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Assessing the Effects of Tourist Provisioning on the Health of Wild Barbary Macaques in Morocco
Feeding wildlife is a very popular tourist activity, largely because it facilitates the close observation of animals in their natural habitat. Such provisioning may benefit animals by improving their survival and reproductive success, especially during periods of natural food shortage. However, provisioning by tourists may also have negative impacts on the health of the animals involved; to date such impacts are poorly understood. Here, we investigated the effects of tourist provisioning on the health of wild adult Barbary macaques, Macaca sylvanus, in Morocco. We compared health measures between a heavily provisioned group and a group that received negligible food from tourists and, in the former group, we also assessed health measures in relation to the intensity of provisioning. We used a broad range of non-invasive health measures relating to birth rate and survival, disease and injury risk, body size and condition, and physiological stress. Our findings indicate that feeding by tourists may overall have negative impacts on the health of Barbary macaques, being linked in particular to larger body size, elevated stress levels and more alopecia. Finally, we propose a framework to help consider the potential costs and benefits of provisioning, which may facilitate future research and management decisions on whether-and how much-provisioning is acceptable.
Journal Article
A Comprehensive Atlas of Immunological Differences Between Humans, Mice, and Non-Human Primates
Animal models are an integral part of the drug development and evaluation process. However, they are unsurprisingly imperfect reflections of humans, and the extent and nature of many immunological differences are unknown. With the rise of targeted and biological therapeutics, it is increasingly important that we understand the molecular differences in the immunological behavior of humans and model organisms. However, very few antibodies are raised against non-human primate antigens, and databases of cross-reactivity between species are incomplete. Thus, we screened 332 antibodies in five immune cell populations in blood from humans and four non-human primate species generating a comprehensive cross-reactivity catalog that includes cell type-specificity. We used this catalog to create large mass cytometry universal cross-species phenotyping and signaling panels for humans, along with three of the model organisms most similar to humans: rhesus and cynomolgus macaques and African green monkeys; and one of the mammalian models most widely used in drug development: C57BL/6 mice. As a proof-of-principle, we measured immune cell signaling responses across all five species to an array of 15 stimuli using mass cytometry. We found numerous instances of different cellular phenotypes and immune signaling events occurring within and between species, and detailed three examples (double-positive T cell frequency and signaling; granulocyte response to Bacillus anthracis antigen; and B cell subsets). We also explore the correlation of herpes simian B virus serostatus on the immune profile. Antibody panels and the full dataset generated are available online as a resource to enable future studies comparing immune responses across species during the evaluation of therapeutics.
Journal Article
Partitioning neuronal variability
The authors developed a model of neuron firing in which spike generation arises from the combination of sensory drive and stimulus-independent modulatory influences. This model provides an accurate account of neuron responses in multiple visual areas, suggesting that variability originates from excitability fluctuations that increase in strength along the visual pathway.
Responses of sensory neurons differ across repeated measurements. This variability is usually treated as stochasticity arising within neurons or neural circuits. However, some portion of the variability arises from fluctuations in excitability due to factors that are not purely sensory, such as arousal, attention and adaptation. To isolate these fluctuations, we developed a model in which spikes are generated by a Poisson process whose rate is the product of a drive that is sensory in origin and a gain summarizing stimulus-independent modulatory influences on excitability. This model provides an accurate account of response distributions of visual neurons in macaque lateral geniculate nucleus and cortical areas V1, V2 and MT, revealing that variability originates in large part from excitability fluctuations that are correlated over time and between neurons, and that increase in strength along the visual pathway. The model provides a parsimonious explanation for observed systematic dependencies of response variability and covariability on firing rate.
Journal Article
Therapeutic potential of in vivo administered pseudouridine-containing mRNA
In vitro-transcribed mRNA has great therapeutic potential to transiently express the encoded protein without the adverse effects associated with viral- and DNA-based deliveries or direct protein supplementation. We have demonstrated that HPLC-purified pseudouridine-containing mRNA is non-immunogenic and translates very efficiently in cultured primary cells. We tested Transit-mRNA-complexed erythropoietin (EPO)-encoding mRNA in mice as a model therapeutic. We observed that a single injection of 100 ng (0.005 mg/kg) of mRNA elevated serum EPO levels significantly by 6 h and levels were maintained for 4 days. In comparison, mRNA containing uridine produced 10 to 100-fold lower levels of EPO that returned to baseline after 1 day. EPO translated from pseudouridine-mRNA was functional and caused a significant increase of both reticulocyte counts and hematocrits. Weekly injection of 100 ng of EPO mRNA containing pseudouridine was sufficient to maintain significantly increased hema tocrits without inducing the production of inflammatory cytokines or anti-EPO antibodies. Extending this approach to macaques, we could detect significantly increased serum EPO levels following intraperitoneal or subcutaneous injection of pseudouridine-containing mRNA coding for rhesus EPO. These results demonstrate that HPLC-purified, pseudouridine-containing mRNAs encoding therapeutic proteins have great potential for clinical applications.
