Terrestriality across the primate order: A review and analysis of ground use in primates.

Terrestriality is relatively rare in the predominantly arboreal primate order. How frequently, and when, terrestriality appears in primate evolution, and the factors that influence this behavior, are not well understood. To investigate this, we compiled data describing terrestriality in 515 extant nonhuman primate taxa. We describe the geographic and phylogenetic distribution of terrestriality, including an ancestral state reconstruction estimating the frequency and timing of evolutionary transitions to terrestriality. We review hypotheses concerning the evolution of primate terrestriality and test these using data we collected pertaining to characteristics including body mass and diet, and ecological factors including forest structure, food availability, weather, and predation pressure. Using Bayesian analyses, we find body mass and normalized difference vegetation index are the most reliable predictors of terrestriality. When considering subsets of taxa, we find ecological factors such as forest height and rainfall, and not body mass, are the most reliable predictors of terrestriality for platyrrhines and lemurs.

Future coexistence with great apes will require major changes to policy and practice.

The great apes-bonobos, chimpanzees, gorillas and orangutans-are critically threatened by human activities. We have destroyed their habitats, hunted them and transmitted fatal diseases to them. Yet we also conduct research on them, try to protect them and live alongside them. They are endangered, and time is running out. Here we outline what must be done to ensure that future generations continue to share this planet with great apes. We urge dialogue with those who live with great apes and interact with them often. We advocate conservation plans that acknowledge the realities of climate change, economic drivers and population growth. We encourage researchers to use technology to minimize risks to great apes. Our proposals will require substantial investment, and we identify ways to generate these funds. We conclude with a discussion of how field researchers might alter their work to protect our closest living relatives more effectively.

The Development of Feeding Competence in Rehabilitant Orphaned Orangutans and How to Measure It.

For critically endangered species, restorative conservation becomes increasingly important. Successful re-introduction of rescued wild orangutan orphans requires rehabilitation mimicking maternal rearing in the wild. Feeding competence-what to eat, where and when to find food-needs to be learned before re-introduction. We observed seven orphans (2-10 years old) for a period of 3 years during their rehabilitation at the Yayasan Jejak Pulang forest school. Of the 111 plant genera eaten by the orphans, 92 percent were known orangutan food plants. Five plant genera were eaten by all orphans in over 90 percent of the months within the observation period. The Fruit Availability Index (FAI) was used to predict which parts of a plant were consumed by the orphans. We found that the orphans ate primarily fruit when the FAI was high, but consumed more young leaves, cambium, and pith when FAI was low. Thus, the orphans exhibited food choices very similar to mature wild orangutans and appropriate to forest productivity. The orphans' acquisition of feeding competence was facilitated by their immersion into a natural forest environment in combination with possibilities for observational learning from conspecifics as well as caregivers modelling food processing and consumption.

mRNA vaccine against malaria tailored for liver-resident memory T cells.

Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria. Although a standard mRNA vaccine was unable to generate liver Trm or protect against challenge with Plasmodium berghei sporozoites in mice, addition of an agonist that recruits T cell help from type I natural killer T cells under mRNA-vaccination conditions resulted in significant generation of liver Trm cells and effective protection. Moreover, whereas previous exposure of mice to blood-stage infection impaired traditional vaccines based on attenuated sporozoites, mRNA vaccination was unaffected, underlining the potential for such a rational mRNA-based strategy in malaria-endemic regions.

MAIT cells activate dendritic cells to promote TFH cell differentiation and induce humoral immunity.

Protective immune responses against respiratory pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus, are initiated by the mucosal immune system. However, most licensed vaccines are administered parenterally and are largely ineffective at inducing mucosal immunity. The development of safe and effective mucosal vaccines has been hampered by the lack of a suitable mucosal adjuvant. In this study we explore a class of adjuvant that harnesses mucosal-associated invariant T (MAIT) cells. We show evidence that intranasal immunization of MAIT cell agonists co-administered with protein, including the spike receptor binding domain from SARS-CoV-2 virus and hemagglutinin from influenza virus, induce protective humoral immunity and immunoglobulin A production. MAIT cell adjuvant activity is mediated by CD40L-dependent activation of dendritic cells and subsequent priming of T follicular helper cells. In summary, we show that MAIT cells are promising vaccine targets that can be utilized as cellular adjuvants in mucosal vaccines.

