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the neonatal fc receptor (fcrn) binds independently to both sites of the igg homodimer with identical affinity.the neonatal fc receptor (fcrn) is expressed by cells of epithelial, endothelial and myeloid lineages and performs multiple roles in adaptive immunity. characterizing the fcrn/igg interaction is fundamental to designing therapeutic antibodies because iggs with moderately increased binding affinities for fcrn exhibit superior serum half-lives and efficacy. it has been hypothesized that 2 fcrn molecules bind an igg homodimer with disparate affinities, yet their affinity constants are inconsistent ...201525658443
nonclinical safety evaluation of vx15/2503, a humanized igg4 anti-sema4d antibody.the humanized igg4 monoclonal antibody vx15/2503 bound with 1 to 5 nmol/l affinity to purified recombinant semaphorin 4d (sema4d; cd100) produced using murine, rat, cynomolgus macaque, and human sequences. the affinity for native sema4d expressed on macaque t lymphocytes was approximately 0.6 nmol/l. tissues from rats and cynomolgus macaques demonstrated specific staining only with resident lymphocytes. single-dose and one-month toxicology/pk studies used vx15/2503 dose levels of 0 to 100 mg/kg. ...201525657333
an extragonadal teratoma in a female cynomolgus monkey (macaca fascicularis).extragonadal teratomas have not been reported in nonhuman primates. a female cynomolgus monkey, a vehicle control in an exploratory toxicity study, was necropsied. microscopic examination of an extragonadal mass in the animal's craniodorsal retroperitoneum revealed a teratoma. this is the first report of an extragonadal teratoma in a nonhuman primate.201525656828
alveolar ridge dimensional changes following ridge preservation procedure with novel devices: part 1--cbct linear analysis in non-human primate model.this study sought to investigate dimensional changes to the alveolar bone following extraction and application of novel devices used for obturation of socket orifice (socket cap) and space maintenance in sockets with facial dehiscence (socket cage).201625655480
sequence of pathogenic events in cynomolgus macaques infected with aerosolized monkeypox virus.to evaluate new vaccines when human efficacy studies are not possible, the fda's "animal rule" requires well-characterized models of infection. thus, in the present study, the early pathogenic events of monkeypox infection in nonhuman primates, a surrogate for variola virus infection, were characterized. cynomolgus macaques were exposed to aerosolized monkeypox virus (10(5) pfu). clinical observations, viral loads, immune responses, and pathological changes were examined on days 2, 4, 6, 8, 10, ...201525653439
anti-pcsk9 antibody pharmacokinetics and low-density lipoprotein-cholesterol pharmacodynamics in nonhuman primates are antigen affinity-dependent and exhibit limited sensitivity to neonatal fc receptor-binding enhancement.proprotein convertase subtilisin/kexin type 9 (pcsk9) has emerged as an attractive therapeutic target for cardiovascular disease. monoclonal antibodies (mabs) that bind pcsk9 and prevent pcsk9:low-density lipoprotein receptor complex formation reduce serum low-density lipoprotein-cholesterol (ldl-c) in vivo. pcsk9-mediated lysosomal degradation of bound mab, however, dramatically reduces mab exposure and limits duration of effect. administration of high-affinity mab1:pcsk9 complex (1:2) to mice ...201525653417
granzyme b-expressing neutrophils correlate with bacterial load in granulomas from mycobacterium tuberculosis-infected cynomolgus macaques.the role of neutrophils in tuberculosis (tb), and whether neutrophils express granzyme b (grzb), a pro-apoptotic enzyme associated with cytotoxic t cells, is controversial. we examined neutrophils in peripheral blood (pb) and lung granulomas of mycobacterium tuberculosis-infected cynomolgus macaques and humans to determine whether mycobacterial products or pro-inflammatory factors induce neutrophil grzb expression. we found large numbers of grzb-expressing neutrophils in macaque and human granul ...201525653138
neutral endopeptidase-resistant c-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism.achondroplasia (ach), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. genetic overexpression of c-type natriuretic peptide (cnp), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ach. however, administration of exogenous cnp is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. using in vitro approaches, we developed mod ...201525650377
identification and analysis of cyp7a1, cyp17a1, cyp20a1, cyp27a1 and cyp51a1 in cynomolgus macaques.cytochromes p450 (p450) are important for not only drug metabolism and toxicity, but also biosynthesis and metabolism of cholesterol and bile acids, and steroid synthesis. in cynomolgus macaques, widely used in biomedical research, we have characterized p450 cdnas, which were isolated as expressed sequence tags of cynomolgus macaque liver. in this study, cynomolgus cyp7a1, cyp17a1, cyp20a1, cyp27a1 and cyp51a1 cdnas were characterized by sequence analysis, phylogenetic analysis and tissue expres ...201425649950
thermosensitive and mucoadhesive pluronic-hydroxypropylmethylcellulose hydrogel containing the mini-cd4 m48u1 is a promising efficient barrier against hiv diffusion through macaque cervicovaginal mucus.to be efficient, vaginal microbicide hydrogels should form a barrier against viral infections and prevent virus spreading through mucus. multiple particle tracking was used to quantify the mobility of 170-nm fluorescently labeled cooh-modified polystyrene particles (cooh-ps) into thermosensitive hydrogels composed of amphiphilic triblock copolymers with block compositions eon-pom-eon (where eo refers to ethylene oxide and po to propylene oxide) containing mucoadhesive hydroxypropylmethylcellulos ...201525645853
influence of menstrual cycle on the expression of clock genes in peripheral blood mononuclear cells in macaca fascicularis.to investigate whether the expression patterns of periphery clock genes were influenced by menstrual cycle in a monkey model.201525637813
comprehensive identification of high-frequency and combination mhc-dma and -dmb alleles in a cohort of chinese rhesus macaques and cynomolgus macaques of vietnamese origin.rhesus and cynomolgus macaques are currently used as ideal animal models of immune response. major histocompatibility complex (mhc) molecules play important roles in the susceptibility and/or resistance to many diseases. in this study, mhc-dma and -dmb were first characterized by sequencing and cloning in 28 unrelated cynomolgus macaques from vietnam and 34 unrelated chinese rhesus macaques. a total of 23 novel alleles, including six high frequency alleles, were identified in this study. our res ...201525636571
