Retinal Explant Culture from Mouse, Human, and Nonhuman Primates and Its Applications in Vision Research.

The retinal explant culture system is a valuable tool for studying the pharmacological, toxicological, and developmental aspects of the retina. It is also used for translational studies such as gene therapy. While no photoreceptor-like cell lines are available for in vitro studies of photoreceptor cell biology, the retinal explant culture maintains the laminated retinal structure ex vivo for as long as a month. Human and nonhuman primate (NHP) postmortem retinal explants cut into small pieces offer the possibility of testing multiple conditions for safety and adeno-associated viral (AAV) vector optimization. In addition, the cone-enriched foveal area can be studied using the retinal explants. Here, we present a detailed working protocol for retinal explant isolation and culture from mouse, human, and NHP for testing drug efficacy and AAV transduction. Future applications of this protocol include combining live imaging and multiwell retinal explant culture for high-throughput drug screening systems in rodent and human retinal explants to identify new drugs against retinal degeneration.

Neural Encoding of Bodies for Primate Social Perception.

Primates, as social beings, have evolved complex brain mechanisms to navigate intricate social environments. This review explores the neural bases of body perception in both human and nonhuman primates, emphasizing the processing of social signals conveyed by body postures, movements, and interactions. Early studies identified selective neural responses to body stimuli in macaques, particularly within and ventral to the superior temporal sulcus (STS). These regions, known as body patches, represent visual features that are present in bodies but do not appear to be semantic body detectors. They provide information about posture and viewpoint of the body. Recent research using dynamic stimuli has expanded the understanding of the body-selective network, highlighting its complexity and the interplay between static and dynamic processing. In humans, body-selective areas such as the extrastriate body area (EBA) and fusiform body area (FBA) have been implicated in the perception of bodies and their interactions. Moreover, studies on social interactions reveal that regions in the human STS are also tuned to the perception of dyadic interactions, suggesting a specialized social lateral pathway. Computational work developed models of body recognition and social interaction, providing insights into the underlying neural mechanisms. Despite advances, significant gaps remain in understanding the neural mechanisms of body perception and social interaction. Overall, this review underscores the importance of integrating findings across species to comprehensively understand the neural foundations of body perception and the interaction between computational modeling and neural recording.

Global primary predictors of extinction risk in primates.

Identifying the main predictors of species' extinction risk while accounting for the effects of spatial and phylogenetic structures in the data is key to preventing species loss in tropical forests through adequate conservation practices. We recorded 22 705 precise geographical locations of primate occurrence across four major geographic realms (Neotropics, mainland Africa, Madagascar and Asia) to assess predictors of threat status using a novel Bayesian spatio-phylogenetic approach. We estimated the relative contributions of fixed factors (forest amount, body mass, home range, diel activity, locomotion, evolutionary distinctiveness and climatic instability) and random factors (space and phylogeny) to primate extinction risk. Precipitation instability increased the extinction risk in the Neotropics but decreased it in mainland Africa and Madagascar. Forest amount was negatively associated with extinction risk in all realms except Madagascar. Body mass increased the extinction risk in the Neotropics and Madagascar, whereas home range increased the extinction risk in mainland Africa and decreased it in Asia. Evolutionary distinctiveness negatively influenced extinction risk only in mainland Africa. Our findings highlight the importance of climate change mitigation and forest protection strategies. Increasing the protection of large primates and reducing hunting are also essential.

First evolutionary insights into the human otolithic system.