Implications of large-scale infrastructure development for biodiversity in Indonesian Borneo.

Indonesia is embarking on an ambitious relocation of its capital city to Kalimantan, Borneo, bringing with it major urban and road infrastructure. Yet, despite being one of the world's most biologically diverse regions, the potential implications of this development for wildlife have yet to be fully assessed. We explored the potential impacts of the capital relocation, and road expansion and upgrades to critical habitat for medium-large mammals (>1 kg) using camera trap data from 11 forested landscapes. We applied Bayesian multi-species occupancy models to predict community and species-level responses to anthropogenic and environmental factors. We extrapolated spatial patterns of occupancy and species diversity across the forests of Kalimantan and identified "critical habitats" as the top 20th percentile of occupancy and species richness values. We subsequently overlapped these critical habitat layers with infrastructure impact zones to estimate the area that could potentially be affected by direct or secondary impacts. At both the community and species-level, distance to primary roads had the strongest negative influence on habitat-use. Occupancy was also influenced by forest quality and multidimensional poverty conditions in adjacent villages, demonstrating the sensitivity of biodiversity to socio-ecological pressures. Less than 1 % of the critical habitat for the threatened mammal community lay within the direct impact zone (30 km radius) of the capital relocation. However, approximately 16 % was located within 200 km and could potentially be affected by uncontrolled secondary impacts such as urban sprawl and associated regional development. The often-overlooked secondary implications of upgrading existing roads could also intersect a large amount of critical habitat for lowland species. Mitigating far-reaching secondary impacts of infrastructure development should be fully incorporated into environmental impact assessments. This will provide Indonesia with an opportunity to set an example of sustainable infrastructure development in the tropics.

Validating Urinary Neopterin as a Biomarker of Immune Response in Captive and Wild Capuchin Monkeys.

Non-invasive health monitoring is advantageous for wild and captive primate populations because it reduces the need for traditional invasive techniques (i.e., anesthetization) that can be stressful and potentially harmful for individuals. The biomarker neopterin is an emerging tool in primatology to measure immune activation and immunosenescence, however, most neopterin studies have focused on catarrhine species with little comparative work examining neopterin and health in platyrrhines. To address this gap, we validated a commercially available enzyme-linked immunosorbent assay (ELISA) to measure urinary neopterin in two types of capuchin monkeys, a wild population of white-faced capuchins (Cebus imitator) and a socially housed captive colony of tufted capuchins (Sapajus apella). We analytically validated methods for measuring urinary neopterin in two capuchin populations and demonstrated that two commonly-used methods to control for urine concentration-creatinine and specific gravity (SG)-produced highly concordant results. We also biologically validated these methods by examining variation in neopterin levels based on environment (captive and wild) and age, and changes in levels associated with immune-response. We found that neopterin increased after immune perturbation (rabies vaccine booster), varied by environmental condition, and mirrored expected trends in immune system ontogeny. Our results improve understanding of the innate immune system in platyrrhine species and suggest neopterin may be useful for non-invasive health monitoring in both captive and wild primates.

Glycolipid-peptide conjugate vaccines elicit CD8+ T-cell responses and prevent breast cancer metastasis.

