Publications

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rhesus macaques as a tractable physiological model of human ageing.research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. the ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. in this review ...202032951555
behavioral mimicry predicts social favor in adolescent rhesus macaques (macaca mulatta).non-conscious mimicry is a highly conserved component of animal behavior with multifaceted connections to sociality across taxa. one intriguing consequence of this mimicry in primates is that it promotes positive social feedback from the recipient toward the mimicker. this suggests that mimicry in primates may be an important aspect of positive social interaction, but few studies have tracked the consequences of mimicry in naturally occurring complex social conditions. here, we designed a novel ...202032949317
a systematic review of the hematopoietic acute radiation syndrome (h-ars) in canines and non-human primates: acute mixed neutron/gamma vs. reference quality radiations.a systematic review of relevant studies that determined the dose response relationship (drr) for the hematopoietic (h) acute radiation syndrome (ars) in the canine relative to radiation quality of mixed neutron:gamma radiations, dose rate, and exposure uniformity relative to selected reference radiation exposure has not been performed. the datasets for rhesus macaques exposure to mixed neutron:gamma radiation are used herein as a species comparative reference to the canine database. the selectio ...202032947486
ethanol-impaired myogenic differentiation is associated with decreased myoblast glycolytic function.myopathy affects nearly half of individuals with alcohol use disorder (aud), and impaired skeletal muscle regenerative potential is a probable contributing factor. previous findings from our laboratory indicate that chronic in vivo and in vitro ethanol (etoh) treatment decreases myogenic potential of skeletal muscle myoblasts. myogenesis, a highly coordinated process, requires shifts in cellular metabolic state allowing for myoblasts to proliferate and differentiate into mature myotubes. the obj ...202032945016
non-human primates receiving high-dose total-body irradiation are at risk of developing cerebrovascular injury years postirradiation.nuclear accidents and acts of terrorism have the potential to expose thousands of people to high-dose total-body iradiation (tbi). those who survive the acute radiation syndrome are at risk of developing chronic, degenerative radiation-induced injuries [delayed effects of acute radiation (deare)] that may negatively affect quality of life. a growing body of literature suggests that the brain may be vulnerable to radiation injury at survivable doses, yet the long-term consequences of high-dose tb ...202032942304
eccentricity-dependent effects of simultaneous competing defocus on emmetropization in infant rhesus monkeys.dual-focus lenses that impose simultaneous competing myopic defocus over the entire visual field produce axial hyperopic shifts in refractive error. the purpose of this study was to characterize the effects of eccentricity on the ability of myopic defocus signals to influence central refractive development in infant monkeys. from 24 to 152 days of age, rhesus monkeys were reared with binocular, dual-focus lenses that had central, zero-powered zones surrounded by alternating concentric annular po ...202032942214
attention-related modulation of caudate neurons depends on superior colliculus activity.recent work has implicated the primate basal ganglia in visual perception and attention, in addition to their traditional role in motor control. the basal ganglia, especially the caudate nucleus 'head' (cdh) of the striatum, receive indirect anatomical connections from the superior colliculus (sc), a midbrain structure that is known to play a crucial role in the control of visual attention. to test the possible functional relationship between these subcortical structures, we recorded cdh neurona ...202032940607
adeno-associated virus capsid-promoter interactions in the brain translate from rat to the nonhuman primate.recently, we established an adeno-associated virus (aav9) capsid-promoter interaction that directly determined cell-specific gene expression across two synthetic promoters, cbh and cba, in the rat striatum. these studies not only expand this capsid-promoter interaction to include another promoter in the rat striatum but also establish aav capsid-promoter interactions in the nonhuman primate brain. when aav serotype 9 (aav9) vectors were injected into the rat striatum, the minimal synthetic promo ...202032940068
effects of blocking mglur5 on primate dorsolateral prefrontal cortical neuronal firing and working memory performance.metabotropic glutamate type 5 receptor (mglur5) antagonists are under development for treating cognitive disorders such as fragile x syndrome and alzheimer's disease, largely based on success in mouse models, where post-synaptic mglur5 stimulation weakens synaptic functions in hippocampus. however, human trials of mglur5 antagonists have yet to be successful. this may be due in part to the differing effects of mglur5 in hippocampus vs. prefrontal cortex, as mglur5 are primarily post-synaptic in ...202032939596
medical, genomic, and evolutionary aspects of the peptide sharing between pathogens, primates, and humans.comparing mammalian proteomes for molecular mimicry with infectious pathogens highlights the highest levels of heptapeptide sharing between pathogens and human, murine, and rat proteomes, while the peptide sharing level is minimal (or absent) with proteomes from nonhuman primates such as gorilla, chimpanzee, and rhesus macaque. from the medical point of view, the data might be useful to clinicians and vaccinologists to develop and evaluate immunomodulatory and immunotherapeutic approaches. as a ...202032939517
signal dynamics of midbrain dopamine neurons during economic decision-making in monkeys.when we make economic choices, the brain first evaluates available options and then decides whether to choose them. midbrain dopamine neurons are known to reinforce economic choices through their signal evoked by outcomes after decisions are made. however, although critical internal processing is executed while decisions are being made, little is known about the role of dopamine neurons during this period. we found that dopamine neurons exhibited dynamically changing signals related to the inter ...202032937434
anti-α4β7 monoclonal antibody-conjugated nanoparticles block integrin α4β7 on intravaginal t cells in rhesus macaques.intravenous administration of anti-α4β7 monoclonal antibody in macaques decreases simian immunodeficiency virus (siv) vaginal infection and reduces gut siv loads. because of potential side effects of systemic administration, a prophylactic strategy based on mucosal administration of anti-α4β7 antibody may be safer and more effective. with this in mind, we developed a novel intravaginal formulation consisting of anti-α4β7 monoclonal antibody-conjugated nanoparticles (nps) loaded in a 1% hydroxyet ...202032937372
