OBJECTIVE: Molar crown configuration plays an important role in systematics, and functional and comparative morphology. In particular, the number of cusps on primate molars is often used to identify fossil species and infer their phylogenetic relationships. However, this variability deserves renewed consideration as a number of studies now highlight important developmental mechanisms that may be responsible for the presence of molar cusps in some mammalian taxa. Experimental studies of rodent molars suggest that cusps form under a morphodynamic, patterning cascade model of development (PCM) that involve the iterative formation of enamel knots. This model posits that the size, shape and location of the first-forming cusps determines the presence and positioning of later-forming cusps.
METHODS: Here we test whether variation in accessory cusp presence in 13 Macaca fascicularis mandibular second molars (M2s) is consistent with predictions of the PCM. Using micro-CT, we imaged these M2s and employed geometric morphometrics to examine whether shape variation in the enamel-dentine junction (EDJ) correlates with accessory cusp presence.
RESULTS: We find that accessory cusp patterning in macaque M2s is broadly consistent with the PCM. Molars with accessory cusps were larger in size and possessed shorter relative cusp heights compared to molars without accessory cusps. Peripheral cusp formation was also associated with more centrally positioned primary cusps, as predicted by the PCM.
CONCLUSIONS: While these results demonstrate that a patterning cascade model is broadly appropriate for interpreting cusp variation in Macaca fascicularis molars, it does not explain all manifestations of accessory cusp expression in this sample.

Broadening gene therapy applications requires manufacturable vectors that efficiently transduce target cells in humans and preclinical models. Conventional selections of adeno-associated virus (AAV) capsid libraries are inefficient at searching the vast sequence space for the small fraction of vectors possessing multiple traits essential for clinical translation. Here, we present Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait AAV capsids. By leveraging a capsid library that uniformly samples the manufacturable sequence space, reproducible screening data are generated to train accurate sequence-to-function models. Combining six models, we designed a multi-trait (liver-targeted, manufacturable) capsid library and validated 88% of library variants on all six predetermined criteria. Furthermore, the models, trained only on mouse in vivo and human in vitro Fit4Function data, accurately predicted AAV capsid variant biodistribution in macaque. Top candidates exhibited production yields comparable to AAV9, efficient murine liver transduction, up to 1000-fold greater human hepatocyte transduction, and increased enrichment relative to AAV9 in a screen for liver transduction in macaques. The Fit4Function strategy ultimately makes it possible to predict cross-species traits of peptide-modified AAV capsids and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits.

Cross-species research has advanced human understanding of brain regions, with cross-species comparisons using magnetic resonance imaging technology becoming increasingly common. Currently, cross-species research on human language regions has primarily focused on traditional brain areas such as the Broca region. While some studies have indicated that human language function also involves other language regions, the corresponding relationships between these brain regions in humans and macaques remain unclear. This study calculated the strength of the connections between the high-level language processing regions in human and macaque brains, identified homologous target areas based on the structural connections of white-matter fiber bundles, and compared the connectivity profiles of both species. The results of the experiment demonstrated that macaques possess brain regions which exhibit connectivity patterns resembling those found in human high-level language processing regions. This discovery suggests that while the function of a human brain region is specialized, it still maintains a structural connectivity similar to that seen in macaques.

Modulation of neuronal firing rates by the spatial locations of physical objects is a widespread phenomenon in the brain. However, little is known about how neuronal responses to the actions of biological entities are spatially tuned and whether such spatially tuned responses are affected by social contexts. These issues are of key importance for understanding the neural basis of embodied social cognition, such as imitation and perspective-taking. Here, we show that spatial representation of actions can be dynamically changed depending on others\' social relevance and agents of action. Monkeys performed a turn-taking choice task with a real monkey partner sitting face-to-face or a filmed partner in prerecorded videos. Three rectangular buttons (left, center, and right) were positioned in front of the subject and partner as their choice targets. We recorded from single neurons in two frontal nodes in the social brain, the ventral premotor cortex (PMv) and the medial prefrontal cortex (MPFC). When the partner was filmed rather than real, spatial preference for partner-actions was markedly diminished in MPFC, but not PMv, neurons. This social context-dependent modulation in the MPFC was also evident for self-actions. Strikingly, a subset of neurons in both areas switched their spatial preference between self-actions and partner-actions in a diametrically opposite manner. This observation suggests that these cortical areas are associated with coordinate transformation in ways consistent with an actor-centered perspective-taking coding scheme. The PMv may subserve such functions in context-independent manners, whereas the MPFC may do so primarily in social contexts.