Objectives: Metastasis is the principal cause of breast cancer mortality. Vaccines targeting breast cancer antigens have yet to demonstrate clinical efficacy, and there remains an unmet need for safe and effective treatment to reduce the risk of metastasis, particularly for people with triple-negative breast cancer (TNBC). Certain glycolipids can act as vaccine adjuvants by specifically stimulating natural killer T (NKT) cells to provide a universal form of T-cell help. Methods: We designed and made a series of conjugate vaccines comprising a prodrug of the NKT cell-activating glycolipid α-galactosylceramide covalently linked to tumor-expressed peptides, and assessed these using E0771- and 4T1-based breast cancer models in vivo. We employed peptides from the model antigen ovalbumin and from clinically relevant breast cancer antigens HER2 and NY-ESO-1. Results: Glycolipid-peptide conjugate vaccines that activate NKT cells led to antigen-presenting cell activation, induced inflammatory cytokines, and, compared with peptide alone or admixed peptide and α-galactosylceramide, specifically enhanced CD8+ T-cell responses against tumor-associated peptides. Primary tumor growth was delayed by vaccination in all tumor models. Using 4T1-based cell lines expressing HER2 or NY-ESO-1, a single administration of the relevant conjugate vaccine prevented tumor colonisation of the lung following intravenous inoculation of tumor cells or spontaneous metastasis from breast, respectively. Conclusion: Glycolipid-peptide conjugate vaccines that activate NKT cells prevent lung metastasis in breast cancer models and warrant investigation as adjuvant therapies for high-risk breast cancer.

Effectiveness of 20 years of conservation investments in protecting orangutans.

Conservation strategies are rarely systematically evaluated, which reduces transparency, hinders the cost-effective deployment of resources, and hides what works best in different contexts. Using data on the iconic and critically endangered orangutan (Pongo spp.), we developed a novel spatiotemporal framework for evaluating conservation investments. We show that around USD 1 billion was invested between 2000 and 2019 into orangutan conservation by governments, nongovernmental organizations, companies, and communities. Broken down by allocation to different conservation strategies, we find that habitat protection, patrolling, and public outreach had the greatest return on investment for maintaining orangutan populations. Given the variability in threats, land-use opportunity costs, and baseline remunerations in different regions, there were differential benefits per dollar invested across conservation activities and regions. We show that although challenging from a data and analysis perspective, it is possible to fully understand the relationships between conservation investments and outcomes and the external factors that influence these outcomes. Such analyses can provide improved guidance toward a more effective biodiversity conservation. Insights into the spatiotemporal interplays between the costs and benefits driving effectiveness can inform decisions about the most suitable orangutan conservation strategies for halting population declines. Although our study focuses on the three extant orangutan species of Sumatra and Borneo, our findings have broad application for evidence-based conservation science and practice worldwide.

Biotic and abiotic drivers of dispersion dynamics in a large-bodied tropical vertebrate, the Western Bornean orangutan.

Understanding of animal responses to dynamic resource landscapes is based largely on research on temperate species with small body sizes and fast life histories. We studied a large, tropical mammal with an extremely slow life history, the Western Bornean orangutan (Pongo pygmaeus wurmbii), across a heterogeneous natural landscape encompassing seven distinct forest types. Our goals were to characterize fluctuations in abundance, test hypotheses regarding the relationship between dispersion dynamics and resource availability, and evaluate how movement patterns are influenced by abiotic conditions. We surveyed abundance in Gunung Palung National Park, West Kalimantan, Indonesia, for 99 consecutive months and simultaneously recorded weather data and assessed fruit availability. We developed a Bayesian hierarchical distance sampling model to estimate population dispersion and assess the roles of fruit availability, rainfall, and temperature in driving movement patterns across this heterogeneous landscape. Orangutan abundance varied dramatically over space and time. Each forest type was important in sustaining more than 40% of the total orangutans on site during at least one month, as animals moved to track asynchronies in fruiting phenology. We conclude that landscape-level movements buffer orangutans against fruit scarcity, peat swamps are crucial fallback habitats, and orangutans' use of high elevation forests is strongly dependent on abiotic conditions. Our results show that orangutans can periodically occupy putative-sink habitats and be virtually absent for extended periods from habitats that are vitally important in sustaining their population, highlighting the need for long-term studies and potential risks in interpreting occurrence or abundance measures as indicators of habitat importance.