histone deacetylase hda-1 modulates mitochondrial stress response and longevity.the ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (uprmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. here we show that hda-1, the c. elegans ortholog of mammalian histone deacetylase (hdac) is required for mitochondrial stress-mediate ...202032934238
retinoic acid improves the recovery of replication-competent virus from latent siv infected cells.the accurate estimation and eradication of human immunodeficiency virus (hiv) viral reservoirs is limited by the incomplete reactivation of cells harboring the latent replication-competent virus. we investigated whether the in vitro and in vivo addition of retinoic acid (ra) enhances virus replication and improves the detection of latent virus. peripheral blood mononuclear cells (pbmcs) from naive and anti-retroviral therapy (art)-treated siv-infected rhesus macaques (rms) were cultured in vitro ...202032932813
mutational resilience of antiviral restriction favors primate trim5α in host-virus evolutionary arms races.host antiviral proteins engage in evolutionary arms races with viruses, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. for example, primate trim5α uses its rapidly evolving 'v1' loop to bind retroviral capsids, and single mutations in this loop can dramatically improve retroviral restriction. however, it is unknown whether such gains of viral restriction are rare, or if they incur loss of pre-existing function against other viruses. using deep mutat ...202032930662
cortical interlaminar astrocytes are generated prenatally, mature postnatally, and express unique markers in human and nonhuman primates.interlaminar astrocytes (ilas) are a subset of cortical astrocytes that reside in layer i, express gfap, have a soma contacting the pia, and contain long interlaminar processes that extend through several cortical layers. we studied the prenatal and postnatal development of ilas in three species of primates (rhesus macaque, chimpanzee, and human). we found that ilas are generated prenatally likely from radial glial (rg) cells, that ilas proliferate locally during gestation, and that ilas extend ...202032930323
immune responses of a cv-a16 live attenuated candidate strain and its protective effects in rhesus monkeys.coxsackievirus a16 (cv-a16) is a major causative pathogen of hand, foot, and mouth diseases (hfmds). the licensed hfmd vaccine targets ev-a71 without cross-protection against cv-a16. thus, a cv-a16 vaccine is needed. in this study, the immunogenicity and protective efficacy of a live attenuated cv-a16 candidate, k168-8ac, were evaluated in a rhesus monkey model. four passages of this strain (p35, p50, p60, and p70) were administered to monkeys, and its protective effect was identified. the immun ...202032930072
correction for nishimura et al., prevention and treatment of shivad8 infection in rhesus macaques by a potent d-peptide hiv entry inhibitor. 202032929023
the innate immune response in zika virus infection.zika virus (zikv; flaviviridae, flavivirus) was discovered in 1947 in uganda, africa, from the serum of a sentinel rhesus monkey (macaca mulatta). it is an enveloped, positive-sense, single-stranded rna virus, which encodes a single polyprotein that is cleaved into 10 individual proteins. in 2015, the zika-epidemic in brazil was marked mainly by the exponential growth of microcephaly cases and other congenital defects. with regard to host-pathogen relationships, understanding the role of the imm ...202032926478
non-invasive cerebral perfusion and oxygenation monitoring augment prolonged field care in a non-human primate model of decompensated hemorrhage and resuscitation.decompensated hemorrhagic shock (dhs) is the leading cause of preventable death in combat casualties. "golden hour" resuscitation effects on cerebral blood flow and perfusion following dhs in prolonged field care (pfc) are not well investigated. using an established non-human primate model of dhs, we hypothesized non-invasive regional tissue oxygenation (rso2) and transcranial doppler (tcd) would correlate to the invasive measurement of partial pressure of oxygen (pto2) and mean arterial pressur ...202032925606
an antioxidant enzyme therapeutic for covid-19.the covid-19 pandemic has taken a significant toll on people worldwide, and there are currently no specific antivirus drugs or vaccines. herein it is a therapeutic based on catalase, an antioxidant enzyme that can effectively breakdown hydrogen peroxide and minimize the downstream reactive oxygen species, which are excessively produced resulting from the infection and inflammatory process, is reported. catalase assists to regulate production of cytokines, protect oxidative injury, and repress re ...202032924219
rhesus cytomegalovirus-specific cd8+ cytotoxic t lymphocytes do not become functionally exhausted in chronic sivmac239 infection.cd8+ cytotoxic t lymphocytes (ctls) exert potent antiviral activity after hiv/siv infection. however, efforts to harness the antiviral efficacy of ctls for hiv/siv prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. by contrast, ctls directed against human cytomegalovirus (hcmv), a ubiquitous chronic herpesvirus, seldom select for escape mutations and remain functional and refractory to exhaustion during chronic hcmv and hiv infection. recently ...202032922404
fast responses to images of animate and inanimate objects in the nonhuman primate amygdala.visual information reaches the amygdala through the various stages of the ventral visual stream. there is, however, evidence that a fast subcortical pathway for the processing of emotional visual input exists. to explore the presence of this pathway in primates, we recorded local field potentials in the amygdala of four rhesus monkeys during a passive fixation task showing images of ten object categories. additionally, in one of the monkeys we also obtained multi-unit spiking activity during the ...202032917917
automated markerless pose estimation in freely moving macaques with openmonkeystudio.the rhesus macaque is an important model species in several branches of science, including neuroscience, psychology, ethology, and medicine. the utility of the macaque model would be greatly enhanced by the ability to precisely measure behavior in freely moving conditions. existing approaches do not provide sufficient tracking. here, we describe openmonkeystudio, a deep learning-based markerless motion capture system for estimating 3d pose in freely moving macaques in large unconstrained environ ...202032917899
cross-species functional alignment reveals evolutionary hierarchy within the connectome.evolution provides an important window into how cortical organization shapes function and vice versa. the complex mosaic of changes in brain morphology and functional organization that have shaped the mammalian cortex during evolution, complicates attempts to chart cortical differences across species. it limits our ability to fully appreciate how evolution has shaped our brain, especially in systems associated with unique human cognitive capabilities that lack anatomical homologues in other spec ...202032916286
