par amplification PCR des séquences ITS-1/5.8S/ITS-2. La prévalence globale des Trichomonadidae dans les PNH a été déterminée à 11,4 % (61 / 533) et le sexe, la diarrhée et la région ont été identifiés comme facteurs de risque potentiels d'infection. L'alignement des séquences et l'analyse phylogénétique ont identifié trois espèces de Trichomonadidae, à savoir Trichomitopsis minor (n = 45), Pentatrichomonas hominis (n = 11) et Tetratrichomonas sp. (n = 5). À notre connaissance, il s'agit de la première étude à signaler une infection par Trichomitopsis minor chez les PNH en Chine. Il convient de noter que Pentatrichomonas hominis est généralement reconnu comme un organisme parasitaire affectant les humains. Collectivement, nos résultats suggèrent que les PNH sont des sources potentielles d'infections zoonotiques à Trichomonadidae, soulignant l'importance des mesures de surveillance et de contrôle pour protéger les populations humaines et animales.

Pathways from the superior colliculus and the nucleus of the optic tract to the posterior parietal cortex in macaque monkeys: Functional frameworks for representation updating and online movement guidance.

The posterior parietal cortex (PPC) integrates multisensory and motor-related information for generating and updating body representations and movement plans. We used retrograde transneuronal transfer of rabies virus combined with a conventional tracer in macaque monkeys to identify direct and disynaptic pathways to the arm-related rostral medial intraparietal area (MIP), the ventral lateral intraparietal area (LIPv), belonging to the parietal eye field, and the pursuit-related lateral subdivision of the medial superior temporal area (MSTl). We found that these areas receive major disynaptic pathways via the thalamus from the nucleus of the optic tract (NOT) and the superior colliculus (SC), mainly ipsilaterally. NOT pathways, targeting MSTl most prominently, serve to process the sensory consequences of slow eye movements for which the NOT is the key sensorimotor interface. They potentially contribute to the directional asymmetry of the pursuit and optokinetic systems. MSTl and LIPv receive feedforward inputs from SC visual layers, which are potential correlates for fast detection of motion, perceptual saccadic suppression and visual spatial attention. MSTl is the target of efference copy pathways from saccade- and head-related compartments of SC motor layers and head-related reticulospinal neurons. They are potential sources of extraretinal signals related to eye and head movement in MSTl visual-tracking neurons. LIPv and rostral MIP receive efference copy pathways from all SC motor layers, providing online estimates of eye, head and arm movements. Our findings have important implications for understanding the role of the PPC in representation updating, internal models for online movement guidance, eye-hand coordination and optic ataxia.

Interactions with humans reduce the success of foraging for anthropogenic food by capuchin monkeys (Sapajus libidinosus) in Brasília National Park, Brazil.

The progressive growth of urban environments has increasingly forced populations of nonhuman primates to coexist with humans in many cities, which has resulted in problems such as behavioral alterations, conflicts with humans, and threats to the health of the monkeys, due to their consumption of anthropogenic foodstuffs. These anthropogenic foods, which are rich in calories, are the principal driver of the proximity between humans and primates, even though the acquisition of these foods tends to be risky for the monkeys and involve a variety of challenges derived from specific features of the urban environment. The present study evaluated the success/risk relationship of foraging for anthropogenic food by tufted capuchins (Sapajus libidinosus) in Brasília National Park. The data were analyzed using a binary logistic regression, with the backward-stepwise Wald method, to investigate the factors related to the foraging success of the capuchins, considering variables such as their sex and age, the type of approach and its context, and interactions with humans. The capuchins were influenced by the anthropogenic context, which affected their foraging strategies and diet. Interactions with humans reduced the success of foraging for anthropogenic foods. Conflicts between humans and the capuchins were common, especially in the context of access to food. The capuchins thus preferred to access feeding resources directly, probably due to the reduced human interference, which resulted in greater foraging success for unattended food brought by park visitors and the raiding of trash cans. Based on the observed behavior patterns, a number of measures can be proposed to mitigate these conflicts. These recommendations include not bringing food into areas frequented by the capuchins, not reacting to approaching animals, and removing all trash generated during a visit. A cleaning team dedicated to the maintenance of the visitation area free of anthropogenic waste is also be recommended.

Personality heterophily and friendship as drivers for successful cooperation.