MR1-dependent immune surveillance of the skin contributes to pathogenesis and is a photobiological target of UV light therapy in a mouse model of atopic dermatitis.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined. METHODS: Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1-dependent immune surveillance in a MC903-driven murine model of AD. RESULTS: The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL-4- and IL-13-producing cells. In addition, the therapeutic efficacy of phototherapy against MC903-driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6-formylpterin. CONCLUSION: We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands.

Corrigendum: A Severe Lack of Evidence Limits Effective Conservation of the World's Primates.

[This corrects the article DOI: 10.1093/biosci/biaa082.].

Suicide Ideation and Thwarted Interpersonal Needs among Psychiatric Inpatients: A Network Approach.

We aimed to demonstrate the utility of an item-level network analysis approach to suicide risk by testing the interpersonal psychological theory of suicide (IPTS) among 402 psychiatric inpatients. We hypothesized specific thwarted belongingness (TB) or perceived burdensomeness (PB; Interpersonal Needs Questionnaire items) facets would positively relate to passive or active suicide ideation, and these facets would positively relate to each other and form distinct clusters. We also tested TB and PB facets central to the networks as predictors of suicide ideation compared to the full TB and PB subscales. Face-valid items congruent with latent constructs proposed by the IPTS (i.e., feelings of burden on society, feeling that one does not belong) were the only two facets uniquely predictive of passive and active suicide ideation. Facets of TB and PB did not form distinct clusters. Item-level network analysis may have important conceptual, assessment, predictive, and clinical implications for understanding suicide risk.

Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal.

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

Assessing the state of knowledge of contemporary climate change and primates.

In recent years, interest in understanding the effects of climate change on species and ecological systems has sharply increased. We quantify and contextualize the current state of knowledge about the effects of contemporary climate change on non-human primates, a taxon of great ecological and anthropological significance. Specifically, we report findings from a systematic literature search designed to assess the allocation of research effort on primates and climate change and consider how the current distribution of knowledge may be influencing our understanding of the topic. We reveal significant phylogenetic and geographic gaps in our knowledge, which is strongly biased towards lemurs, apes, and a relatively small subset of primate range countries. We show that few analyses investigate changes in primate foods relative to changes in primates themselves or their habitats, and observe that few longitudinal datasets are of sufficient duration to detect effects on the generational scale. We end by identifying areas of research inquiry that would advance our theoretical understanding of primate ecology, evolution, and adaptability, and meaningfully contribute to primate conservation.

Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy.

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.

A novel suprachoroidal microinvasive glaucoma implant: in vivo biocompatibility and biointegration.

BACKGROUND: A major challenge for any glaucoma implant is their ability to provide long-term intraocular pressure lowering efficacy. The formation of a low-permeability fibrous capsule around the device often leads to obstructed drainage channels, which may impair the drainage function of devices. These foreign body-related limitations point to the need to develop biologically inert biomaterials to improve performance in reaching long-term intraocular pressure reduction. The aim of this study was to evaluate in vivo (in rabbits) the ocular biocompatibility and tissue integration of a novel suprachoroidal microinvasive glaucoma implant, MINIject™ (iSTAR Medical, Wavre, Belgium). RESULTS: In two rabbit studies, no biocompatibility issue was induced by the suprachoroidal, ab-externo implantation of the MINIject™ device. Clinical evaluation throughout the 6 post-operative months between the sham and test groups were similar, suggesting most reactions were related to the ab-externo surgical technique used for rabbits, rather than the implant material itself. Histological analysis of ocular tissues at post-operative months 1, 3 and 6 revealed that the implant was well-tolerated and induced only minimal fibroplasia and thus minimal encapsulation around the implant. The microporous structure of the device became rapidly colonized by cells, mostly by macrophages through cell migration, which do not, by their nature, impede the flow of aqueous humor through the device. Time-course analysis showed that once established, pore colonization was stable over time. No fibrosis nor dense connective tissue development were observed within any implant at any time point. The presence of pore colonization may be the process by which encapsulation around the implant is minimized, thus preserving the permeability of the surrounding tissues. No degradation nor structural changes of the implant occurred during the course of both studies. CONCLUSIONS: The novel MINIject™ microinvasive glaucoma implant was well-tolerated in ocular tissues of rabbits, with observance of biointegration, and no biocompatibility issues. Minimal fibrous encapsulation and stable cellular pore colonization provided evidence of preserved drainage properties over time, suggesting that the implant may produce a long-term ability to enhance aqueous outflow.