design, synthesis, and evaluation of linker-duocarmycin payloads: toward selection of her2-targeting antibody-drug conjugate syd985.antibody-drug conjugates (adcs) that are currently on the market or in clinical trials are predominantly based on two drug classes: auristatins and maytansinoids. both are tubulin binders and block the cell in its progression through mitosis. we set out to develop a new class of linker-drugs based on duocarmycins, potent dna-alkylating agents that are composed of a dna-alkylating and a dna-binding moiety and that bind into the minor groove of dna. linker-drugs were evaluated as adcs by conjugati ...201525635711
ch5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.resistance of prostate cancer to castration is currently an unavoidable problem. the major mechanisms underlying such resistance are androgen receptor (ar) overexpression, androgen-independent activation of ar, and ar mutation. to address this problem, we developed an ar pure antagonist, ch5137291, with ar nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. cell lines corresponding to the mechanisms of castration resistance were use ...201525634071
thalamic projections to visual and visuomotor areas (v6 and v6a) in the rostral bank of the parieto-occipital sulcus of the macaque.the medial posterior parietal cortex of the primate brain includes different functional areas, which have been defined based on the functional properties, cyto- and myeloarchitectural criteria, and cortico-cortical connections. here, we describe the thalamic projections to two of these areas (v6 and v6a), based on 14 retrograde neuronal tracer injections in 11 hemispheres of 9 macaca fascicularis. the injections were placed either by direct visualisation or using electrophysiological guidance, a ...201625633471
extraparenchymal bile/pancreatic ducts and duodenal papillae: pathologic evaluation in nonclinical species--a brief review.this review focuses on the anatomy, histologic preparation, and pathologic evaluation of extraparenchymal bile and pancreatic ducts (bpds) and their openings at the duodenal papillae in the cynomolgus macaque (macaca fascicularis), the beagle dog (canis familiaris), the wistar hanover rat (rattus norvegicus), and the cd1 mouse (mus musculus). in nonclinical safety assessment, intraparenchymal bpds (with sections of liver and pancreas, respectively) are evaluated routinely. however, detailed eval ...201525633421
effects of prior cocaine self-administration on cognitive performance in female cynomolgus monkeys.cocaine use has been associated with cognitive impairments that may contribute to poor treatment outcomes. however, the degree to which these deficits extend into periods of abstinence has not been completely elucidated. this study tested whether prior experience self-administering cocaine affected acquisition of two cognitive tasks in 16 adult female cynomolgus monkeys. seven monkeys had previously self-administered cocaine but had not had access to cocaine for 2 months at the start of this stu ...201525633093
short-term variability in qt interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations.the present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated k(+) channel, herg, on cardiac autonomic control. combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency.201525625756
[uterine autologous transplantation in cynomolgus monkeys: a preliminary report of 6 case].to evaluate the surgical feasibility of uterine autologous transplantation in female cynomolgus monkeys and explore the effect of microsurgical technique.201425623107
quantitative expression analysis of app pathway and tau phosphorylation-related genes in the icv stz-induced non-human primate model of sporadic alzheimer's disease.the accumulation and aggregation of misfolded proteins in the brain, such as amyloid-β (aβ) and hyperphosphorylated tau, is a neuropathological hallmark of alzheimer's disease (ad). previously, we developed and validated a novel non-human primate model for sporadic ad (sad) research using intracerebroventricular administration of streptozotocin (icv stz). to date, no characterization of ad-related genes in different brain regions has been performed. therefore, in the current study, the expressio ...201525622254
variability in tuberculosis granuloma t cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization.lung granulomas are the pathologic hallmark of tuberculosis (tb). t cells are a major cellular component of tb lung granulomas and are known to play an important role in containment of mycobacterium tuberculosis (mtb) infection. we used cynomolgus macaques, a non-human primate model that recapitulates human tb with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of t cells in individual granulomas. we sought to correlate t cel ...201525611466
a nonhuman primate scrub typhus model: protective immune responses induced by pkarp47 dna vaccination in cynomolgus macaques.we developed an intradermal (id) challenge cynomolgus macaque (macaca fascicularis) model of scrub typhus, the leading cause of treatable undifferentiated febrile illness in tropical asia, caused by the obligate intracellular bacterium, orientia tsutsugamushi. a well-characterized animal model is required for the development of clinically relevant diagnostic assays and evaluation of therapeutic agents and candidate vaccines. we investigated scrub typhus disease pathophysiology and evaluated two ...201525601925
method validation and reference range values for a peripheral blood immunophenotyping assay in non-human primates.a peripheral blood immunophenotyping assay was developed and validated for determination of total t-lymphocytes, helper t-lymphocytes, cytotoxic t-lymphocytes, b-lymphocytes, and natural killer cells in cynomolgus monkeys. validation parameters included assessment of precision, linearity, antibody optimization, stability of peripheral blood samples, and stability of fixed immunophenotyping samples. total lymphocyte populations were determined using a heterogeneous lymphocyte gating strategy cons ...201625600312
novel potential treatment modalities for ocular hypertension: focus on angiotensin and bradykinin system axes.despite the availability of modern surgical procedures, new drug delivery techniques, health authority-approved single topical ocular drugs, and combination products thereof, there continues to be an unmet medical need for novel treatment modalities for preserving vision. this is especially true for the treatment of glaucoma and the high risk factor often associated with this ocular disease, elevated intraocular pressure (iop). undesirable local or systemic side effects, frequency of dosing, lac ...201525599263