Journal Article
Considerations in the Use of Nonhuman Primate Models of Ebola Virus and Marburg Virus Infection
The filoviruses, Ebola virus and Marburg virus, are zoonotic pathogens that cause severe hemorrhagic fever in humans and nonhuman primates (NHPs), with case-fatality rates ranging from 23% to 90%. The current outbreak of Ebola virus infection in West Africa, with >26 000 cases, demonstrates the long-underestimated public health danger that filoviruses pose as natural human pathogens. Currently, there are no vaccines or treatments licensed for human use. Licensure of any medical countermeasure may require demonstration of efficacy in the gold standard cynomolgus or rhesus macaque models of filovirus infection. Substantial progress has been made over the last decade in characterizing the filovirus NHP models. However, there is considerable debate over a variety of experimental conditions, including differences among filovirus isolates used, routes and doses of exposure, and euthanasia criteria, all of which may contribute to variability of results among different laboratories. As an example of the importance of understanding these differences, recent data with Ebola virus shows that an addition of a single uridine residue in the glycoprotein gene at the editing site attenuates the virus. Here, we draw on decades of experience working with filovirus-infected NHPs to provide a perspective on the importance of various experimental conditions.
Journal Article
Parkinson disease: Overcoming hurdles to stem-cell transplantation for treatment of Parkinson disease
Transplantation of stem cells to replace degenerating dopaminergic neurons is an attractive therapeutic option for Parkinson disease (PD), but has so far had limited success in patients. A recent study in macaques has suggested a novel approach to this strategy that has potential to improve therapeutic outcomes.
Journal Article
161 15–30 Hz intermuscular coherence as a potential biomarker of upper motor neuron dysfunction in motor neuron disease
Motor neuron disease (MND) involves the degeneration of variable proportions of upper and lower motor neurons (UMNs, LMNs). Electrophysiological tests for LMN degeneration are well established but an analogous biomarker of UMN damage is lacking. We are investigating 15–30 Hz intermuscular coherence (IMC) as a candidate; such coherence is prominent in normal humans and macaques during certain motor tasks. Selective corticospinal tract (CST) ablation in macaques caused loss of significant 15–30 Hz IMC on the side of the lesion, which persisted despite functional recovery. In patients with primary lateral sclerosis (PLS) no significant 15–30 Hz IMC was detected; by contrast, patients with progressive muscular atrophy (PMA) retained significant 15–30 Hz IMC. Similarly, in MND-mimicking conditions 15–30 Hz IMC was typically only diminished where the condition involved UMN damage. In hereditary spastic paraparesis, lower limb 15–30 Hz IMC was diminished but remained statistically significant in 50% of cases. Patients with neuropathies or myopathies typically retained significant 15–30 Hz IMC unless afferent pathways were involved, reflecting the role of afferent systems in generating 15–30 Hz IMC. Two prospectively assessed MND patients (ALS phenotype) showed significantly decreased 15–30 Hz IMC at least 8 months before a definitive diagnosis. Hence, 15–30 Hz IMC is a potential biomarker of UMN dysfunction in MND.
Journal Article
mRNA-based gene delivery shows promise
The use of mRNA-based gene therapy avoids many of the side effects and risks associated with DNA-based plasmid and viral gene vectors. However, in vitro transcribed RNA activates cellular RNA sensors, leading to degradation and poor expression. This problem can be avoided in cultured cells by using highly-purified mRNAs containing the modified nucleoside pseudouridine. Kariko et al. show that a single injection of such modified mRNA encoding erythropoietin (EPO) elevates serum EPO levels in both mice and macaques, suggesting the possible clinical utility of modified mRNAs. Another paper, by Al-Saif and Khabar, shows that UU/UA dinucleotide frequency reduction in the coding region also enhances mRNA stability and protein expression.
Journal Article
Neonatal face-to-face interactions promote later social behaviour in infant rhesus monkeys
In primates, including humans, mothers engage in face-to-face interactions with their infants, with frequencies varying both within and across species. However, the impact of this variation in face-to-face interactions on infant social development is unclear. Here we report that infant monkeys (
Macaca mulatta
) who engaged in more neonatal face-to-face interactions with mothers have increased social interactions at 2 and 5 months. In a controlled experiment, we show that this effect is not due to physical contact alone: monkeys randomly assigned to receive additional neonatal face-to-face interactions (mutual gaze and intermittent lip-smacking) with human caregivers display increased social interest at 2 months, compared with monkeys who received only additional handling. These studies suggest that face-to-face interactions from birth promote young primate social interest and competency.
Like humans, neonatal primates engage in face-to-face interactions with their mothers from an early age. Dettmer and colleagues demonstrate that in monkeys, increasing neonatal face-to-face interactions enhances social interest in infants of two and five months.
Journal Article