Non-human primates remain the most useful and reliable pre-clinical model for many human diseases. Primate breath profiles have previously distinguished healthy animals from diseased, including non-human primates. Breath collection is relatively non-invasive, so this motivated us to define a healthy baseline breath profile that could be used in studies evaluating disease, therapies, and vaccines in non-human primates. A pilot study, which enrolled 30 healthy macaques, was conducted. Macaque breath molecules were sampled into a Tedlar bag, concentrated onto a thermal desorption tube, then desorbed and analyzed by comprehensive two-dimensional gas chromatography-time of flight mass spectrometry. These breath samples contained 2,017 features, of which 113 molecules were present in all breath samples. The core breathprint was dominated by aliphatic hydrocarbons, aromatic compounds, and carbonyl compounds. The data were internally validated with additional breath samples from a subset of 19 of these non-human primates. A critical core consisting of 23 highly abundant and invariant molecules was identified as a pragmatic breathprint set, useful for future validation studies in healthy primates.

The archaeological record offers insights into our evolutionary past by revealing ancient behaviour through stone and fossil remains. Percussive foraging is suggested to be particularly relevant for the emergence of tool-use in our lineage, yet early hominin percussive behaviours remain largely understudied compared to flaked technology. Stone tool-use of extant primates allows the simultaneous investigation of their artefacts and the associated behaviours. This is important for understanding the development of tool surface modification, and crucial for interpreting damage patterns in the archaeological record. Here, we compare the behaviour and the resulting material record across stone tool-using primates. We investigate the relationship of nut-cracking technique and stone tool modification across chimpanzees, capuchins, and long-tailed macaques by conducting standardized field experiments with comparable raw materials. We show that different techniques likely emerged in response to diverse nut hardness, leading to variation in foraging success across species. Our experiments further demonstrate a correlation between techniques and the intensity of visible percussive damage on the tools. Tools used with more precision and efficiency as demonstrated by macaques, show fewer use wear traces. This suggests that some percussive techniques may be less readily identified in the archaeological record.

While the hippocampus is key for human cognitive abilities, it is also a phylogenetically old cortex and paradoxically considered evolutionarily preserved. Here, we introduce a comparative framework to quantify preservation and reconfiguration of hippocampal organisation in primate evolution, by analysing the hippocampus as an unfolded cortical surface that is geometrically matched across species. Our findings revealed an overall conservation of hippocampal macro- and micro-structure, which shows anterior-posterior and, perpendicularly, subfield-related organisational axes in both humans and macaques. However, while functional organisation in both species followed an anterior-posterior axis, we observed a marked reconfiguration in the latter across species, which mirrors a rudimentary integration of the default-mode-network in non-human primates. Here we show that microstructurally preserved regions like the hippocampus may still undergo functional reconfiguration in primate evolution, due to their embedding within heteromodal association networks.