androgen correlates of male reproductive effort in wild male long-tailed macaques (macaca fascicularis): a multi-level test of the challenge hypothesis.the challenge hypothesis (wingfield et al., 1990) has been broadly utilised as a conceptual framework to study male androgen correlates of reproductive challenges in mammals. these studies mainly assessed male androgen responsiveness to a general degree of challenge over extended periods of time. short term co-variation between the socio-sexual challenging context and androgen levels remains, however, largely understudied. we thus aim at providing a multi-level test of the challenge hypothesis b ...201525596329
long-term toxicity study of rad5-htertc27 in sd rats and cynomolgus monkeys by intravenous injection.rad5-htertc27, a replication-defective adenovirus vector carrying htertc27, has been proposed for possible use against hepatocellular carcinoma (hcc). in this study, we investigated the long-term toxicity of rad5-htertc27 in sd rats and cynomolgus monkeys. rad5-htertc27 was administered intravenously once a week for 13 weeks followed by a one-month recovery period. as of 4 months, all animals displayed overall good health. anti-adenoviral antibodies emerged in a dose-independent manner. the leve ...201525592546
long-term control of simian immunodeficiency virus (siv) in cynomolgus macaques not associated with efficient siv-specific cd8+ t-cell responses.the spontaneous control of human and simian immunodeficiency viruses (hiv/siv) is typically associated with specific major histocompatibility complex (mhc) class i alleles and efficient cd8(+) t-cell responses, but many controllers maintain viral control despite a nonprotective mhc background and weak cd8(+) t-cell responses. therefore, the contribution of this response to maintaining long-term viral control remains unclear. to address this question, we transiently depleted cd8(+) t cells from f ...201525589645
next-generation sequencing reveals a controlled immune response to zaire ebola virus challenge in cynomolgus macaques immunized with vesicular stomatitis virus expressing zaire ebola virus glycoprotein (vsvδg/ebovgp).vesicular stomatitis virus expressing zaire ebola virus (ebov) glycoprotein (vsvδg/ebovgp) could be used as a vaccine to meet the 2014 ebola virus outbreak. to characterize the host response to this vaccine, we used mrna sequencing to analyze peripheral blood mononuclear cells (pbmcs) from cynomolgus macaques after vsvδg/ebovgp immunization and subsequent ebov challenge. we found a controlled transcriptional response that transitioned to immune regulation as the ebov was cleared. this observatio ...201525589554
fully human anti-baff inhibitory monoclonal antibody tabalumab does not adversely affect t-dependent antibody responses in cynomolgus monkey (macaca fasicularis): a summary of three pre-clinical immunotoxicology evaluations.the potential immunotoxicity of tabalumab was assessed as a component of standard pre-clinical toxicology studies in cynomolgus monkeys. to evaluate potential tabalumab-associated immunosuppression after antigen challenge, cynomolgus monkeys were administered placebo control or tabalumab in three immunotoxicological safety studies. study 1, a 4-week pilot study, evaluated biweekly intravenous (iv) control, and 0.3, 1.0, 5.0, and 15.0 mg/kg tabalumab doses. study 2 evaluated iv control, and 0.1, ...201625585959
radiosynthesis and in vivo evaluation of a novel σ1 selective pet ligand.the σ1 receptor is an important target for cns disorders. we previously identified a σ1 ligand tz3108 having highly potent (ki-σ1 = 0.48 nm) and selective affinity for σ1 versus σ2 receptors. tz3108 was (18)f-labeled with f-18 for in vivo evaluation. biodistribution and blocking studies of [(18)f]tz3108 in male sprague-dawley rats demonstrated high brain uptake, which was σ1-specific with no in vivo defluorination. micropet studies in cynomolgus macaques showed high brain penetration of [(18)f]t ...201425584182
sildenafil-induced reversible impairment of rod and cone phototransduction in monkeys.to investigate functional alteration of the retina induced by sildenafil in monkeys.201525574056
an evolving uncontrolled hemorrhage model using cynomolgus macaques.trauma-induced hemorrhagic shock produces hemodynamic changes that often result in a systemic inflammatory response that can lead to multiple organ failure and death. in this prospective study, the pathophysiology of a nonhuman primate uncontrolled hemorrhagic shock model is evaluated with the goal of creating an acute systemic inflammatory syndrome response and a reproducible hemorrhage.201525565642
compete to play: trade-off with social contact in long-tailed macaques (macaca fascicularis).many animal species engage in various forms of solitary object play, but this activity seems to be of particular importance in primates. if playing objects constitute a valuable resource, and access to such objects is limited, a competitive context may arise. we inserted a unique toy within a mini-colony of long-tailed macaque (macaca fascicularis) and compared their behaviors to sessions without playing object. an automatic color-based 3d video device was used to track the positions of each ani ...201425551755
properties of soluble glycoprotein vi, a potential platelet activation biomarker.glycoprotein vi (gpvi) plays a critical role in the platelet response to collagen. clinical studies suggest that the plasma level of soluble gpvi (sgpvi) is a highly specific and useful platelet activation marker. however, many properties of sgpvi have not been fully characterized, such as its sensitivity in detecting platelet activation and its elimination rate from the blood. in this study we established a sandwich enzyme-linked immunosorbent assay for human sgpvi, which cross-reacts to cynomo ...201525549161
monkey models of tuberculosis: lessons learned.the use of animal models has been invaluable for studying the pathogenesis of mycobacterium tuberculosis infection, as well as for testing the efficacy of vaccines and drug regimens for tuberculosis. among the applied animal models, nonhuman primates, particularly macaques, share the greatest anatomical and physiological similarities with humans. as such, macaque models have been used for investigating tuberculosis pathogenesis and preclinical testing of drugs and vaccines. this review focuses o ...201525547788
a novel nonhuman primate model of cigarette smoke-induced airway disease.small animal models of chronic obstructive pulmonary disease (copd) have several limitations for identifying new therapeutic targets and biomarkers for human copd. these include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. thus, we assessed the utility of cigarette smoke (cs)-exposed cynomolgus macaque as a nonhuman primate (nhp) large animal ...201525542772
preclinical evaluation of bioabsorbable polyglycolic acid spacer for particle therapy.to evaluate the efficacy and safety of a polyglycolic acid (pga) spacer through physical and animal experiments.201425539373