Cooperation is widespread and arguably a pivotal evolutionary force in maintaining animal societies. Yet, proximately, what underlying motivators drive individuals to cooperate remains relatively unclear. Since 'free-riders' can exploit the benefits by cheating, selecting the right partner is paramount. Such decision rules need not be based on complex calculations and can be driven by cognitively less-demanding mechanisms, like social relationships (e.g. kinship, non-kin friendships, dyadic tolerance), social status (e.g. dominance hierarchies) and personalities (social and non-social traits); however, holistic evidence related to those mechanisms is scarce. Using the classical 'loose-string paradigm', we tested cooperative tendencies of a hierarchical primate, the long-tailed macaque (Macaca fascicularis). We studied three groups (n = 21) in their social settings, allowing partner choice. We supplemented cooperation with observational and experimental data on social relationships, dominance hierarchies and personality. Friendship and dissimilarities in non-social 'exploration' and 'activity-sociability' personality traits predicted the likelihood of cooperative dyad formation. Furthermore, the magnitude of cooperative success was positively associated with friendship, low rank-distance and dissimilarity in the activity-sociability trait. Kinship did not affect cooperation. While some findings align with prior studies, the evidence of (non-social) personality heterophily promoting cooperation may deepen our understanding of the proximate mechanisms and, broadly, the evolution of cooperation.

Metabolomics and Lipidomics Analyses Aid Model Classification of Type 2 Diabetes in Non-Human Primates.

Type 2 diabetes (T2D) is a global public health issue characterized by excess weight, abdominal obesity, dyslipidemia, hyperglycemia, and a progressive increase in insulin resistance. Human population studies of T2D development and its effects on systemic metabolism are confounded by many factors that cannot be controlled, complicating the interpretation of results and the identification of early biomarkers. Aged, sedentary, and overweight/obese non-human primates (NHPs) are one of the best animal models to mimic spontaneous T2D development in humans. We sought to identify and distinguish a set of plasma and/or fecal metabolite biomarkers, that have earlier disease onset predictability, and that could be evaluated for their predictability in subsequent T2D studies in human cohorts. In this study, a single plasma and fecal sample was collected from each animal in a colony of 57 healthy and dysmetabolic NHPs and analyzed for metabolomics and lipidomics. The samples were comprehensively analyzed using untargeted and targeted LC/MS/MS. The changes in each animal's disease phenotype were monitored using IVGTT, HbA1c, and other clinical metrics, and correlated with their metabolic profile. The plasma and fecal lipids, as well as bile acid profiles, from Healthy, Dysmetabolic (Dys), and Diabetic (Dia) animals were compared. Following univariate and multivariate analyses, including adjustments for weight, age, and sex, several plasma lipid species were identified to be significantly different between these animal groups. Medium and long-chain plasma phosphatidylcholines (PCs) ranked highest at distinguishing Healthy from Dys animals, whereas plasma triglycerides (TG) primarily distinguished Dia from Dys animals. Random Forest (RF) analysis of fecal bile acids showed a reduction in the secondary bile acid glycoconjugate, GCDCA, in diseased animals (AUC 0.76[0.64, 0.89]). Moreover, metagenomics results revealed several bacterial species, belonging to the genera Roseburia, Ruminococcus, Clostridium, and Streptococcus, to be both significantly enriched in non-healthy animals and associated with secondary bile acid levels. In summary, our results highlight the detection of several elevated circulating plasma PCs and microbial species associated with fecal secondary bile acids in NHP dysmetabolic states. The lipids and metabolites we have identified may help researchers to differentiate individual NHPs more precisely between dysmetabolic and overtly diabetic states. This could help assign animals to study groups that are more likely to respond to potential therapies where a difference in efficacy might be anticipated between early vs. advanced disease.

New insights into patterns of integration in the femur and pelvis among catarrhines.

