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receptor occupancy and blocking of stat5 signaling by an anti-il-7 receptor α antibody in cynomolgus monkeys.interleukin-7 receptor α (il-7rα) is associated with autoimmune disease. blocking its activation by interleukin-7 (il-7) with a therapeutic monoclonal antibody may reduce pathogenic t cells and effectively control the autoimmune response in these disorders.201625914284
a suitable method for the detection of a potential fraud of bringing macaque monkey meat into the food chain.being the third-largest primate population has not made macaque (macaca fascicularis sp.) monkeys less exposed to threats and dangers. despite wildlife protection, they have been widely hunted and consumed in several countries because of their purported nutritional values. in addition to trading as pure bush meats in several places, monkey meat has been sold in meatball and soup products in indonesia. thus the possibility of macaque meat trafficking under the label of common meats is quite high. ...201525906074
selective targeting of the il23 pathway: generation and characterization of a novel high-affinity humanized anti-il23a antibody.herein, we describe the generation and characterization of bi 655066, a novel, highly potent neutralizing anti-interleukin-23 (il23) monoclonal antibody in clinical development for autoimmune conditions, including psoriasis and crohn's disease. il23 is a key driver of the differentiation, maintenance, and activity of a number of immune cell subsets, including t helper 17 (th17) cells, which are believed to mediate the pathogenesis of several immune-mediated disorders. thus, il23 neutralization i ...201525905918
characterization of organic anion transporter 2 (slc22a7): a highly efficient transporter for creatinine and species-dependent renal tubular expression.the contribution of organic anion transporter oat2 (slc22a7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. in the present investigation, the transport of creatinine was assessed in human embryonic kidney (hek) cells that stably expressed human oat2 (oat2-hek) and isolated human renal proximal tubule cells (hrptcs). the tubular localization of oat2 in human, monkey, and rat kidney was characterized. the overexpression of oat2 s ...201525904762
particle-to-pfu ratio of ebola virus influences disease course and survival in cynomolgus macaques.this study addresses the role of ebola virus (ebov) specific infectivity in virulence. filoviruses are highly lethal, enveloped, single-stranded negative-sense rna viruses that can cause hemorrhagic fever. no approved vaccines or therapies exist for filovirus infections, and infectious virus must be handled in maximum containment. efficacy testing of countermeasures, in addition to investigations of pathogenicity and immune response, often requires a well-characterized animal model. for ebov, an ...201525903348
effects of group housing on ecg assessment in conscious cynomolgus monkeys.assessing the cardiovascular safety of new chemical or biological entities is important during pre-clinical development. electrocardiogram (ecg) assessments in non-human primate (nhp) toxicology studies are often made using non-invasive telemetry systems. we investigated whether ecg recording was feasible during group housing of nhps, rather than the usual single housed arrangement, and whether it would impact the data collected or affect the ability to detect drug-induced changes in qtc interva ...201525901446
circadian modulation in the intestinal absorption of p-glycoprotein substrates in monkeys.recent studies in laboratory rodents have revealed that circadian oscillation in the physiologic functions affecting drug disposition underlies the dosing time-dependent change in pharmacokinetics. however, it is difficult to predict the circadian change in the drug pharmacokinetics in a diurnal human by using the data collected from nocturnal rodents. in this study, we used cynomolgus monkeys, diurnal active animals, to evaluate the relevance of intestinal expression of p-glycoprotein (p-gp) to ...201525901027
postmortem stability of ebola virus.the ongoing ebola virus outbreak in west africa has highlighted questions regarding stability of the virus and detection of rna from corpses. we used ebola virus-infected macaques to model humans who died of ebola virus disease. viable virus was isolated <7 days posteuthanasia; viral rna was detectable for 10 weeks.201525897646
treatment with the smallpox antiviral tecovirimat (st-246) alone or in combination with acam2000 vaccination is effective as a postsymptomatic therapy for monkeypox virus infection.the therapeutic efficacies of smallpox vaccine acam2000 and antiviral tecovirimat given alone or in combination starting on day 3 postinfection were compared in a cynomolgus macaque model of lethal monkeypox virus infection. postexposure administration of acam2000 alone did not provide any protection against severe monkeypox disease or mortality. in contrast, postexposure treatment with tecovirimat alone or in combination with acam2000 provided full protection. additionally, tecovirimat treatmen ...201525896687
anti-repulsive guidance molecule c (rgmc) antibodies increases serum iron in rats and cynomolgus monkeys by hepcidin downregulation.high levels of hepcidin, the main regulator of systemic iron metabolism, lead to various diseases. targeting hepcidin and lowering its concentration is a possible form of intervention in order to treat these diseases. high turnover rate of hepcidin is a major drawback of therapies directly targeting this peptide. we developed two monoclonal antibodies abt-207 and h5f9-am8 which inhibit hemojuvelin/repulsive guidance molecule c (rgmc) and downregulate hepcidin. we conducted single-application and ...201525896304