The human otolithic system (utricle and saccule), housed within the bony vestibule of the inner ear, establishes our sense of balance in conjunction with the semicircular canals. Yet, while the morphological evolution of the semicircular canals is actively explored, comparative morphological analyses of the otolithic system are lacking. This is regrettable because functional links with head orientation suggest the otolithic system could be used to track postural change throughout human evolution and across primates more broadly. In this context, we present the first analysis of the evolution of the human otolithic system within an anthropoid primate setting. Using the vestibule as a morphological proxy for the utricle and saccule, we compare humans to 13 other extant anthropoid species, and use phylogenetically-informed methods to find correlations with body size, endocranial flexion, and head-neck posture. Our results, obtained through micro-CT of 136 inner ears, reveal two major evolutionary transitions in hominoids, leading to distinctive vestibular morphology in humans, characterized by otolithic morphology resembling squirrel monkeys (possibly due to reversal), with a pronounced supraovalic fossa. Finally, we find a positional signal embedded in the anthropoid bony vestibule, providing the foundation to further explore the evolution of human head-neck posture using inner ear morphology.

Easy to gain but hard to lose: the evolution of the knee sesamoid bones in Primates-a systematic review and phylogenetic meta-analysis.

Sesamoids are variably present skeletal elements found in tendons and ligaments near joints. Variability in sesamoid size, location and presence/absence is hypothesized to enable skeletal innovation, yet sesamoids are often ignored. Three knee sesamoids-the cyamella, medial fabella and lateral fabella-are present in primates, but we know little about how they evolved, if they are skeletal innovations, or why they are largely missing from Hominoidea. Our phylogenetic comparative analyses suggest that sesamoid presence/absence is highly phylogenetically structured and contains phylogenetic signal. Models suggest that it is easy to gain but difficult/impossible to lose knee sesamoids and that the fabellae may have similar developmental/evolutionary pathways that are distinct from the cyamella. Sesamoid presence/absence is uncorrelated to the mode of locomotion, suggesting that sesamoid biomechanical function may require information beyond sesamoid presence, such as size and location. Ancestral state reconstructions were largely uninformative but highlighted how reconstructions using parsimony can differ from those that are phylogenetically informed. Interestingly, there may be two ways to evolve fabellae, with humans evolving fabellae differently from most other primates. We hypothesize that the 're-emergence' of the lateral fabella in humans may be correlated with the evolution of a unique developmental pathway, potentially correlated with the evolution of straight-legged, bipedal locomotion.

Development and validation of RT-LAMP for detecting yellow fever virus in non-human primates samples from Brazil.

Monitoring yellow fever in non-human primates (NHPs) is an early warning system for sylvatic yellow fever outbreaks, aiding in preventing human cases. However, current diagnostic tests for this disease, primarily relying on RT-qPCR, are complex and costly. Therefore, there is a critical need for simpler and more cost-effective methods to detect yellow fever virus (YFV) infection in NHPs, enabling early identification of viral circulation. In this study, an RT-LAMP assay for detecting YFV in NHP samples was developed and validated. Two sets of RT-LAMP primers targeting the YFV NS5 and E genes were designed and tested together with a third primer set to the NS1 locus using NHP tissue samples from Southern Brazil. The results were visualized by colorimetry and compared to the RT-qPCR test. Standardization and validation of the RT-LAMP assay demonstrated 100% sensitivity and specificity compared to RT-qPCR, with a detection limit of 12 PFU/mL. Additionally, the cross-reactivity test with other flaviviruses confirmed a specificity of 100%. Our newly developed RT-LAMP diagnostic test for YFV in NHP samples will significantly contribute to yellow fever monitoring efforts, providing a simpler and more accessible method for viral early detection. This advancement holds promise for enhancing surveillance and ultimately preventing the spread of yellow fever.

Neuro-evolutionary evidence for a universal fractal primate brain shape.

The cerebral cortex displays a bewildering diversity of shapes and sizes across and within species. Despite this diversity, we present a universal multi-scale description of primate cortices. We show that all cortical shapes can be described as a set of nested folds of different sizes. As neighbouring folds are gradually merged, the cortices of 11 primate species follow a common scale-free morphometric trajectory, that also overlaps with over 70 other mammalian species. Our results indicate that all cerebral cortices are approximations of the same archetypal fractal shape with a fractal dimension of df = 2.5. Importantly, this new understanding enables a more precise quantification of brain morphology as a function of scale. To demonstrate the importance of this new understanding, we show a scale-dependent effect of ageing on brain morphology. We observe a more than fourfold increase in effect size (from two standard deviations to eight standard deviations) at a spatial scale of approximately 2 mm compared to standard morphological analyses. Our new understanding may, therefore, generate superior biomarkers for a range of conditions in the future.