OBJECTIVES: Integration reflects the level of coordinated variation of the phenotype. The integration of postcranial elements can be studied from a functional perspective, especially with regards to locomotion. This study investigates the link between locomotion, femoral structural properties, and femur-pelvis complex morphology. MATERIALS AND METHODS: We measured (1) morphological integration between femoral and pelvic morphologies using geometric morphometrics, and (2) covariation between femoral/pelvic morphologies and femoral diaphyseal cross-sectional properties, which we defined as morpho-structural integration. Morphological and morpho-structural integration patterns were measured among humans (n = 19), chimpanzees and bonobos (n = 16), and baboons (n = 14), whose locomotion are distinct. RESULTS: Baboons show the highest magnitude of morphological integration and the lowest of morpho-structural integration. Chimpanzees and bonobos show intermediate magnitude of morphological and morpho-structural integration. Yet, body size seems to have a considerable influence on both integration patterns, limiting the interpretations. Finally, humans present the lowest morphological integration and the highest morpho-structural integration between femoral morphology and structural properties but not between pelvic morphology and femur. DISCUSSION: Morphological and morpho-structural integration depict distinct strategies among the samples. A strong morphological integration among baboon's femur-pelvis module might highlight evidence for long-term adaptation to quadrupedalism. In humans, it is likely that distinct selective pressures associated with the respective function of the pelvis and the femur tend to decrease morphological integration. Conversely, high mechanical loading on the hindlimbs during bipedal locomotion might result in specific combination of structural and morphological features within the femur.

The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression.

While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.

Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques.

BACKGROUND: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. METHODS: We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. RESULTS: Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. CONCLUSIONS: These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.

A brief review of the current status of pig islet xenotransplantation.

An estimated 1.5 million Americans suffer from Type I diabetes mellitus, and its incidence is increasing worldwide. Islet allotransplantation offers a treatment, but the availability of deceased human donor pancreases is limited. The transplantation of islets from gene-edited pigs, if successful, would resolve this problem. Pigs are now available in which the expression of the three known xenoantigens against which humans have natural (preformed) antibodies has been deleted, and in which several human 'protective' genes have been introduced. The transplantation of neonatal pig islets has some advantages over that of adult pig islets. Transplantation into the portal vein of the recipient results in loss of many islets from the instant blood-mediated inflammatory reaction (IBMIR) and so the search for an alternative site continues. The adaptive immune response can be largely suppressed by an immunosuppressive regimen based on blockade of the CD40/CD154 T cell co-stimulation pathway, whereas conventional therapy (e.g., based on tacrolimus) is less successful. We suggest that, despite the need for effective immunosuppressive therapy, the transplantation of 'free' islets will prove more successful than that of encapsulated islets. There are data to suggest that, in the absence of rejection, the function of pig islets, though less efficient than human islets, will be sufficient to maintain normoglycemia in diabetic recipients. Pig islets transplanted into immunosuppressed nonhuman primates have maintained normoglycemia for periods extending more than two years, illustrating the potential of this novel form of therapy.

Antibody-mediated depletion of select leukocyte subsets in blood and tissue of nonhuman primates.

Understanding the immunological control of pathogens requires a detailed evaluation of the mechanistic contributions of individual cell types within the immune system. While knockout mouse models that lack certain cell types have been used to help define the role of those cells, the biological and physiological characteristics of mice do not necessarily recapitulate that of a human. To overcome some of these differences, studies often look towards nonhuman primates (NHPs) due to their close phylogenetic relationship to humans. To evaluate the immunological role of select cell types, the NHP model provides distinct advantages since NHP more closely mirror the disease manifestations and immunological characteristics of humans. However, many of the experimental manipulations routinely used in mice (e.g., gene knock-out) cannot be used with the NHP model. As an alternative, the in vivo infusion of monoclonal antibodies that target surface proteins on specific cells to either functionally inhibit or deplete cells can be a useful tool. Such depleting antibodies have been used in NHP studies to address immunological mechanisms of action. In these studies, the extent of depletion has generally been reported for blood, but not thoroughly assessed in tissues. Here, we evaluated four depleting regimens that primarily target T cells in NHP: anti-CD4, anti-CD8α, anti-CD8ß, and immunotoxin-conjugated anti-CD3. We evaluated these treatments in healthy unvaccinated and IV BCG-vaccinated NHP to measure the extent that vaccine-elicited T cells - which may be activated, increased in number, or resident in specific tissues - are depleted compared to resting populations in unvaccinated NHPs. We report quantitative measurements of in vivo depletion at multiple tissue sites providing insight into the range of cell types depleted by a given mAb. While we found substantial depletion of target cell types in blood and tissue of many animals, residual cells remained, often residing within tissue. Notably, we find that animal-to-animal variation is substantial and consequently studies that use these reagents should be powered accordingly.