ph-dependent binding engineering reveals an fcrn affinity threshold that governs igg recycling.the fc domain of igg has been the target of multiple mutational studies aimed at altering the ph-dependent igg/fcrn interaction to modulate igg pharmacokinetics. these studies have yielded antibody variants with disparate pharmacokinetic characteristics, ranging from extended in vivo half-life to those exhibiting extremely rapid clearance. to better understand ph-dependent binding parameters that govern these outcomes and limit fcrn-mediated half-life extension, we generated a panel of novel fc ...201525538249
evidence for an intranasal immune response to human respiratory syncytial virus infection in cynomolgus macaques.there is no large-scale therapy available against human respiratory syncytial virus (hrsv), a major pathogen responsible for acute respiratory diseases. macaques represent an interesting animal model to evaluate potential treatments because of their genetic, anatomical and immunological proximity with humans. however, the parameters that influence hrsv growth and control in this model are still poorly understood. we have documented in the following study the influence of age as well as repeated ...201525537374
interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics.we quantified, by liquid chromatography tandem mass spectrometry, transporter protein expression of bsep, mate1, mrp3, mrp4, ntcp, and oct1 in our human liver bank (n = 55) and determined the relationship between protein expression and sex, age and genotype. these data complement our previous work in the same liver bank where we quantified the protein expression of oatps, bcrp, mdr1, and mrp2. in addition, we quantified and compared the interspecies differences in expression of the hepatobiliary ...201525534768
comparative microrna expression profiles of cynomolgus monkeys, rat, and human reveal that mir-182 is involved in t2d pathogenic processes.type 2 diabetes (t2d) is a prevalent disease that happens around the world and usually happens with insulin resistance. micrornas (mirnas) represented important roles in the suppression of gene expression and were proven to be related to human diseases. in this study, we used cynomolgus monkey fed with normal and high fatty diet (hfd), respectively, to analyze the mirna expression profile in whole blood by deep sequencing. finally in total 24 mirnas with differential expression were filtered. am ...201425530976
nonclinical reproductive and developmental safety evaluation of the mage-a3 cancer immunotherapeutic, a therapeutic vaccine for cancer treatment.we assessed potential toxic effects of the mage-a3 cancer immunotherapeutic on female fertility and embryo-fetal, pre- and post-natal development in rats and on male fertility in rats and monkeys. three groups of 48 female (study 1) or 22 male (study 2) cd rats received 5 or 3 injections of 100μl of saline, as15 immunostimulant, or mage-a3 cancer immunotherapeutic (mage-a3 recombinant protein combined with as15) at various timepoints pre- or post-mating. male cynomolgus monkeys (study 3) receive ...201525530039
use of generic lc-ms/ms assays to characterize atypical pk profile of a biotherapeutic monoclonal antibody.the fully human monoclonal antibody mab123, which binds to and neutralizes chemokine motif ligand-21 (ccl21) displays a faster clearance in cynomolgus monkey compared with typical igg kinetics. a direct and an immunoaffinity lc-ms/ms assays were developed to compare with the previously established ligand-binding assays (lbas).201425529889
spatial patterning of bone stiffness in the anterior mandibular corpus of macaca fascicularis: implications for models of bone adaptation.elastic modulus of bone from the anterior mandibular corpus was determined via microindentation in a mixed-sex ontogenetic sample (n = 14) of macaca fascicularis. this investigation focused on the hypothesis that material heterogeneity in the macaque mandibular symphysis-provided an accounting of age and sex variation-is explicable as a means to homogenize strains in this region. experimental data and theoretical models of masticatory loading indicate that in the absence of material compensation ...201525521934
delayed inflammatory and cell death responses are associated with reduced pathogenicity in lujo virus-infected cynomolgus macaques.to identify host factors associated with arenavirus virulence, we used a cynomolgus macaque model to evaluate the pathogenesis of lujo virus (lujv), a recently emerged arenavirus that caused an outbreak of severe viral hemorrhagic fever in southern africa. in contrast to human cases, lujv caused mild, nonlethal illness in macaques. we then compared this to contrasting clinical outcomes during arenavirus infection, specifically to samples obtained from macaques infected with three highly pathogen ...201525520505
framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge.pharmacokinetic (pk) testing of a humanized (κi, vh3 framework) and affinity matured anti-hepatitis c virus e2-glycoprotein (hcv-e2) antibody (hu5b3.κ1vh3.v3) in rats revealed unexpected fast clearance (34.9 ml/day/kg). this antibody binds to the rat recycling receptor fcrn as expected for a human igg1 antibody and does not display non-specific binding to baculovirus particles in an assay that is correlated with fast clearance in cynomolgus monkey. the antigen is not expressed in rat so target-d ...201425517310
effect of antigen-dependent clearance on pharmacokinetics of anti-heparin-binding egf-like growth factor (hb-egf) monoclonal antibody.heparin-binding egf-like growth factor (hb-egf) is a member of the egf family and is an important therapeutic target in some types of human cancers. km3566 is a mouse anti-hb-egf monoclonal antibody that neutralizes hb-egf activity by inhibiting the binding of hb-egf to its receptors. based on the results of our pharmacokinetics study, a humanized derivative antibody, khk2866, is rapidly cleared from serum and shows nonlinear pharmacokinetics in cynomolgus monkeys. in this study, we examined the ...201425517307
hybrid bioartificial liver support in cynomolgus monkeys with d-galactosamine-induced acute liver failure.to evaluate a hybrid bioartificial liver support system (hbalss) in cynomolgus monkeys with acute liver failure.201425516651
a critical analysis of the cynomolgus macaque, macaca fascicularis, as a model to test hiv-1/siv vaccine efficacy.the use of a number of non-rhesus macaque species, but especially cynomolgus macaques as a model for hiv-1 vaccine development has increased in recent years. cynomolgus macaques have been used in the united kingdom, europe, canada and australia as a model for hiv vaccine development for many years. unlike rhesus macaques, cynomolgus macaques infected with siv show a pattern of disease pathogenesis that more closely resembles that of human hiv-1 infection, exhibiting lower peak and set-point vira ...201525510387