Many of the brain's essential functions ­ from decision-making to movement ­ take place in its outer layer known as the cerebral cortex. The shape of the cerebral cortex varies significantly between species. For instance, in humans, it is folded in to grooves and ridges, whereas in other animals, including mice, it is completely smooth. The structure of the cortex can also differ within a species, and be altered by aging and certain diseases. This vast variation can make it difficult it to characterize and compare the structure of the cortex between different species, ages and diseases. To address this, Wang et al. developed a new mathematical model for describing the shape of the cortex. The model uses a method known as coarse graining to erase, or 'melt away', any cortical folds or structures smaller than a given threshold size. As this threshold increases, the cortex becomes progressively smoother. The relationship between surface areas and threshold sizes indicates the fractal dimension ­ that is, how fragmented the cortex is across different scales. Wang et al. applied their model to the brain scans of eleven primates, including humans, and found the fractal dimension of the cortex was almost exactly 2.5 for all eleven species. This suggests that the cortices of the different primates follow a single fractal shape, which means the folds of each cortex have a similar branching pattern. Although there were distinctions between the species, they were mainly due to the different ranges of fold sizes in each cortex. The model revealed that the broader the range of fold sizes, the more folded the brain ­ but the fractal pattern remains the same. The brain melting method created by Wang et al. provides a new way to characterise cortical shape. Besides revealing a hitherto hidden regularity of nature, they hope that in the future their new method will be useful in assessing brain changes during human development and ageing, and in diseases like Alzheimer's and epilepsy.

SCANellome V2: Update of the Primate Anellovirus Reference Sequences Database.

Anelloviruses are ubiquitous in humans and represent a major component of the human virome. Its best-known representative is Torque teno virus (i.e., the Alphatorquevirus genus), which is considered a potential immunity biomarker. Recent metagenomic investigations revealed not only the extraordinary genomic diversity of anellovirus sequences, but also that co-detection of genera, genotypes, or species seems to be the rule in humans. SCANellome was developed to represent a user-friendly tool to analyze the primate (both human and non-human) anellovirus composition at the genus, species, and genotype level from metagenomics data based on an up-to-date database. This SCANellome update includes >900 additional reference sequences from GenBank. Using a clustering at 90% identity, the FASTA database was updated and generated 134 new representative sequences. Based on ORF1, the analysis of these new sequences indicates the presence of 206 potential new species, including four nonhuman primates, and adds four new non-human primate species which will be the subject of a proposal to the International Committee on Taxonomy of Viruses (ICTV). In addition, SCANellome V2 provides now the user with an interactive up-to-date phylogenetic analysis (of ORF1) to show the distribution among the 12 human and nonhuman primate genera of these new potential species. Finally, the Anelloviridae taxonomy was updated to rename species names in binomial format as required by the ICTV.

Spatial dissociation between recognition and navigation in the primate hippocampus.

The primate hippocampus, crucial for both episodic memory and spatial navigation, remains an enigma regarding whether these functions share the same neural substrates. We investigated how identical hippocampal neurons in macaque monkeys dynamically shifted their representations between tasks. In a recognition memory task, a notable fraction of hippocampal neurons showed that rate modulation strongly correlated with recognition performance. During free navigation in an open arena, spatial view, rather than position, predominantly influenced the spatial selectivity of hippocampal neurons. Neurons selective for recognition memory displayed minimal spatial tuning, while spatially tuned neurons exhibited limited memory-related activity. These neural correlates of recognition memory and space were more pronounced in the anterior and posterior portions of the hippocampus, respectively. These opposing gradients extended further into the anterior and posterior neocortices. Overall, our findings suggest the presence of orthogonal long-axis gradients between recognition memory and spatial navigation in the hippocampal-neocortical networks of macaque monkeys.