neural variability determines coding strategies for natural self-motion in macaque monkeys.we have previously reported that central neurons mediating vestibulo-spinal reflexes and self-motion perception optimally encode natural self-motion (mitchell et al., 2018). importantly however, the vestibular nuclei also comprise other neuronal classes that mediate essential functions such as the vestibulo-ocular reflex (vor) and its adaptation. here we show that heterogeneities in resting discharge variability mediate a trade-off between faithful encoding and optimal coding via temporal whiten ...202032915134
the new zealand white rabbit animal model of acute radiation syndrome: hematopoietic and coagulation-based parameters by radiation dose following supportive care.animal models that accurately reflect human responses to radiation injury are needed for advanced mechanistic investigation and development of effective therapeutics. the rabbit is an established animal model accepted by the fda for studies of cardiovascular disease, lipid metabolism, the development of anticoagulants, testing of bone implants, and the development of treatments for infectious diseases such as hiv. the purpose of this study was to investigate the new zealand white (nzw) rabbit mo ...202032909860
the impact of supportive care on survival in large animal models of total body irradiation.well-characterized animal models that mimic the human response to potentially lethal doses of radiation are necessary in order to assess the efficacy of candidate medical countermeasures under the criteria of the u.s. food and drug administration 'animal rule'. development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity under scenarios likely to be present in the human population during mass casualty situations. these s ...202032909856
quantification of neurons in the hippocampal formation of chimpanzees: comparison to rhesus monkeys and humans.the hippocampal formation is important for higher brain functions such as spatial navigation and the consolidation of memory, and it contributes to abilities thought to be uniquely human, yet little is known about how the human hippocampal formation compares to that of our closest living relatives, the chimpanzees. to gain insight into the comparative organization of the hippocampal formation in catarrhine primates, we quantified neurons stereologically in its major subdivisions-the granular lay ...202032909100
early antiretroviral therapy prevents viral infection of monocytes and inflammation in simian immunodeficiency virus-infected rhesus macaques.despite early antiretroviral therapy (art), treatment interruption is associated with viral rebound, indicating early viral reservoir (vr) seeding and absence of full eradication of human immunodeficiency virus type 1 (hiv-1) that may persist in tissues. herein, we address the contributing role of monocytes in maintaining vrs under art, since these cells may represent a source of viral dissemination due to their ability to replenish mucosal tissues in response to injury. to this aim, monocytes w ...202032907978
biomechanics of the mandible of macaca mulatta during the power stroke of mastication: loading, deformation, and strain regimes and the impact of food type.mandible morphology has yet to yield definitive information on primate diet, probably because of poor understanding of mandibular loading and strain regimes, and overreliance on simple beam models of mandibular mechanics. we used a finite element model of a macaque mandible to test hypotheses about mandibular loading and strain regimes and relate variation in muscle activity during chewing on different foods to variation in strain regimes. the balancing-side corpus is loaded primarily by sagitta ...202032905895
mapping neutralizing antibody epitope specificities to an hiv env trimer in immunized and in infected rhesus macaques.bg505 sosip is a well-characterized near-native recombinant hiv envelope (env) trimer that holds promise as part of a sequential hiv immunogen regimen to induce broadly neutralizing antibodies (bnabs). rhesus macaques are considered the most appropriate pre-clinical animal model for monitoring antibody (ab) responses. accordingly, we report here the isolation of 45 bg505 autologous neutralizing antibodies (nabs) with multiple specificities from sosip-immunized and bg505 shiv-infected rhesus maca ...202032905766
a special cranial nucleus (csf-contacting nucleus) in primates.there is a unique nucleus (csf-contacting nucleus) in the brain of rat. it has been demonstrated in our previous research. the extraordinary feature of this nucleus is that it is not connected to any parenchymal organ but to the csf. in primates, however, the presence or absence of this nucleus has not been proven. confirmation of the presence of this nucleus in primates will provide the structural basis for brain-csf communication and help to understand the neurohumoral regulatory mechanisms in ...202032903455
minimally dependent activity subspaces for working memory and motor preparation in the lateral prefrontal cortex.the lateral prefrontal cortex is involved in the integration of multiple types of information, including working memory and motor preparation. however, it is not known how downstream regions can extract one type of information without interference from the others present in the network. here, we show that the lateral prefrontal cortex of non-human primates contains two minimally dependent low-dimensional subspaces: one that encodes working memory information, and another that encodes motor prepa ...202032902383
lack of effect of short-term dhea supplementation on the perimenopause ovary†.dehydroepiandrosterone (dhea) hormonal supplementation can improve oocyte quality in women with diminished ovarian function. however, it is unclear whether dhea supplementation can also enhance ovarian function during the perimenopause (i.e., when the number of follicles in the ovary has undergone a marked reduction). to address this question, we examined the impact of 2.5-months of daily 5-mg oral dhea supplementation on the number of ovarian follicles and the concentrations of anti-müllerian h ...202032901819
corticocortical and thalamocortical changes in functional connectivity and white matter structural integrity after reward-guided learning of visuospatial discriminations in rhesus monkeys.the frontal cortex and temporal lobes together regulate complex learning and memory capabilities. here, we collected resting-state functional and diffusion-weighted mri data before and after male rhesus macaque monkeys received extensive training to learn novel visuospatial discriminations (reward-guided learning). we found functional connectivity changes in orbitofrontal, ventromedial prefrontal, inferotemporal, entorhinal, retrosplenial, and anterior cingulate cortices, the subicular complex, ...202032900835
ultra-high field (10.5 t) resting state fmri in the macaque.resting state functional connectivity refers to the temporal correlations between spontaneous hemodynamic signals obtained using functional magnetic resonance imaging. this technique has demonstrated that the structure and dynamics of identifiable networks are altered in psychiatric and neurological disease states. thus, resting state network organizations can be used as a diagnostic, or prognostic recovery indicator. however, much about the physiological basis of this technique is unknown. thus ...202032898683
