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.

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.

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

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

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.

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.

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.

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.

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).

Responses to Spatial and Temporal Variation in Food Availability on the Feeding Ecology of Proboscis Monkeys (Nasalis larvatus) in West Kalimantan, Indonesia.

Folivorous primates have long been assumed to experience food competition less acutely than frugivores due to their ability to eat leaves, an abundant resource in most forest systems. Consequently, the behavioural responses of leaf-eating primates to variation in food availability are less well characterised than those of frugivores. Recent empirical studies have demonstrated that many colobine species are more affected by food availability and distribution than previously thought; they employ multiple strategies to survive during periods of food scarcity. We studied a population of proboscis monkeys (Nasalis larvatus) over 16 months in three forest types in West Kalimantan, Indonesia, to examine their responses to temporal fluctuation and spatial variation in food availability. We examined how feeding behaviour was influenced by the availability of plants in botanical plots to identify important and preferred foods of proboscis monkeys across months and in different forest types. Proboscis monkeys consumed foods from 68 genera, comprising 35% young leaves, 27% unripe fruit, 12% flowers and 6% mature leaves. Consumption of plant parts and genera by proboscis monkeys varied in response to monthly changes in food availability but did not vary among forest types despite substantial differences in phenology and floristics among them. The monkeys preferred unripe fruits and flowers and used young and mature leaves as fallback foods in mangrove forests. Documentation of proboscis monkey responses to variation in food availability contributes to our understanding of how monkeys respond to changes in their environments due to climate change and habitat degradation.

Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides.

A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.

Understanding sources of variance and correlation among features of Bornean gibbon (Hylobates muelleri) female calls.

Acoustic signals serve important functions in mate choice, resource defense, and species recognition. Quantifying patterns and sources of variation in acoustic signals can advance understanding of the evolutionary processes that shape behavioral diversity more broadly. Animal vocalization datasets are inherently multivariate and hierarchical, wherein multiple features are estimated from calls of many individuals across different recording locations. Patterns of variation within different hierarchical levels-notwithstanding the challenges they present for modeling and inference-can provide insight into processes shaping vocal variation. The current work presents a multivariate, variance components model to investigate three levels of variance (within-female, between-female, and between-site) in Bornean gibbon calls. For six of the eight features estimated from call spectrograms, between-female variance was the most important contributor to total variance. For one feature, trill rate, there were site-level differences, which may be related to geographic isolation of certain gibbon populations. There was also a negative relationship between trill rate and duration of the introduction, suggesting trade-offs in the production of gibbon calls. Given substantial inter-individual variation in gibbon calls, it seems likely that there has been selection to confer information regarding caller identity, but mechanisms leading to site-level variation in trill rate remain to be determined.

Separating Common from Unique Variance Within Emotional Distress: An Examination of Reliability and Relations to Worry.

BACKGROUND: High comorbidity rates among emotional disorders have led researchers to examine transdiagnostic factors that may contribute to shared psychopathology. Bifactor models provide a unique method for examining transdiagnostic variables by modelling the common and unique factors within measures. Previous findings suggest that the bifactor model of the Depression Anxiety and Stress Scale (DASS) may provide a method for examining transdiagnostic factors within emotional disorders. AIMS: This study aimed to replicate the bifactor model of the DASS, a multidimensional measure of psychological distress, within a US adult sample and provide initial estimates of the reliability of the general and domain-specific factors. Furthermore, this study hypothesized that Worry, a theorized transdiagnostic variable, would show stronger relations to general emotional distress than domain-specific subscales. METHOD: Confirmatory factor analysis was used to evaluate the bifactor model structure of the DASS in 456 US adult participants (279 females and 177 males, mean age 35.9 years) recruited online. RESULTS: The DASS bifactor model fitted well (CFI = 0.98; RMSEA = 0.05). The General Emotional Distress factor accounted for most of the reliable variance in item scores. Domain-specific subscales accounted for modest portions of reliable variance in items after accounting for the general scale. Finally, structural equation modelling indicated that Worry was strongly predicted by the General Emotional Distress factor. CONCLUSIONS: The DASS bifactor model is generalizable to a US community sample and General Emotional Distress, but not domain-specific factors, strongly predict the transdiagnostic variable Worry.