A Severe Lack of Evidence Limits Effective Conservation of the World's Primates.

Threats to biodiversity are well documented. However, to effectively conserve species and their habitats, we need to know which conservation interventions do (or do not) work. Evidence-based conservation evaluates interventions within a scientific framework. The Conservation Evidence project has summarized thousands of studies testing conservation interventions and compiled these as synopses for various habitats and taxa. In the present article, we analyzed the interventions assessed in the primate synopsis and compared these with other taxa. We found that despite intensive efforts to study primates and the extensive threats they face, less than 1% of primate studies evaluated conservation effectiveness. The studies often lacked quantitative data, failed to undertake postimplementation monitoring of populations or individuals, or implemented several interventions at once. Furthermore, the studies were biased toward specific taxa, geographic regions, and interventions. We describe barriers for testing primate conservation interventions and propose actions to improve the conservation evidence base to protect this endangered and globally important taxon.

The Intervening Roles of Psychological Inflexibility and Functional Impairment in the Relation between Cancer-related Pain and Psychological Distress.

BACKGROUND: Psychological distress is a significant problem among patients with a diagnosis of cancer and is associated with elevated risk for mortality; however, not all patients with a diagnosis of cancer experience significant psychological distress. Cancer-related pain has been associated with greater psychological distress among patients with a cancer diagnosis (current or previous). The current study aimed to examine potential theoretical mechanisms (i.e., cognitive fusion, experiential avoidance, and functional impairment) as proposed by the psychological flexibility model, for the association between cancer-related pain and psychological distress. We hypothesized that cancer-related pain would be indirectly positively associated with psychological distress among patients with a cancer diagnosis (current or previous) through psychological inflexibility (i.e., cognitive fusion and experiential avoidance) related to pain and functional impairment, in serial. METHOD: Sixty-one adult outpatients diagnosed with cancer completed self-report assessments of cancer-related pain, psychological inflexibility related to pain, pain-related functional impairment, and psychological distress. RESULTS: Cancer-related pain was positively associated with psychological distress indirectly through greater pain-related psychological inflexibility (i.e., cognitive fusion and experiential avoidance) and functional impairment, in serial. Alternative models were explored but unsupported. CONCLUSION: Consistent with the psychological flexibility model, psychological inflexibility and functional impairment may be potential mechanisms underlying the association between cancer-related pain and psychological distress among patients with a cancer diagnosis (current or previous).

The Chemical Synthesis, Stability, and Activity of MAIT Cell Prodrug Agonists That Access MR1 in Recycling Endosomes.

Mucosal-associated invariant T (MAIT) cells are antibacterial effector T cells that react to pyrimidines derived from bacterial riboflavin synthesis presented by the monomorphic molecule MR1. A major challenge in MAIT cell research is that the commonly used MAIT agonist precursor, 5-amino-6-d-ribitylaminouracil (5-A-RU), is labile to autoxidation, resulting in a loss of biological activity. Here, we characterize two independent autoxidation processes by LCMS. To overcome the marked instability, we report the synthesis of a 5-A-RU prodrug generated by modification of the 5-amino group with a cleavable valine-citrulline-p-aminobenzyl carbamate. The compound is stable in prodrug form, with the parent amine (i.e., 5-A-RU) released only after enzymatic cleavage. Analysis of the prodrug in vitro and in vivo showed an enhanced MAIT cell activation profile compared to 5-A-RU, which was associated with preferential loading within recycling endosomes, a route used by some natural agonists. This prodrug design therefore overcomes the difficulties associated with 5-A-RU in biological studies and provides an opportunity to explore different presentation pathways.