bcl11a enhancer-edited hematopoietic stem cells persist in rhesus monkeys without toxicity.gene editing of the erythroid-specific bcl11a enhancer in hematopoietic stem and progenitor cells (hspcs) from patients with sickle cell disease (scd) induces fetal hemoglobin (hbf) without detectable toxicity, as assessed by mouse xenotransplant. here, we evaluated autologous engraftment and hbf induction potential of erythroid-specific bcl11a enhancer-edited hspcs in 4 nonhuman primates. we used a single guide rna (sgrna) with identical human and rhesus target sequences to disrupt a gata1 bind ...202032897878
maternal neglect and the serotonin system are associated with daytime sleep in infant rhesus monkeys.environmental and biological factors contribute to sleep development during infancy. parenting plays a particularly important role in modulating infant sleep, potentially via the serotonin system, which is itself involved in regulating infant sleep. we hypothesized that maternal neglect and serotonin system dysregulation would be associated with daytime sleep in infant rhesus monkeys. subjects were nursery-reared infant rhesus macaques (n = 287). during the first month of life, daytime sleep-wak ...202030712526
a computational model of dual competition between the basal ganglia and the cortex.we propose a model that includes interactions between the cortex, the basal ganglia (bg), and the thalamus based on a dual competition. we hypothesize that the striatum, the subthalamic nucleus (stn), the internal globus pallidus (gpi), the thalamus, and the cortex are involved in closed feedback loops through the hyperdirect and direct pathways. these loops support a competition process that results in the ability of bg to make a cognitive decision followed by a motor one. considering lateral c ...202030627653
development and validation of a primate model for liver fibrosis.many liver diseases involve liver fibrosis. most preclinical studies of liver fibrosis are carried out in small animals such as rodents, and thus lack direct potential for extrapolation to human diseases. the aim of the current study was to develop a primate model for liver fibrosis with greater relevance to translational research.202031247307
digit ratio (2d:4d) and its behavioral correlates in infant rhesus macaques (macaca mulatta).2d:4d ratios are typically lower in adult human males than females and are linked to numerous sex-differentiated behaviors. 2d:4d ratios are considered an indicator of prenatal androgen exposure; if so, children's 2d:4d ratios would arguably be even better indicators of prenatal androgen exposure since children have experienced fewer postnatal influences than adults. however, sex differences in 2d:4d ratios as well as associations between 2d:4d ratios and sex-typed behaviors in children have bee ...202031512755
effects of the extremely low frequency electromagnetic fields on nmda-receptor gene expression and visual working memory in male rhesus macaques.the present research aimed to examine visual working memory (vwm) test scores, as well as hormonal, genomic, and brain anatomic changes in the male rhesus macaques exposed to extremely low frequency magnetic field (elf-mf).202030034647
is male rhesus macaque facial coloration under intrasexual selection?exaggerated male traits can evolve under intra- or intersexual selection, but it remains less clear how often both mechanisms act together on trait evolution. while the males of many anthropoid primate species exhibit colorful signals that appear to be badges of status under intrasexual selection, the red facial coloration of male rhesus macaques (macaca mulatta) appears to have evolved primarily under intersexual selection and female mate choice. nonetheless, experiments show that red color is ...202029622929
characterization of a partial-body irradiation model with oral cavity shielding in nonhuman primates.purpose: characterization of a novel partial-body irradiation (pbi) shielding strategy in nonhuman primates (nhp; rhesus macaques), aimed at protecting the oral cavity, with respect to various gastrointestinal acute radiation syndrome (gi-ars) syndrome parameters as well as buccal ulceration development.materials and methods: nhps were irradiated using a cobalt-60 gamma source, in a single uniform dose, ranging from 9-13 gy and delivered at 0.60-0.80 gy min-1. animals were either partially shiel ...202029447591
who cares? experimental attention biases provide new insights into a mammalian sexual signal.the effects of intrasexual and intersexual selection on male trait evolution can be difficult to disentangle, especially based on observational data. male-male competition can limit an observer's ability to identify the effect of female mate choice independently from sexual coercion. here, we use an experimental approach to explore whether an ornament, the red facial skin exhibited by male rhesus macaques (macaca mulatta), might be involved in both female mate choice and male-male competition. w ...202029622915
consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury.yellow fever (yf) is a mosquito-transmitted viral disease that causes tens of thousands of deaths each year despite the long-standing deployment of an effective vaccine. in its most severe form, yf manifests as a hemorrhagic fever that causes severe damage to visceral organs. although coagulopathy is a defining feature of severe yf in humans, the mechanism by which it develops remains uncertain. hepatocytes are a major target of yellow fever virus (yfv) infection, and the coagulopathy in severe ...202033268494
low aedes aegypti vector competence for zika virus from viremic rhesus macaques.despite worldwide efforts to understand the transmission dynamics of zika virus (zikv), scanty evaluation has been made on the vector competence of aedes aegypti fed directly on viremic human and non-human primates (nhps). we blood-fed ae. aegypti from two districts in rio de janeiro on six zikv infected pregnant rhesus macaques at several time points, half of which were treated with sofosbuvir (sof). mosquitoes were analyzed for vector competence after 3, 7 and 14 days of incubation. although v ...202033255150
in vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome.cytomegaloviruses (cmvs) are highly adapted to their host species resulting in strict species specificity. hence, in vivo examination of all aspects of cmv biology employs animal models using host-specific cmvs. infection of rhesus macaques (rm) with rhesus cmv (rhcmv) has been established as a representative model for infection of humans with hcmv due to the close evolutionary relationships of both host and virus. however, the only available rhcmv clone that permits genetic modifications is bas ...202033232376
membrane-associated and secreted forms of the rhesus macaque rhadinovirus-encoded cd200 homologue and cellular cd200 demonstrate differential effects on rhesus macaque cd200 receptor signaling and regulation of myeloid cell activation.the cd200-cd200r pathway is involved in inhibition of immune responses, and the importance of this pathway to infectious disease is highlighted by the fact that viral cd200 (vcd200) molecules have been found to be encoded by several dna viruses, including the human gammaherpesvirus kaposi's sarcoma-associated herpesvirus (kshv), and the closely related rhesus macaque rhadinovirus (rrv). kshv vcd200 is the most extensively studied vcd200 molecule, however, the only herpesvirus vcd200 molecule to ...202033328302