Person-specific validation and testing of functional relations in cognitive-behavioural case formulation: Guidelines and options.

Although a number of manuals describe how to develop a cognitive-behavioural case formulation (CBCF) to assist the clinician in developing and implementing tailored CB treatment for complex or comorbid cases, methods to evaluate and test functional hypotheses in the formulation for a particular case are not widely known or used. Thus, formulation-based, tailored treatments for such cases are likely to be guided by case formulations of uncertain validity. The present article presents guidelines and choices available to the clinical trainee, researcher, or practitioner planning to use a person-specific (PS) approach to testing CBCF hypotheses about functional relations between triggers, cognitions, and distress or dysfunction. This approach involves repeated assessments completed by the client using an individualized questionnaire that includes both nomothetic and idiographic items of greatest relevance to the client. Guidelines and options for developing this questionnaire and for data collection within the context of a collaborative therapist-client relationship are described. PS data analyses are then used to test case formulation hypotheses that vary in complexity from simple bivariate relations to complex dynamic mediation. A case example using this PS approach is described. Simpler options for the PS evaluation of a CBCF usable by practitioners and trainees as well as more complex options for clinical researchers are included.

The clinical application of suicide risk assessment: A theory-driven approach.

The interpersonal theory of suicide posits that thwarted belongingness (TB) and perceived burdensomeness (PB) increase suicide ideation; however, studies have found mixed results regarding this hypothesis among psychiatric inpatients. This study aimed to (a) demonstrate how assessing TB and PB using the Interpersonal Needs Questionnaire (INQ) can provide clinically useful information and (b) investigate how statistical methodology may impact the clinical application of the INQ. Participants were 139 (Sample 1) and 104 (Sample 2) psychiatric inpatients. In both samples, ordinal logistic regression results indicated TB and PB, separately, were significant predictors of suicide ideation-related outcomes; however, when examined as simultaneous predictors, TB was no longer a significant predictor. The interaction between TB and PB was not significant for either sample. Despite this, TB and PB scores provided clinically relevant information about suicide ideation-related outcomes. For example, the highest scores on TB and PB indicated a 93% and 95% chance of having some level of distress due to suicide ideation (Sample 1), a 91% and 92% chance of having some level of desire for death, and a 79% and 84% chance of having some level of desire for suicide, respectively (Sample 2). This study also proposes clinical cutoff scores for the INQ (for TB and PB, respectively, cutoff scores were 22 and 17 for distress due to suicide ideation, 33 and 17 for desire for death, and 31 and 22 for desire for suicide). Although these results indicate that multicollinearity between TB and PB may create interpretational ambiguity for clinicians, TB and PB may each be useful separate predictors of suicide ideation-related outcomes in psychiatric inpatient settings and should be incorporated into suicide risk assessment. KEY PRACTITIONER MESSAGE: The 15-item Interpersonal Needs Questionnaire (an assessment of thwarted belongingness and perceived burdensomeness) should be incorporated into suicide risk assessment. Among psychiatric inpatients, greater thwarted belongingness and perceived burdensomeness, as separate predictors, were associated with increased levels of distress due to suicide ideation, desire for death, and desire for suicide. The highest scores on thwarted belongingness and perceived burdensomeness indicated a 79% to 95% chance of experiencing an elevated level of distress due to suicide ideation, desire for death, or desire for suicide. Recommended clinical cutoff scores were provided. For example, thwarted belongingness cutoff score of 31 and perceived burdensomeness cutoff score of 22 maximized the sensitivity and specificity of the INQ to detect some level of desire for suicide.

Exploring the isoform selectivity of TGX-221 related pyrido[1,2-a]pyrimidinone-based Class IA PI 3-kinase inhibitors: synthesis, biological evaluation and molecular modelling.