metabolism and disposition of mm-433593, a selective faah-1 inhibitor, in monkeys.mm-433593 is a highly potent and selective inhibitor of fatty acid amide hydrolase-1 (faah-1) with potential utility as an orally administered treatment of pain, inflammation, and other disorders. in this study, we investigated the metabolism and pharmacokinetics of mm-433593 in monkeys, and compared plasma and urine metabolites of this compound to the in vitro metabolites produced by monkey hepatocytes. intravenous administration of mm-433593 to cynomolgus monkeys produced a rapid distribution ...201425505606
the in vivo efficacy and side effect pharmacology of gs-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting β 2-adrenoceptor agonist in preclinical animal species.bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (copd) and asthma, with inhaled β 2-adrenoceptor agonists and anticholinergics being the primary treatments available. the present studies evaluated the in vivo pharmacology of (r)-6-[[3-[[4-[5-[[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (gs-57 ...201425505595
in vitro metabolism and metabolic effects of ajulemic acid, a synthetic cannabinoid agonist.ajulemic acid is a synthetic analog of δ(8)-thc-11-oic acid, the terminal metabolite of δ(8)-thc. unlike δ(9)-thc, the psychoactive principle of cannabis, it shows potent anti-inflammatory action and has minimal cns cannabimimetic activity. its in vitro metabolism by hepatocytes from rats, dogs, cynomolgus monkeys and humans was studied and the results are reported here. five metabolites, m1 to m5, were observed in human hepatocyte incubations. one metabolite, m5, a glucuronide, was observed in ...201325505570
evaluation of amg 076, a potent and selective mchr1 antagonist, in rodent and primate obesity models.melanin-concentrating hormone (mch) regulates food intake through activation of the receptor, mchr1. we have identified amg 076 as an orally bioavailable potent and selective small molecule antagonist of mchr1. in mouse models of obesity, amg 076 caused a reduction in body weight gain in wild-type (mchr1+/+) but not in knockout (mchr1-/-) mice. the body weight reduction was associated with decreases in food intake and increases in energy expenditure. importantly, we show that these mchr1-depende ...201325505557
targeting an acid labile aspartyl-prolyl amide bond as a viable alternative to trypsin digestion to generate a surrogate peptide for lc-ms/ms analysis.fgf21-adpke is a fusion protein and functionally inactivated in vivo by cleavage around the c-terminus. it is important to quantify the intact active protein in serum.201425496253
[18f]dpa-714 pet imaging of translocator protein tspo (18 kda) in the normal and excitotoxically-lesioned nonhuman primate brain.we aimed to characterize pharmacologically the tspo- radioligand [(18)f]dpa-714 in the brain of healthy cynomolgus monkeys and evaluate the cellular origin of its binding in a model of neurodegeneration induced by intrastriatal injection of quinolinic acid (qa).201525488184
treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone.eldecalcitol (eld), an active form of vitamin d analog approved for the treatment of osteoporosis in japan, increases lumbar spine bone mineral density (bmd), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. we have previously reported that treatment with eld for 6 months improved the mechanical properties of the lumbar spine in ovariectomized (ovx) cynomolgus monkeys. eld treatment increased lumbar bmd, suppressed bone turnover markers, and reduced hist ...201525482210
engraftable neural crest stem cells derived from cynomolgus monkey embryonic stem cells.neural crest stem cells (ncscs), a population of multipotent cells that migrate extensively and give rise to diverse derivatives, including peripheral and enteric neurons and glia, craniofacial cartilage and bone, melanocytes and smooth muscle, have great potential for regenerative medicine. non-human primates provide optimal models for the development of stem cell therapies. here, we describe the first derivation of ncscs from cynomolgus monkey embryonic stem cells (cmescs) at the neural rosett ...201525477174
in vivo occupancy of the 5-ht1a receptor by a novel pan 5-ht1(a/b/d) receptor antagonist, gsk588045, using positron emission tomography.5-hydroxytryptamine 1 (5-ht1) receptor blockade in combination with serotonin reuptake inhibition may provide a more rapid elevation of synaptic 5-ht compared to serotonin reuptake alone, by blocking the inhibitory effect of 5-ht1 receptor activation on serotonin release. gsk588045 is a novel compound with antagonist activity at 5-ht1a/1b/1d receptors and nanomolar affinity for the serotonin transporter, which was in development for the treatment of depression and anxiety. here we present the re ...201525476970
live-attenuated measles virus vaccine targets dendritic cells and macrophages in muscle of nonhuman primates.although live-attenuated measles virus (mv) vaccines have been used successfully for over 50 years, the target cells that sustain virus replication in vivo are still unknown. we generated a reverse genetics system for the live-attenuated mv vaccine strain edmonston-zagreb (ez), allowing recovery of recombinant (r)mv(ez). three recombinant viruses were generated that contained the open reading frame encoding enhanced green fluorescent protein (egfp) within an additional transcriptional unit (atu) ...201525473055
pet/ct imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis.oxazolidinone antibiotics such as linezolid have shown significant therapeutic effects in patients with extensively drug-resistant (xdr) tuberculosis (tb) despite modest effects in rodents and no demonstrable early bactericidal activity in human phase 2 trials. we show that monotherapy with either linezolid or azd5847, a second-generation oxazolidinone, reduced bacterial load at necropsy in mycobacterium tuberculosis-infected cynomolgus macaques with active tb. this effect coincided with a decli ...201425473035
therapeutic c3 inhibitor cp40 abrogates complement activation induced by modern hemodialysis filters.approximately 350,000 individuals in the united states rely on maintenance hemodialysis treatment because of end-stage renal disease. despite improvements in dialysis technology, the mortality rate for patients treated with maintenance dialysis is still exceptionally high, with a 5-year survival rate of only 35%. many patients succumb to conditions resulting at least in part from the chronic induction of inflammation. among the triggers of inflammation, the complement system is of particular imp ...201525468722
semi-mechanistic multiple-analyte pharmacokinetic model for an antibody-drug-conjugate in cynomolgus monkeys.a semi-mechanistic multiple-analyte population pharmacokinetics (pk) model was developed to describe the complex relationship between the different analytes of monomethyl auristatin e (mmae) containing antibody-drug conjugates (adcs) and to provide insight regarding the major pathways of conjugate elimination and unconjugated mmae release in vivo.201525467958