Fins, feathers, fingers, and finding an explanation for the puzzle of ephemeral rewards.

This article discusses the ephemeral reward task and how it is not always a clear and concise choice. This is demonstrated through some animal studies involving birds and primates. This article also shows that when compared to human studies, that there are positive correlations between the BART and optimal choice in the ephemeral reward task, meaning that those who took more risks also were more inclined to be optimal. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Humanity and Inhumanity of Nonhuman Primate Research.

This illustration depicts important biomedical advancements generated by nonhuman primate (NHP) research. NHPs' value in human-centered research is their unique evolutionary proximity to humans.

The big mixup: Neural representation during natural modes of primate visual behavior.

The primate brain has evolved specialized visual capacities to navigate complex physical and social environments. Researchers studying cortical circuits underlying these capacities have traditionally favored the use of simplified tasks and brief stimulus presentations in order to isolate cognitive variables with tight experimental control. As a result, operational theories about visual brain function have come to emphasize feature detection, hierarchical stimulus encoding, top-down task modulation, and functional segregation in distinct cortical areas. Recently, however, experimental paradigms combining natural behavior with electrophysiological recordings have begun to offer a distinctly different portrait of how the brain takes in and analyzes its visual surroundings. The present article reviews recent work in this area, highlighting some of the more surprising findings in domains of social vision and spatial navigation along with shifts in thinking that have begun to emanate from this approach.

The self-in-the-world map emerged in the primate brain as a basis for Homo sapiens abilities.

The brain in the genus Homo expanded rapidly during evolution, accelerated by a reciprocated interaction between neural, cognitive, and ecological niches (triadic niche construction, or TNC). This biologically costly expansion incubated latent cognitive capabilities that, with a quick and inexpensive rewiring of brain areas in a second phase of TNC, provided the basis for Homo sapiens specific abilities. The neural demands for perception of the human body in interaction with tools and the environment required highly integrated sensorimotor domains, inducing the parietal lobe expansion seen in humans. These newly expanded brain areas allowed connecting the sensations felt in the body to the actions in the world through the cognitive function of "projection". In this opinion article, we suggest that as a relationship of equivalence between body parts, tools and their external effects was established, mental mechanisms of self-objectification might have emerged as described previously, grounding notions of spatial organization, idealized objects, and their transformations, as well as socio-emotional states in the sensing agent through a self-in-the-world map. Therefore, human intelligence and its features such as symbolic thought, language, mentalizing, and complex technical and social behaviors could have stemmed from the explicit awareness of the causal relationship between the self and intentional modifications to the environment.

Heterogeneous orientation tuning in the primary visual cortex of mice diverges from Gabor-like receptive fields in primates.

A key feature of neurons in the primary visual cortex (V1) of primates is their orientation selectivity. Recent studies using deep neural network models showed that the most exciting input (MEI) for mouse V1 neurons exhibit complex spatial structures that predict non-uniform orientation selectivity across the receptive field (RF), in contrast to the classical Gabor filter model. Using local patches of drifting gratings, we identified heterogeneous orientation tuning in mouse V1 that varied up to 90° across sub-regions of the RF. This heterogeneity correlated with deviations from optimal Gabor filters and was consistent across cortical layers and recording modalities (calcium vs. spikes). In contrast, model-synthesized MEIs for macaque V1 neurons were predominantly Gabor like, consistent with previous studies. These findings suggest that complex spatial feature selectivity emerges earlier in the visual pathway in mice than in primates. This may provide a faster, though less general, method of extracting task-relevant information.

A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development.