A novel series of TGX-221 analogues was prepared and tested for their potency against the p110α, p110ß, and p110δ isoforms of the PI3K enzyme, and in two cellular assays. The biological results were interpreted in terms of a p110ß comparative model, in order to account for their selectivity towards this isoform. A CH2NH type linker is proposed to allow binding into the specificity pocket proposed to accommodate the high p110ß-selectivity of TGX-221, although there was limited steric tolerance for substituents on the pendant ring with the 2-position most favourable for substitution.

Sleeping site selection by proboscis monkeys (Nasalis larvatus) in West Kalimantan, Indonesia.

Primates spend at least half their lives sleeping; hence, sleeping site selection can have important effects on behavior and fitness. As proboscis monkeys (Nasalis larvatus) often sleep along rivers and form bands (aggregations of one male groups) at their sleeping sites, understanding sleeping site selection may shed light on two unusual aspects of this species' socioecology: their close association with rivers and their multilevel social organization. We studied sleeping site selection by proboscis monkeys for twelve months at Sungai Tolak, West Kalimantan, Indonesia to test two main hypotheses regarding the drivers of sleeping site selection: reduction of molestation by mosquitoes and anti-predator behavior. We identified to genus and collected data on the physical structure (diameter at breast height, relative height, branch structure, and leaf coverage) of sleeping trees and available trees in three forest types. We used resource selection function models to test specific predictions derived from our two hypotheses. The monkeys preferred to sleep in large trees with few canopy connections located along rivers. The selection of large emergent trees was consistent with both of our main hypotheses: decreased molestation by mosquitoes and reduced potential entry routes for terrestrial predators. Although we are only beginning to understand how sleeping sites might influence behavior, grouping, and potential survival of this species, our study has shown that proboscis monkeys (at Sungai Tolak) have a very strong preference for large trees located near the river. As these trees are often the first to be logged by local villagers, this may exacerbate the problems of forest loss for these endangered monkeys.

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.

Conservation strategies for species affected by apparent competition.

Apparent competition is an indirect interaction between 2 or more prey species through a shared predator, and it is increasingly recognized as a mechanism of the decline and extinction of many species. Through case studies, we evaluated the effectiveness of 4 management strategies for species affected by apparent competition: predator control, reduction in the abundances of alternate prey, simultaneous control of predators and alternate prey, and no active management of predators or alternate prey. Solely reducing predator abundances rapidly increased abundances of alternate and rare prey, but observed increases are likely short-lived due to fast increases in predator abundance following the cessation of control efforts. Substantial reductions of an abundant alternate prey resulted in increased predation on endangered huemul (Hippocamelus bisulcus) deer in Chilean Patagonia, which highlights potential risks associated with solely reducing alternate prey species. Simultaneous removal of predators and alternate prey increased survival of island foxes (Urocyon littoralis) in California (U.S.A.) above a threshold required for population recovery. In the absence of active management, populations of rare woodland caribou (Rangifer tarandus caribou) continued to decline in British Columbia, Canada. On the basis of the cases we examined, we suggest the simultaneous control of predators and alternate prey is the management strategy most likely to increase abundances and probabilities of persistence of rare prey over the long term. Knowing the mechanisms driving changes in species' abundances before implementing any management intervention is critical. We suggest scientists can best contribute to the conservation of species affected by apparent competition by clearly communicating the biological and demographic forces at play to policy makers responsible for the implementation of proposed management actions.

Long-chain triazolyl acids as inhibitors of osteoclastogenesis.

Saturated fatty acids (e.g., palmitic acid) are known to moderately inhibit the development of osteoclasts in vitro. In pursuit of more effective inhibitors of osteoclastogenesis we explored two new classes of palmitic acid analogues containing either an ether or triazolyl group at various positions along the chain. The compounds were evaluated for their ability to inhibit the formation of osteoclasts in primary mouse bone marrow cultures. The oxyacids were generally prepared by condensation of the appropriate alkyl halides and diols, followed by Jones oxidation. The triazolyl acids were prepared by copper-catalysed click chemistry between alkyl azides and acetylenic acids, or with the appropriately-protected azides and alkynes, followed by deprotection and oxidation. The oxyacids were little more effective than palmitic acid, but the triazolyl analogues were much more effective osteoclastogenesis inhibitors, especially when the triazole was distant from the acid unit.