single amino acid mutations affect zika virus replication in vitro and virulence in vivo.the 2014-2016 zika virus (zikv) epidemic in the americas resulted in large deposits of next-generation sequencing data from clinical samples. this resource was mined to identify emerging mutations and trends in mutations as the outbreak progressed over time. information on transmission dynamics, prevalence, and persistence of intra-host mutants, and the position of a mutation on a protein were then used to prioritize 544 reported mutations based on their ability to impact zikv phenotype. using t ...202033198111
pharmacokinetics and immunological effects of romidepsin in rhesus macaques.hiv/siv persistence in latent reservoirs requires lifelong antiretroviral treatment and calls for effective cure strategies. romidepsin (rmd), a histone deacetylase inhibitor, was reported to reactivate hiv/siv from reservoirs in virus-suppressed individuals. we characterized in detail the pharmacokinetics and safety profile of rmd in three siv-naïve rhesus macaques which received two rounds of treatment. in plasma, rmd mean terminal half-life was 15.3 h. in comparison, rmd mean terminal half-li ...202033362765
icu-like care of nonhuman primates with ebola virus disease.ebola virus disease (evd) supportive care strategies are largely guided by retrospective observational research. this study investigated the effect of evd supportive care algorithms on duration of survival in a controlled nonhuman primate (nhp) model.202033367826
induction of alarmin s100a8/a9 mediates activation of aberrant neutrophils in the pathogenesis of covid-19.the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) pandemic poses an unprecedented public health crisis. evidence suggests that sars-cov-2 infection causes dysregulation of the immune system. however, the unique signature of early immune responses remains elusive. we characterized the transcriptome of rhesus macaques and mice infected with sars-cov-2. alarmin s100a8 was robustly induced in sars-cov-2-infected animal models as well as in covid-19 patients. paquinimod, a specific inh ...202033388094
responses to acute infection with sars-cov-2 in the lungs of rhesus macaques, baboons and marmosets.non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (covid-19) to clinical trials. here, we compare acute severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in young and old rhesus macaques, baboons and old marmosets. macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. baboons had prolonged viral rna shedding and substantially more lu ...202033340034
the gastrointestinal tract is an alternative route for sars-cov-2 infection in a nonhuman primate model.gastrointestinal (gi) manifestations have been increasingly reported in patients with coronavirus disease 2019 (covid-19). however, the roles of the gi tract in severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection are not fully understood. we investigated how the gi tract is involved in sars-cov-2 infection to elucidate the pathogenesis of covid-19.202033307034
correlates of protection against sars-cov-2 in rhesus macaques.recent studies have reported the protective efficacy of both natural1 and vaccine-induced2-7 immunity against challenge with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) in rhesus macaques. however, the importance of humoral and cellular immunity for protection against infection with sars-cov-2 remains to be determined. here we show that the adoptive transfer of purified igg from convalescent rhesus macaques (macaca mulatta) protects naive recipient macaques against challenge wit ...202033276369
nanoparticle vaccines based on the receptor binding domain (rbd) and heptad repeat (hr) of sars-cov-2 elicit robust protective immune responses.various vaccine strategies have been proposed in response to the global covid-19 pandemic, each with unique strategies for eliciting immune responses. here, we developed nanoparticle vaccines by covalently conjugating the self-assembled 24-mer ferritin to the receptor binding domain (rbd) and/or heptad repeat (hr) subunits of the severe acute respiratory syndrome coronavirus-2 (sars-cov-2) spike (s) protein. compared to monomer vaccines, nanoparticle vaccines elicited more robust neutralizing an ...202033275896
dalbavancin binds ace2 to block its interaction with sars-cov-2 spike protein and is effective in inhibiting sars-cov-2 infection in animal models.infection with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has caused a pandemic worldwide. currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (covid-19). here, we report our discovery of a promising anti-covid-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the fda-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. our re ...202033262453
age-related seroprevalence of antibodies against aav-lk03 in a uk population cohort.recombinant adeno-associated virus (raav) vectors are a promising platform for in vivo gene therapy. the presence of neutralizing antibodies (nab) against aav capsids decreases cell transduction efficiency and is a common exclusion criterion for participation in clinical trials. novel engineered capsids are being generated to improve gene delivery to the target cells and facilitate success of clinical trials; however, the prevalence of antibodies against such capsids remains largely unknown. we ...201930027761
porcine endothelial grafts could survive for a long term without using systemic immunosuppressors: an investigation of feasibility and efficacy of xeno-descemet's stripping automated endothelial keratoplasty from wzs-pig to rhesus monkey.in current non-human primate models, full-thickness porcine grafts could not achieve long-term survival without using potent systemic immunosuppressors. moreover, the thickness disparity in xeno-pkp proved to be hard to manipulate and may cause several complications which also could prevent the grafts from long survival. considering the advantages of descemet's stripping automated endothelial keratoplasty (dsaek) derived from its ultrathin graft and lower rejection rate, we hypothesize xeno-dsae ...201929932259
[stimulation of cognitive abilities in aged macaques by moderate hypobaric hypoxia.]the importance of studying neurological and mental changes in aged non-human primates, in particular rhesus macaques (macaca mulatta), is due to their genetic and physiological similarity with humans, which in preclinical studies of age-dependent cognitive decline correction makes them preferable to rodents. in this paper we study the behavior of three older monkeys in solving conditioned-reflex task of image differentiation. the obtained values of several cognitive characteristics were compared ...201930877829
immunochemical analysis of the expression of sv2c in mouse, macaque and human brain.the synaptic vesicle glycoprotein 2c (sv2c) is an undercharacterized protein with enriched expression in phylogenetically old brain regions. its precise role within the brain is unclear, though various lines of evidence suggest that sv2c is involved in the function of synaptic vesicles through the regulation of vesicular trafficking, calcium-induced exocytosis, or synaptotagmin function. sv2c has been linked to multiple neurological disorders, including parkinson's disease and psychiatric condit ...201929274878