reprint of "effects of amphetamine, diazepam and caffeine on polysomnography (eeg, emg, eog)-derived variables measured using telemetry in cynomolgus monkeys".medication-induced sleep disturbances are a major concern in drug development as a multitude of prescription drugs alter sleep patterns, often negatively. polysomnography is used in clinical diagnostics but is also applicable to animal models. rodent sleep architecture (nocturnal) differs from larger diurnal mammals, including humans, increasing the translational potential of non-rodent species to the clinic. this study aimed to characterize the response to pharmacological agents known to affect ...201425467813
reprint of "non-invasive measure of respiratory mechanics and conventional respiratory parameters in conscious large animals by high frequency airwave oscillometry".a number of drugs in clinical trials are discontinued due to potentially life-threatening airway obstruction. as some drugs may not cause changes in core battery parameters such as tidal volume (vt), respiratory rate (rr) or minute ventilation (mv), including measurements of respiratory mechanics in safety pharmacology studies represents an opportunity for design refinement. the present study aimed to test a novel non-invasive methodology to concomitantly measure respiratory system resistance (r ...201425467812
pharmacological characterization of a novel liver x receptor agonist with partial lxrα activity and a favorable window in nonhuman primates.liver x receptors (lxrs) α and β are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (rct) and are potential drug targets for atherosclerosis. however, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. we report the pharmacology of bms-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1h-imidazol-4-yl)-2-propanol], a potent partial lxr agonist with lxrβ selectivity, ...201525467132
detection of drug specific circulating immune complexes from in vivo cynomolgus monkey serum samples.administration of a biotherapeutic can result in the formation of anti-drug antibodies (adas). the resulting ada can potentially form immune complexes (ics) with the drug leading to altered pharmacokinetic (pk) profiles and/or adverse events. furthermore the presence of such complexes may interfere with accurate pk assessment, and/or detection of ada in immunogenicity assays. here, we present two assays to detect the presence of drug-ada immune complexes in cynomolgus monkeys.201525462536
developmental toxicity assessment of tanezumab, an anti-nerve growth factor monoclonal antibody, in cynomolgus monkeys (macaca fascicularis).two intravenous studies with tanezumab, an anti-nerve growth factor monoclonal antibody, were conducted in pregnant cynomolgus monkeys to assess potential effects on pregnancy and pre- and postnatal development. study 1 evaluated infants up to 12 months of age following weekly maternal dosing (0, 0.5, 4 or 30 mg/kg; 18 per group) from gestation day (gd) 20 through parturition. study 2 evaluated infants 2 months postnatally following weekly maternal dosing (0, 0.5 or 30 mg/kg; 20-21 per group) fr ...201525461901
hazard quotient profiles used as a risk assessment tool for pfos and pfoa serum levels in three distinctive european populations.perfluorooctane sulfonate (pfos) and perfluorooctanoic acid (pfoa) blood levels are commonly used as biomarkers of human environmental exposure to these compounds. many biomonitoring studies indicate 100% detection for pfos and pfoa thus justifying a concern of possible risk for the most exposed individuals. this study addresses the predictive value of hazard quotients (hqs) calculated on the basis of serum pfos and pfoa in male and female populations of reproductive age in greenland, poland and ...201525454227
characterization of cellular immune response and innate immune signaling in human and nonhuman primate primary mononuclear cells exposed to burkholderia mallei.burkholderia pseudomallei infection causes melioidosis and is often characterized by severe sepsis. although rare in humans, burkholderia mallei has caused infections in laboratory workers, and the early innate cellular response to b. mallei in human and nonhuman primates has not been characterized. in this study, we examined the primary cellular immune response to b. mallei in pbmc cultures of non-human primates (nhps), chlorocebus aethiops (african green monkeys), macaca fascicularis (cynomolg ...201525450887
replication of live attenuated cold-adapted h2n2 influenza virus vaccine candidates in non human primates.the development of an h2n2 vaccine is a priority in pandemic preparedness planning. we previously showed that a single dose of a cold-adapted (ca) h2n2 live attenuated influenza vaccine (laiv) based on the influenza a/ann arbor/6/60 (aa ca) virus was immunogenic and efficacious in mice and ferrets. however, in a phase i clinical trial, viral replication was restricted and immunogenicity was poor. in this study, we compared the replication of four h2n2 laiv candidate viruses, aa ca, a/tecumseh/3/ ...201525444799
differential behavior patterns in cynomolgus monkey macaca fascicularis in home cage in response to human gaze.non-human primates, when encountering human beings, show wariness and alertness. these behaviors differ when there is direct human gaze vs. when human averts his gaze.201525440079
the lxr-idol axis differentially regulates plasma ldl levels in primates and mice.the lxr-regulated e3 ubiquitin ligase idol controls ldlr receptor stability independent of srebp and pcsk9, but its relevance to plasma lipid levels is unknown. here we demonstrate that the effects of the lxr-idol axis are both tissue and species specific. in mice, lxr agonist induces idol transcript levels in peripheral tissues but not in liver, and does not change plasma ldl levels. accordingly, idol-deficient mice exhibit elevated ldlr protein levels in peripheral tissues, but not in the live ...201425440061
evaluation of the zoonotic potential of transmissible mink encephalopathy.successful transmission of transmissible mink encephalopathy (tme) to cattle supports the bovine hypothesis for the still controversial origin of tme outbreaks. human and primate susceptibility to classical bovine spongiform encephalopathy (c-bse) and the transmissibility of l-type bse to macaques indicate a low cattle-to-primate species barrier. we therefore evaluated the zoonotic potential of cattle-adapted tme. in less than two years, this strain induced in cynomolgus macaques a neurological ...201325437205