foodborne-transmitted prions from the brain of cows with bovine spongiform encephalopathy ascend in afferent neurons to the simian central nervous system and spread to tonsils and spleen at a late stage of the incubation period.protease-resistant prion protein (prp(res)) accumulation in lymphoreticular tissues indicates prion infection. to date, tonsillectomy and appendectomy samples have been used in population prevalence surveys to detect clinically silent carriers of variant creutzfeldt-jakob disease (vcjd). however, the temporal sequence of prion spread in the human body is still not known. we therefore traced the temporal-spatial pattern of prp(res) accumulation in the body of a simian vcjd model.201525895987
the efficacy of inactivated west nile vaccine (wn-vax) in mice and monkeys.west nile virus (wnv) belonging to the genus flavivirus of the family flaviviridae causes nervous system disorder in humans, horses and birds. licensed wnv vaccines are available for use in horses but not for humans. we previously developed an inactivated west nile virus vaccine (wn-vax) using a seed virus from west nile virus (wnv ny99) that was originally isolated in new york city in 1999. in this study, we report the immunogenicity of wn-vax in both mice and non-human primates.201525889682
mitogenomic phylogeny of the common long-tailed macaque (macaca fascicularis fascicularis).long-tailed macaques (macaca fascicularis) are an important model species in biomedical research and reliable knowledge about their evolutionary history is essential for biomedical inferences. ten subspecies have been recognized, of which most are restricted to small islands of southeast asia. in contrast, the common long-tailed macaque (m. f. fascicularis) is distributed over large parts of the southeast asian mainland and the sundaland region. to shed more light on the phylogeny of m. f. fasci ...201525887664
motor neuron transduction after intracisternal delivery of aav9 in a cynomolgus macaque.the image shows a section of the lumbar spinal cord from a cynomolgus macaque that had received aav9.cb.egfp via the cisterna magna. expression of gfp in multiple motor neurons is visible. injection into the cerebrospinal fluid has been shown to be an effective route of vector administration for neuron transduction.201525885277
characterization of cerebral damage in a monkey model of alzheimer's disease induced by intracerebroventricular injection of streptozotocin.in line with recent findings showing alzheimer's disease (ad) as an insulin-resistant brain state, a non-transgenic animal model with intracerebroventricular streptozotocin (icv-stz) administration has been proposed as a representative experimental model of ad. although icv-stz rodent models of ad have been increasingly researched, studies in non-human primate models are very limited. in this study, we aimed to characterize the cerebral damage caused by icv-stz in non-human primates; to achieve ...201525881906
voluntary ethanol intake predicts κ-opioid receptor supersensitivity and regionally distinct dopaminergic adaptations in macaques.the dopaminergic projections from the ventral midbrain to the striatum have long been implicated in mediating motivated behaviors and addiction. previously it was demonstrated that κ-opioid receptor (kor) signaling in the striatum plays a critical role in the increased reinforcing efficacy of ethanol following ethanol vapor exposure in rodent models. although rodents have been used extensively to determine the neurochemical consequences of chronic ethanol exposure, establishing high levels of vo ...201525878269
[small hairpin rna targeting inhibition of nf-κb gene in endometriosis therapy of macaca fascicularis].to observe the therapeutic effect of nf-κb gene short hairpin rna (shrna) on endometriosis and identify the function of nf-κb on the maintenance and development of endometriosis in macaca fascicularis.201525877425
correction: reactivation of latent tuberculosis in cynomolgus macaques infected with siv is associated with early peripheral t cell depletion and not virus load. 201525874371
distribution and pharmacokinetics of etamicastat and its n-acetylated metabolite (bia 5-961) in dog and monkey.1. the disposition etamicastat was evaluated in the cynomolgus monkey after intravenous and oral administration of [(14)c]-etamicastat. the pharmacokinetics of etamicastat and its n-acetylated metabolite bia 5-961 were also evaluated in monkeys and dogs. 2. in the monkey, 7 days after intravenous and oral administration of [(14)c]-etamicastat, 76.6-91.1% of the etamicastat-related radioactivity had been excreted mainly in urine. the radioactivity peaked in plasma between 4- and 8-h post-dosing f ...201525869244
sequence characterization and phylogenetic analysis of toll-like receptor (tlr) 4 gene in the tibetan macaque (macaca thibetana).in this study, the complete coding region sequence of an innate immune-related tlr4 gene was obtained from the tibetan macaque (macaca thibetana) genome via pcr and direct sequencing. the sequence had a total length of 2481 bp, contained 3 complete exons, and encoded 826 amino acids (aas); its isoelectric point was 5.703, and the molecular weight was 94.72 kda. the high structure prediction showed that the protein was comprised of one extracellular region, one transmembrane region, and one intra ...201525867333
germline and somatic imprinting in the nonhuman primate highlights species differences in oocyte methylation.genomic imprinting is an epigenetic mechanism resulting in parental allele-specific gene expression. defects in normal imprinting are found in cancer, assisted reproductive technologies, and several human syndromes. in mouse models, germline-derived dna methylation is shown to regulate imprinting. though imprinting is largely conserved between mammals, species- and tissue-specific domains of imprinted expression exist. using the cynomolgus macaque (macaca fascicularis) to assess primate-specific ...201525862382