transformation of visual representations across ventral stream body-selective patches.although the neural processing of visual images of bodies is critical for survival, it is much less well understood than face processing. functional imaging studies demonstrated body selective regions in primate inferior temporal cortex. to advance our understanding of how the visual brain represents bodies, we compared the representation of animate and inanimate objects in two such body patches with fmri-guided single unit recordings in rhesus monkeys. we found that the middle superior temporal ...201929186363
a trivalent hcv vaccine elicits broad and synergistic polyclonal antibody response in mice and rhesus monkey.despite the development of highly effective direct-acting antivirals, a prophylactic vaccine is needed for eradicating hcv. a major hurdle of hcv vaccine development is to induce immunity against hcv with high genome diversity. we previously demonstrated that a soluble e2 (se2) expressed from insect cells induces broadly neutralising antibodies (nabs) and prevents hcv infection. the objective of this study is to develop a multivalent hcv vaccine to increase the antigenic coverage.201929180585
uncoupling the widespread occurrence of anti-nmdar1 autoantibodies from neuropsychiatric disease in a novel autoimmune model.autoantibodies of the igg class against n-methyl-d-aspartate-receptor subunit-nr1 (nmdar1-ab) were considered pathognomonic for anti-nmdar encephalitis. this view has been challenged by the age-dependent seroprevalence (up to >20%) of functional nmdar1-ab of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. these findings question a merely encephalitogenic role of nmdar1-ab. here, we show that nmdar1-ab belong to the normal autoimmune repertoire of ...201929426955
frontal eye field inactivation reduces saccade preparation in the superior colliculus but does not alter how preparatory activity relates to saccades of a given latency.a neural correlate for saccadic reaction times (srts) in the gap saccade task is the level of low-frequency activity in the intermediate layers of the superior colliculus (isc) just before visual target onset: greater levels of such preparatory isc low-frequency activity precede shorter srts. the frontal eye fields (fefs) are one likely source of isc preparatory activity, since fef preparatory activity is also inversely related to srt. to better understand the fef's role in saccade preparation, ...201929766038
neuronal connections of direct and indirect pathways for stable value memory in caudal basal ganglia.direct and indirect pathways in the basal ganglia work together for controlling behavior. however, it is still a controversial topic whether these pathways are segregated or merged with each other. to address this issue, we studied the connections of these two pathways in the caudal parts of the basal ganglia of rhesus monkeys using anatomical tracers. our previous studies showed that the caudal basal ganglia control saccades by conveying long-term values (stable values) of many visual objects t ...201929737578
lifespan trajectories of white matter changes in rhesus monkeys.progress in neurodevelopmental brain research has been achieved through the use of animal models. such models not only help understanding biological changes that govern brain development, maturation and aging, but are also essential for identifying possible mechanisms of neurodevelopmental and age-related chronic disorders, and to evaluate possible interventions with potential relevance to human disease. genetic relationship of rhesus monkeys to humans makes those animals a great candidate for s ...201929701751
social status predicts response to dietary cycling in female rhesus monkeys.with the prevalence of obesity among women the united states surpassing 40%, it is critical to understand how environmental factors influence appetite, body fat accumulation, and the ability to lose weight and maintain weight loss. psychosocial stress exposure is a risk factor for increased consumption of calorically dense diets (cdd), which are high in fat and sugars and promote both increased food intake and weight gain. however, it remains unclear how appetite is affected by psychosocial fact ...201930032952
in vitro and in vivo models of hiv latency.latently infected cells are very infrequent in cd4+ t cells from antiretroviral (arv) treated individuals, with only approximately one in a million infected cd4+ t cells in blood. given the low frequency of infected cells in vivo, multiple in vitro latency models have been developed to facilitate investigations into mechanisms of hiv latency, as well as to enable the evaluation of pharmacological and immunological interventions aimed at depleting latently infected cells. these in vitro models in ...201930030796
monkey models and hiv vaccine research.since the discovery of acquired immunodeficiency syndrome (aids) in 1981, it has been extremely difficult to develop an effective vaccine or a therapeutic cure despite over 36 years of global efforts. one of the major reasons is due to the lack of an immune-competent animal model that supports live human immunodeficiency virus (hiv) infection and disease progression such that vaccine-induced correlates of protection and efficacy can be determined clearly before human trials. nevertheless, rhesus ...201930030791
macaque parvocellular mediodorsal thalamus: dissociable contributions to learning and adaptive decision-making.distributed brain networks govern adaptive decision-making, new learning and rapid updating of information. however, the functional contribution of the rhesus macaque monkey parvocellular nucleus of the mediodorsal thalamus (mdpc) in these key higher cognitive processes remains unknown. this study investigated the impact of mdpc damage in cognition. preoperatively, animals were trained on an object-in-place scene discrimination task that assesses rapid learning of novel information within each s ...201930022540
microglia: an intrinsic component of the proliferative zones in the fetal rhesus monkey (macaca mulatta) cerebral cortex.microglial cells are increasingly recognized as modulators of brain development. we previously showed that microglia colonize the cortical proliferative zones in the prenatal brain and regulate the number of precursor cells through phagocytosis. to better define cellular interactions between microglia and proliferative cells, we performed lentiviral vector-mediated intraventricular gene transfer to induce enhanced green fluorescent protein expression in fetal cerebrocortical cells. tissues were ...201929992243
behavioral impact of long-term chronic implantation of neural recording devices in the rhesus macaque.ensemble recording methods are pervasive in basic and clinical neuroscience research. invasive neural implants are used in patients with drug resistant epilepsy to localize seizure origin, in neuropsychiatric or parkinson's patients to alleviate symptoms via deep brain stimulation, and with animal models to conduct basic research. studies addressing the brain's physiological response to chronic electrode implants demonstrate that the mechanical trauma of insertion is followed by an acute inflamm ...201930016006