When stimulated, neural populations in the visual cortex exhibit fast rhythmic activity with frequencies in the gamma band (30-80 Hz). The gamma rhythm manifests as a broad resonance peak in the power-spectrum of recorded local field potentials, which exhibits various stimulus dependencies. In particular, in macaque primary visual cortex (V1), the gamma peak frequency increases with increasing stimulus contrast. Moreover, this contrast dependence is local: when contrast varies smoothly over visual space, the gamma peak frequency in each cortical column is controlled by the local contrast in that column\'s receptive field. No parsimonious mechanistic explanation for these contrast dependencies of V1 gamma oscillations has been proposed. The stabilized supralinear network (SSN) is a mechanistic model of cortical circuits that has accounted for a range of visual cortical response nonlinearities and contextual modulations, as well as their contrast dependence. Here, we begin by showing that a reduced SSN model without retinotopy robustly captures the contrast dependence of gamma peak frequency, and provides a mechanistic explanation for this effect based on the observed non-saturating and supralinear input-output function of V1 neurons. Given this result, the local dependence on contrast can trivially be captured in a retinotopic SSN which however lacks horizontal synaptic connections between its cortical columns. However, long-range horizontal connections in V1 are in fact strong, and underlie contextual modulation effects such as surround suppression. We thus explored whether a retinotopically organized SSN model of V1 with strong excitatory horizontal connections can exhibit both surround suppression and the local contrast dependence of gamma peak frequency. We found that retinotopic SSNs can account for both effects, but only when the horizontal excitatory projections are composed of two components with different patterns of spatial fall-off with distance: a short-range component that only targets the source column, combined with a long-range component that targets columns neighboring the source column. We thus make a specific qualitative prediction for the spatial structure of horizontal connections in macaque V1, consistent with the columnar structure of cortex.

Malaria continues to be a global public health problem although it has been eliminated from many countries. Sri Lanka and China are two countries that recently achieved malaria elimination status, and many countries in Southeast Asia are currently in the pipeline for achieving the same goal by 2030. However, Plasmodium knowlesi, a non-human primate malaria parasite continues to pose a threat to public health in this region, infecting many humans in all countries in Southeast Asia except for Timor-Leste. Besides, other non-human primate malaria parasite such as Plasmodium cynomolgi and Plasmodium inui are infecting humans in the region. The non-human primates, the long-tailed and pig-tailed macaques which harbour these parasites are now increasingly prevalent in farms and forest fringes close by to the villages. Additionally, the Anopheles mosquitoes belonging to the Lecuosphyrus Group are also present in these areas which makes them ideal for transmitting the non-human primate malaria parasites. With changing landscape and deforestation, non-human primate malaria parasites will affect more humans in the coming years with the elimination of human malaria. Perhaps due to loss of immunity, more humans will be infected as currently being demonstrated in Malaysia. Thus, control measures need to be instituted rapidly to achieve the malaria elimination status by 2030. However, the zoonotic origin of the parasite and the changes of the vectors behaviour to early biting seems to be the stumbling block to the malaria elimination efforts in this region. In this review, we discuss the challenges faced in malaria elimination due to deforestation and the serious threat posed by non-human primate malaria parasites.

Sulawesi crested macaques (Macaca nigra) (SCMs) are critically endangered and frequently suffer from chronic intestinal disease in captivity. Often, despite routine diagnostic investigations and confirmation of intestinal inflammation, an aetiology cannot be identified, leading to a non-specific categorization as chronic enterocolitis rather than an aetiological diagnosis. This study evaluates the histological features of gastrointestinal tissues from 23 SCMs, comparing animals with a clinical history suggestive of chronic enterocolitis (n = 14) with those without gastrointestinal clinical signs (n = 9). Tissues were graded according to the Nancy index (NI), a scoring system used in human medicine to evaluate disease activity in ulcerative colitis, a common form of human inflammatory bowel disease (IBD). Additionally, inflammatory cells in the colonic lamina propria were visually identified by type, counted and subsequently compared between diseased and control animals. Moderate to severe lymphoplasmacytic inflammation and structural changes were most common in the colons of affected SCMs, whereas histopathological changes were absent or mild in all examined small intestine (n = 17) and stomach (n = 11) tissues. The colonic NI had a significant positive correlation with clinical disease severity and 57% (n = 8) of animals with clinical signs had a NI grade of ≥2, consistent with moderate to severe, active IBD. Half of SCMs with recurrent rectal prolapse (n = 6) had a NI grade of 0, suggesting that intestinal inflammation is not always part of this condition\'s pathogenesis. The numbers of colonic lymphocytes, plasma cells, neutrophils, macrophages and total leucocytes were significantly higher in diseased animals. This study validated the use of the NI in SCMs, enabling a more standardized histopathological evaluation of the colon in this species.