a potential function for neuronal exosomes: sequestering intracerebral amyloid-β peptide.elevated amyloid-β peptide (aβ) in brain contributes to alzheimer's disease (ad) pathogenesis. we demonstrated the presence of exosome-associated aβ in the cerebrospinal fluid (csf) of cynomolgus monkeys and app transgenic mice. the levels of exosome-associated aβ notably decreased in the csf of aging animals. we also determined that neuronal exosomes, but not glial exosomes, had abundant glycosphingolipids and could capture aβ. infusion of neuronal exosomes into brains of app transgenic mice de ...201525436414
modeling and design of challenge tests: inflammatory and metabolic biomarker study examples.given the complexity of pharmacological challenge experiments, it is perhaps not surprising that design and analysis, and in turn interpretation and communication of results from a quantitative point of view, is often suboptimal. here we report an inventory of common designs sampled from anti-inflammatory, respiratory and metabolic disease drug discovery studies, all of which are based on animal models of disease involving pharmacological and/or patho/physiological interaction challenges. the co ...201525435491
characterization of anastrozole effects, delivered by an intravaginal ring in cynomolgus monkeys.is it feasible to deliver anastrozole (atz), an aromatase inhibitor (ai), by a vaginal polymer-based drug delivery system in the cynomolgus monkey (macaca fascicularis) to describe the pharmacokinetic profile?201525432919
one-step generation of p53 gene biallelic mutant cynomolgus monkey via the crispr/cas system. 201525430965
amyloid beta1-42 and the phoshorylated tau threonine 231 in brains of aged cynomolgus monkeys (macaca fascicularis).pathological hallmarks indicative of alzheimer's disease (ad), which are the plaques of amyloid beta1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. the aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers indicative of ad, had brain lesions similar to human patients suffering from senile dementia. generating immunohistochemistry technique to biomarkers of amyloid beta1-42 and the phosphorylated tau 231 ...201425426069
whole genome sequencing of siv-infected macaques identifies candidate loci that may contribute to host control of virus replication.a small percentage of human immunodeficiency virus (hiv)-infected people and simian immunodeficiency virus (siv)-infected macaques control virus replication without antiretroviral treatment. the major determinant of this control is host expression of certain major histocompatibility complex alleles. however, this association is incompletely penetrant, suggesting that additional loci modify the major histocompatibility complex's protective effect. here, to identify candidate control-modifying loc ...201425418588
bringing non-human primate research into the post-genomic era: how monkeys are teaching us about elite controllers of hiv/aids.whole-genome sequencing of mauritian cynomolgus macaques reveals novel candidate loci for controlling simian immunodeficiency virus replication.201425417723
effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.it is known that endothelial cells in the kidney are also strongly vegf-dependent. whether intravitreal drugs can be detected within the glomeruli or affect vegf in glomerular podocytes is not known. therefore, the aim of this pilot study was to investigate the effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.201425415380
comparative assessment of the interfacial soft and hard tissues investing implants and natural teeth in the macaque mandible.the aim of this study was to conduct a comparative qualitative and quantitative assessment of the interfacial soft and hard tissues investing implants and natural teeth.201525411082
cynomolgus monkey induced pluripotent stem cells generated by using allogeneic genes.induced pluripotent stem (ips) cells that are potentially similar to embryonic stem (es) cells can be artificially established by introduction into somatic cells of the transgenes pou5f1 (also known as oct3/4), sox2, klf4, and c-myc. in cynomolgus monkeys (macaca fascicularis), ips cells generated by using these four allogeneic transgenes should be an important resource for various types of biomedical research because the use of xenogeneic transgenes may cause complications. to establish such ip ...201625410287
a study of free portal pressure in cynomolgus monkeys with different degrees of liver fibrosis.the aim of this study was to investigate the patterns of changes in free portal pressure (fpp) in cynomolgus monkeys with different levels of liver fibrosis and to lay a theoretical foundation for the study of fpp in patients with liver fibrosis. liver fibrosis models were successfully established in 15 of 20 cynomolgus monkeys using carbon tetrachloride, among which 10 monkeys developed severe liver fibrosis (s4; i.e., early cirrhosis). a randomized block design was used to study fpp in the 10 ...201425404378
effects of oral and intravenous administration of buspirone on food-cocaine choice in socially housed male cynomolgus monkeys.drugs acting at d3 dopamine receptors have been suggested as medications for cocaine dependence. these experiments examined the effects of intravenously and orally administered buspirone, a d2-like receptor antagonist with high affinity for d3 and d4 receptors, on the relative reinforcing strength of cocaine in group-housed male cynomolgus monkeys. use of socially housed monkeys permitted the assessment of whether social status, known to influence d2-like receptor availability, modulates the beh ...201525393717
online two-dimensional porous graphitic carbon/reversed phase liquid chromatography platform applied to shotgun proteomics and glycoproteomics.a novel fully automatable two-dimensional liquid chromatography (2dlc) platform has been integrated into a modified commercial off-the-shelf lc instrument, incorporating porous graphitic carbon (pgc) separation and conventional low-ph reversed-phase (rp) separation for both proteomics and n-glycomics analyses; the dual-trap column configuration of this platform offers desirable high-throughput analyses with almost no idle time, in addition to a miniaturized setup and simplified operation. the to ...201425393709
mimicking hypoxia to treat anemia: hif-stabilizer bay 85-3934 (molidustat) stimulates erythropoietin production without hypertensive effects.oxygen sensing by hypoxia-inducible factor prolyl hydroxylases (hif-phs) is the dominant regulatory mechanism of erythropoietin (epo) expression. in chronic kidney disease (ckd), impaired epo expression causes anemia, which can be treated by supplementation with recombinant human epo (rhepo). however, treatment can result in rhepo levels greatly exceeding the normal physiological range for endogenous epo, and there is evidence that this contributes to hypertension in patients with ckd. mimicking ...201425392999