the effects of breastfeeding versus formula-feeding on cerebral cortex maturation in infant rhesus macaques.breastfeeding is positively associated with several outcomes reflecting early brain development and cognitive functioning. brain neuroimaging studies have shown that exclusively breastfed children have increased white matter and subcortical gray matter volume compared to formula-fed children. however, it is difficult to disentangle the effects of nutrition in breast milk from other confounding factors that affect brain development, particularly in studies of human subjects. among the nutrients p ...201930201462
ascites formation accompanied by portal vein thrombosis after porcine islet xenotransplantation via the portal vein in rhesus macaque (macaca mulatta).pig-to-nonhuman primate (nhp) islet transplantation has been widely conducted as a preclinical xenotransplantation model prior to human clinical trial. portal vein thrombosis is one of the complications associated with islet infusion through the portal vein into the liver. here, we briefly report severe case of ascites formation accompanied by portal vein thrombi after pig-to-nhp islet xenotransplantation in a rhesus monkey. meticulous prophylactic treatment such as continuous heparin infusion s ...201930194788
joint representation of connectome-scale structural and functional profiles for identification of consistent cortical landmarks in macaque brain.discovery and representation of common structural and functional cortical architectures has been a significant yet challenging problem for years. due to the remarkable variability of structural and functional cortical architectures in human brain, it is challenging to jointly represent a common cortical architecture which can comprehensively encode both structure and function characteristics. in order to better understand this challenge and considering that macaque monkey brain has much less var ...201930178424
uteroplacental and fetal 4d flow mri in the pregnant rhesus macaque.pregnancy complications are often associated with poor uteroplacental vascular adaptation and standard diagnostics are unable to reliably quantify flow in all uteroplacental vessels and have poor sensitivity early in gestation.201930102431
nonnavigational spatial memory performance is unaffected by hippocampal damage in monkeys.evidence that the hippocampus is critical for spatial memory in nonnavigational tests is mixed. a recent study reported that temporary hippocampal inactivation impaired spatial memory in the nonnavigational hamilton search task in monkeys. however, several studies have documented no impairment on other nonnavigational spatial memory tests following permanent hippocampal lesions. it was hypothesized that transient, but not permanent, hippocampal disruption produces deficits because monkeys underg ...201930069946
new minipromoter ple345 (nefl) drives strong and specific expression in retinal ganglion cells of mouse and primate retina.retinal gene therapy is leading the neurological gene therapy field, with 32 ongoing clinical trials of recombinant adeno-associated virus (raav)-based therapies. importantly, over 50% of those trials are using restricted promoters from human genes. promoters that restrict expression have demonstrated increased efficacy and can limit the therapeutic to the target cells thereby reducing unwanted off-target effects. retinal ganglion cells are a critical target in ocular gene therapy; they are invo ...201930062914
exploring the neuromechanism of chronic ephedrine addiction in rhesus monkeys: a behavioural and brain resting-state fmri study.ephedrine is thought to exert behavioural effects primarily through actions on the central nervous system. however, the neuromechanism underlying the effects of ephedrine addiction still remains unclear. our study aimed to establish chronic ephedrine addiction models in rhesus monkeys and to investigate the neuromechanism of chronic ephedrine addiction using the behavioural methods combined with resting-state blood oxygenation level dependent-functional magnetic resonance imaging (bold-fmri). mo ...201930059694
convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei of nonhuman primates.muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function.201929931364
gdnf revisited: a novel mammalian cell-derived variant form of gdnf increases dopamine turnover and improves brain biodistribution.parkinson's disease (pd) is a disorder affecting dopamine neurons for which there is no cure. glial cell line-derived neurotrophic factor (gdnf) and the closely related protein neurturin are two trophic factors with demonstrated neuroprotective and neurorestorative properties on dopamine neurons in multiple animal species. however, gdnf and neurturin phase-2 clinical trials have failed to demonstrate a significant level of improvement over placebo controls. insufficient drug distribution in the ...201929857941
[features of endocrine function of the pancreas with aging in nonhuman primates with various types of adaptive behavior.]an increasing number of studies are devoted to the study of the relationship of mental disorders, such as depression and anxiety, with the risk of developing type 2 diabetes mellitus. however, in the literature there are practically no publications on the study of the relationship of the features of higher nervous activity, in particular, adaptive behavior, in healthy individuals with the risk of developing age-related dysfunction of the pancreatic islet apparatus (pia). the purpose of this stud ...201931512416
functionally defined white matter of the macaque monkey brain reveals a dorso-ventral attention network.classical studies of attention have identified areas of parietal and frontal cortex as sources of attentional control. recently, a ventral region in the macaque temporal cortex, the posterior infero-temporal dorsal area pitd, has been suggested as a third attentional control area. this raises the question of whether and how spatially distant areas coordinate a joint focus of attention. here we tested the hypothesis that parieto-frontal attention areas and pitd are directly interconnected. by com ...201930601116
aging affects correlation within the v1 neuronal population in rhesus monkeys.visual function declines with age. this deterioration results not only from changes in the optical system but also from the functional degradation of the central visual cortex. although numerous studies have explored the mechanisms of age-related influences on vision, they have failed to acknowledge the significance of neuronal correlation in dysfunction of the visual cortex. previous research has focused on the functional degradation of individual neurons, with age-induced changes in correlatio ...201930599290
ratio of the bronchial lumen to pulmonary artery diameter in rhesus macaques (macaca mulatta) without clinical pulmonary disease.in human medicine, ct is widely used to detect changes in bronchial luminal diameter. the diameter of the artery that runs adjacent to the bronchus does not change dramatically along the airway path, such that this artery can be used as a reference to detect changes in the bronchial luminal diameter. the bronchoarterial ratio is increasingly used in veterinary medicine for the detection of lower airway diseases in animals. the purpose of this study was to establish the bronchoarterial ratio in r ...201930591089