Endogenous retroviruses (ERVs) occupy a significant part of the human genome, with some encoding proteins that influence the immune system or regulate cell-cell fusion in early extra-embryonic development. However, whether ERV-derived proteins regulate somatic development is unknown. Here, we report a somatic developmental function for the primate-specific ERVH48-1 (SUPYN/Suppressyn). ERVH48-1 encodes a fragment of a viral envelope that is expressed during early embryonic development. Loss of ERVH48-1 led to impaired mesoderm and cardiomyocyte commitment and diverted cells to an ectoderm-like fate. Mechanistically, ERVH48-1 is localized to sub-cellular membrane compartments through a functional N-terminal signal peptide and binds to the WNT antagonist SFRP2 to promote its polyubiquitination and degradation, thus limiting SFRP2 secretion and blocking repression of WNT/ß-catenin signaling. Knockdown of SFRP2 or expression of a chimeric SFRP2 with the ERVH48-1 signal peptide rescued cardiomyocyte differentiation. This study demonstrates how ERVH48-1 modulates WNT/ß-catenin signaling and cell type commitment in somatic development.

Novel crossover and recombination hotspots massively spread across primate genomes.

BACKGROUND: The recombination landscape and subsequent natural selection have vast consequences forevolution and speciation. However, most of the crossover and recombination hotspots are yet to be discovered. We previously reported the relevance of C and G trinucleotide two-repeat units (CG-TTUs) in crossovers and recombination. METHODS: On a genome-wide scale, here we mapped all combinations of A and T trinucleotide two-repeat units (AT-TTUs) in human, consisting of AATAAT, ATAATA, ATTATT, TTATTA, TATTAT, and TAATAA. We also compared a number of the colonies formed by the AT-TTUs (distance between consecutive AT-TTUs < 500 bp) in several other primates and mouse. RESULTS: We found that the majority of the AT-TTUs (> 96%) resided in approximately 1.4 million colonies, spread throughout the human genome. In comparison to the CG-TTU colonies, the AT-TTU colonies were significantly more abundant and larger in size. Pure units and overlapping units of the pure units were readily detectable in the same colonies, signifying that the units were the sites of unequal crossover. We discovered dynamic sharedness of several of the colonies across the primate species studied, which mainly reached maximum complexity and size in human. CONCLUSIONS: We report novel crossover and recombination hotspots of the finest molecular resolution, massively spread and shared across the genomes of human and several other primates. With respect to crossovers and recombination, these genomes are far more dynamic than previously envisioned.

Compared to other NHEJ factors, DNA-PK protein and RNA levels are markedly increased in all higher primates, but not in prosimians or other mammals.

The DNA dependent protein kinase (DNA-PK) initiates non-homologous recombination (NHEJ), the predominate DNA double-strand break (DSBR) pathway in higher vertebrates. It has been known for decades that the enzymatic activity of DNA-PK [that requires its three component polypeptides, Ku70, Ku80 (that comprise the DNA-end binding Ku heterodimer), and the catalytic subunit (DNA-PKcs)] is present in humans at 10-50 times the level observed in other mammals. Here, we show that the high level of DNA-PKcs protein expression appears evolutionarily in mammals between prosimians and higher primates. Moreover, the RNAs encoding the three component polypeptides of DNA-PK are present at similarly high levels in hominids, new-, and old-world monkeys, but expression of these RNAs in prosimians is ∼5-50 fold less, analogous to the levels observed in other non-primate species. This is reminiscent of the appearance of Alu repeats in primate genomes -- abundant in higher primates, but present at much lower density in prosimians. Alu repeats are well-known for their capacity to promote non-allelic homologous recombination (NAHR) a process known to be inhibited by DNA-PK. Nanopore sequence analyses of cultured cells proficient or deficient in DNA-PK revealed an increase of inter-chromosomal translocations caused by NAHR. Although the high levels of DNA-PK in primates may have many functions, we posit that high levels of DNA-PK may function to restrain deleterious NAHR events between Alu elements.