tissue-specific transcriptome sequencing analysis expands the non-human primate reference transcriptome resource (nhprtr).the non-human primate reference transcriptome resource (nhprtr, available online at http://nhprtr.org/) aims to generate comprehensive rna-seq data from a wide variety of non-human primates (nhps), from lemurs to hominids. in the 2012 phase i of the nhprtr project, 19 billion fragments or 3.8 terabases of transcriptome sequences were collected from pools of ∼ 20 tissues in 15 species and subspecies. here we describe a major expansion of nhprtr by adding 10.1 billion fragments of tissue-specific ...201525392405
evaluation of the usefulness of breast cancer resistance protein (bcrp) knockout mice and bcrp inhibitor-treated monkeys to estimate the clinical impact of bcrp modulation on the pharmacokinetics of bcrp substrates.to evaluate whether the impact of functional modulation of the breast cancer resistance protein (bcrp, abcg2 421c>a) on human pharmacokinetics after oral administration is predictable using bcrp knockout mice and cynomolgus monkeys pretreated with a bcrp inhibitor, elacridar.201525380981
preclinical pharmacokinetics, tolerability, and pharmacodynamics of metuzumab, a novel cd147 human-mouse chimeric and glycoengineered antibody.metuzumab is an affinity-optimized and nonfucosylated anti-cd147 human-mouse chimeric igg1 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (adcc). the purpose of this study was to characterize the pharmacokinetics, safety, and antitumor activities of metuzumab in mouse, rat, and monkey. the adcc activity was assessed by a lactate dehydrogenase release assay. the pharmacokinetics of metuzumab were determined in sprague-dawley rats and in cynomolgus monkeys. single- and ...201525376611
angiogenesis in the primate ovulatory follicle is stimulated by luteinizing hormone via prostaglandin e2.rapid angiogenesis occurs as the ovulatory follicle is transformed into the corpus luteum. to determine if luteinizing hormone (lh)-stimulated prostaglandin e2 (pge2) regulates angiogenesis in the ovulatory follicle, cynomolgus macaques received gonadotropins to stimulate multiple follicular development and chorionic gonadotropin (hcg) substituted for the lh surge to initiate ovulatory events. before hcg, vascular endothelial cells were present in the perifollicular stroma but not amongst granul ...201525376231
effects of denosumab, alendronate, or denosumab following alendronate on bone turnover, calcium homeostasis, bone mass and bone strength in ovariectomized cynomolgus monkeys.postmenopausal osteoporosis is a chronic disease wherein increased bone remodeling reduces bone mass and bone strength. antiresorptive agents including bisphosphonates are commonly used to mitigate bone loss and fracture risk. osteoclast inhibition via denosumab (dmab), a rankl inhibitor, is a newer approach for reducing fracture risk in patients at increased risk for fracture. the safety of transitioning from bisphosphonate therapy (alendronate; aln) to dmab was examined in mature ovariectomize ...201525369992
age-related changes of hepatic clearances of cytochrome p450 probes, midazolam and r-/s-warfarin in combination with caffeine, omeprazole and metoprolol in cynomolgus monkeys using in vitro-in vivo correlation.1. pharmacokinetics of human cytochrome p450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) were investigated after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg(-1), respectively, in combination to three young (3-year-old) and three aged (16-year-old) cynomolgus monkeys. 2. the plasma concentrations of caffeine and r-/s-warfarin decreased slowly in a monophasic manner, but those of omeprazole, metoprolol and midazolam decreased rapidly, in ...201525364857
what is your diagnosis? urine from a cynomolgus monkey. 201525361214
standardized full-field electroretinography in the green monkey (chlorocebus sabaeus).full-field electroretinography is an objective measure of retinal function, serving as an important diagnostic clinical tool in ophthalmology for evaluating the integrity of the retina. given the similarity between the anatomy and physiology of the human and green monkey eyes, this species has increasingly become a favorable non-human primate model for assessing ocular defects in humans. to test this model, we obtained full-field electroretinographic recordings (erg) and normal values for standa ...201425360686
biocompatible anionic polymeric microspheres as priming delivery system for effetive hiv/aids tat-based vaccines.here we describe a prime-boost regimen of vaccination in macaca fascicularis that combines priming with novel anionic microspheres designed to deliver the biologically active hiv-1 tat protein and boosting with tat in alum. this regimen of immunization modulated the igg subclass profile and elicited a balanced th1-th2 type of humoral and cellular responses. remarkably, following intravenous challenge with shiv89.6pcy243, vaccinees significantly blunted acute viremia, as compared to control monke ...201425356594
guiding intramuscular diaphragm injections using real-time ultrasound and electromyography.we describe a unique method that combines ultrasound and electromyography to guide intramuscular diaphragm injections in anesthetized large animals.201525354257
quantitative proteomics for cardiac biomarker discovery using isoproterenol-treated nonhuman primates.to identify new cardiac biomarkers, a quantitative proteomic analysis has been performed on serum and heart tissue proteins from three species of nonhuman primates following isoproterenol (iso) treatment. three serum proteins--serum amyloid a (saa), α-1-acid glycoprotein (a1ag), and apolipoprotein a-1 (apo a1)--were consistently identified as changed and remained altered 72 h post dose in all three species post iso treatment, indicating the potential of including these proteins in preclinical or ...201425345801
stronger dopamine d1 receptor-mediated neurotransmission in dyskinesia.radioligand binding assays to rat striatal dopamine d1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. d1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. d1 receptors heteromerize with dopamine d3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. expression of both d3 and d1-d3 receptor heteromers were inc ...201525344317
use of photogrammetry as a means to assess hybrids of rhesus (macaca mulatta) and long-tailed (m. fascicularis) macaques.rhesus (macaca mulatta) and long-tailed (m. fascicularis) macaques are the most commonly used non-human primate models for biomedical research, but it is difficult to identify these two species in the hybrid zone (15-20°n). in this work, we used morphological values obtained via photogrammetry to assess hybrids of rhesus and long-tailed macaques at khao khieow open zoo (kkz; 13°21'n, 101°06'e), eastern thailand. long-tailed and rhesus macaques have species-specific tail lengths and contrasts of ...201525341523
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