gonadotrophin-mediated mirna expression in testis at onset of puberty in rhesus monkey: predictions on regulation of thyroid hormone activity and dlk1-dio3 locus.molecular mechanisms responsible for the initiation of primate spermatogenesis remain poorly characterized. previously, 48 h stimulation of the testes of three juvenile rhesus monkeys with pulsatile lh and fsh resulted in down-regulation of a cohort of genes recognized to favor spermatogonia stem cell renewal. this change in genetic landscape occurred in concert with amplification of sertoli cell proliferation and the commitment of undifferentiated spermatogonia to differentiate. in this report, ...201930590698
testosterone augments fsh signaling by upregulating the expression and activity of fsh-receptor in pubertal primate sertoli cells.the synergistic actions of testosterone (t) and fsh via testicular sertoli cells (sc) regulate male fertility. we have previously reported that the actions of these hormones (t and fsh) in infant monkey testes are restricted only to the expansion of sc and spermatogonial cells. the robust differentiation of male germ cells (gc) occurs after pubertal maturation of testis. the present study was aimed to investigate the molecular basis of the synergy between t and fsh action in pubertal primate (ma ...201930579957
the scalar property during isochronous tapping is disrupted by a d2-like agonist in the nonhuman primate.dopamine, and specifically the d2 system, has been implicated in timing tasks where the absolute duration of individual time intervals is encoded discretely, yet the role of d2 during beat perception and entrainment remains largely unknown. in this type of timing, a beat is perceived as the pulse that marks equally spaced points in time and, once extracted, produces the tendency in humans to entrain or synchronize their movements to it. hence, beat-based timing is crucial for musical execution. ...201930575431
dynamic changes in insulin and glucagon during disease progression in rhesus monkeys with obesity-related type 2 diabetes mellitus.to investigate the progression of obesity-related type 2 diabetes mellitus (t2dm) in rhesus monkeys, especially dynamic changes in insulin and glucagon.201930575251
the caudal part of putamen represents the historical object value information.the basal ganglia, especially the circuits originating from the putamen, are essential for controlling normal body movements. notably, the putamen receives inputs not only from motor cortical areas but also from multiple sensory cortices. however, how these sensory signals are processed in the putamen remains unclear. we recorded the activity of tentative medium spiny neurons in the caudal part of the putamen when the monkey viewed many fractal objects. we found many neurons that responded to th ...201930573645
vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of parkinson's disease.ever since its introduction 40 years ago l-3,4-dihydroxyphenylalanine (l-dopa) therapy has retained its role as the leading standard medication for patients with parkinson's disease. with time, however, the shortcomings of oral l-dopa treatment have become apparent, particularly the motor fluctuations and troublesome dyskinetic side effects. these side effects, which are caused by the excessive swings in striatal dopamine caused by intermittent oral delivery, can be avoided by delivering l-dopa ...201931243443
gene expression across mammalian organ development.the evolution of gene expression in mammalian organ development remains largely uncharacterized. here we report the transcriptomes of seven organs (cerebrum, cerebellum, heart, kidney, liver, ovary and testis) across developmental time points from early organogenesis to adulthood for human, rhesus macaque, mouse, rat, rabbit, opossum and chicken. comparisons of gene expression patterns identified correspondences of developmental stages across species, and differences in the timing of key events ...201931243369
developmental dynamics of lncrnas across mammalian organs and species.although many long noncoding rnas (lncrnas) have been identified in human and other mammalian genomes, there has been limited systematic functional characterization of these elements. in particular, the contribution of lncrnas to organ development remains largely unexplored. here we analyse the expression patterns of lncrnas across developmental time points in seven major organs, from early organogenesis to adulthood, in seven species (human, rhesus macaque, mouse, rat, rabbit, opossum and chick ...201931243368
a method to investigate astrocyte and microglial morphological changes in the aging brain of the rhesus macaque.with a rapidly aging population, studies of neuroinflammation and degeneration associated with eugeric aging are becoming critical. using the unique archive at the tulane national primate research center as a resource, we have developed tools to quantify morphological changes in astrocytes and microglia across the life span of monkeys. this method can be used for morphometric studies of multiple parameters simultaneously in an unbiased manner.201930617987
modulation of gpr39, a g-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice.alcohol use disorder (aud) is a chronic condition with devastating health and socioeconomic effects. still, pharmacotherapies to treat aud are scarce. in a prior study aimed at identifying novel aud therapeutic targets, we investigated the dna methylome of the nucleus accumbens core (nacc) of rhesus macaques after chronic alcohol use. the g-protein coupled receptor 39 (gpr39) gene was hypermethylated and its expression downregulated in heavy alcohol drinking macaques. gpr39 encodes a zn2+-bindin ...201930610192
frequency shifts and depth dependence of premotor beta band activity during perceptual decision-making.neural activity in the premotor and motor cortices shows prominent structure in the beta frequency range (13-30 hz). currently, the behavioral relevance of this beta band activity (bba) is debated. the underlying source of motor bba and how it changes as a function of cortical depth are also not completely understood. here, we addressed these unresolved questions by investigating bba recorded using laminar electrodes in the dorsal premotor cortex of 2 male rhesus macaques performing a visual rea ...201930606756
sevoflurane exposure has minimal effect on cognitive function and does not alter microglial activation in adult monkeys.postoperative cognitive dysfunction (pocd) is a complication that has been observed in a subset of adult and elderly individuals after general anesthesia and surgery. although the pathogenesis of pocd is largely unknown, a growing body of preclinical research suggests that pocd may be caused by general anesthesia. a significant amount of research has examined the effects of general anesthesia on neurocognitive function in rodents, yet no studies have assessed the adverse effects of general anest ...201930605762
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