effects of dulaglutide on thyroid c cells and serum calcitonin in male monkeys.glucagon-like peptide-1 (glp-1) receptor agonists, used for the treatment of type 2 diabetes, have caused hyperplasia/neoplasia of thyroid c cells in rodent carcinogenicity studies. studies in monkeys have not identified an effect of glp-1 receptor agonists on thyroid c cells; however, group sizes were small. dulaglutide is a once-weekly, long-acting human glp-1 receptor agonist recently approved in the united states and the european union. the objective of this study was to determine whether du ...201525860028
a central mesencephalic reticular formation projection to the supraoculomotor area in macaque monkeys.the central mesencephalic reticular formation is physiologically implicated in oculomotor function and anatomically interwoven with many parts of the oculomotor system's premotor circuitry. this study in macaca fascicularis monkeys investigates the pattern of central mesencephalic reticular formation projections to the area in and around the extraocular motor nuclei, with special emphasis on the supraoculomotor area. it also examines the location of the cells responsible for this projection. inj ...201625859632
substrate selectivities and catalytic activities of marmoset liver cytochrome p450 2a6 differed from those of human p450 2a6.the common marmoset (callithrix jacchus), a new world primate species, is potentially a useful animal model for preclinical studies in drug development. however, cytochrome p450 (p450) enzymes have not been fully identified and characterized in marmosets. in this study, we identified p450 2a6 cdna with the sequence highly identical (91-94%) to human p450 2a6, 2a7, and 2a13 cdna and cynomolgus monkey p450 2a23, 2a24, and 2a26 cdna. among the tissue types examined, marmoset p450 2a6 mrna was most ...201525858611
jaw-muscle architecture and mandibular morphology influence relative maximum jaw gapes in the sexually dimorphic macaca fascicularis.maximum jaw gape is a performance variable related to feeding and non-feeding oral behaviors, such as canine gape displays, and is influenced by several factors including jaw-muscle fiber architecture, muscle position on the skull, and jaw morphology. maximum gape, jaw length, and canine height are strongly correlated across catarrhine primates, but relationships between gape and other aspects of masticatory apparatus morphology are less clear. we examine the effects of jaw-adductor fiber archit ...201525858337
platelet transfusion reverses bleeding evoked by triple anti-platelet therapy including vorapaxar, a novel platelet thrombin receptor antagonist.vorapaxar is a novel protease-activated receptor-1 (par-1) antagonist recently approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. patients who received vorapaxar in addition to standard of care antiplatelet therapy had an increased incidence of major bleeding events compared with placebo. to assess whether platelet transfusion can restore hemostasis in primates on triple antiplatelet therapy, tem ...201525857224
network structure shapes spontaneous functional connectivity dynamics.the structural organization of the brain constrains the range of interactions between different regions and shapes ongoing information processing. therefore, it is expected that large-scale dynamic functional connectivity (fc) patterns, a surrogate measure of coordination between brain regions, will be closely tied to the fiber pathways that form the underlying structural network. here, we empirically examined the influence of network structure on fc dynamics by comparing resting-state fc (rsfc) ...201525855174
synaptic connectivity of the cholinergic axons in the olfactory bulb of the cynomolgus monkey.the olfactory bulb (ob) of mammals receives cholinergic afferents from the horizontal limb of the diagonal band of broca (hdb). at present, the synaptic connectivity of the cholinergic axons on the circuits of the ob has only been investigated in the rat. in this report, we analyze the synaptic connectivity of the cholinergic axons in the ob of the cynomolgus monkey (macaca fascicularis). our aim is to investigate whether the cholinergic innervation of the bulbar circuits is phylogenetically con ...201525852490
measurement of 25-hydroxyvitamin d(2&3) and 1,25-dihydroxyvitamin d(2&3) by tandem mass spectrometry: a primate multispecies comparison.vitamin d metabolites are widely studied for their roles in bone health, immune functions, and other potential physiologic roles in humans. however, the optimal blood levels of vitamin d metabolites are still unclear. various methods for measuring vitamin d metabolites have been used and recently liquid chromatography tandem mass spectroscopy (lc-ms/ms) has been adopted as the gold standard for vitamin d metabolite measurement. here, we report the use of lc-ms/ms to measure 25-hydroxyvitamin d ( ...201525845705
human infections with plasmodium knowlesi--zoonotic malaria.in 2004 a large focus of plasmodium knowlesi malaria was reported in the human population in sarawak, malaysian borneo. plasmodium knowlesi, a parasite of the south-east asian macaques (macaca fascicularis and macaca nemestrina), had entered the human population. plasmodium knowlesi is transmitted by the leucosphyrus group of anopheline mosquitoes and transmission is largely zoonotic and restricted to the jungle setting. humans entering jungle transmission sites are at risk. since 2004, human ca ...201525843504
evaluation of the toxicology, pharmacokinetics, and local tolerance of recombinant factor ix fc fusion protein in animals.recombinant factor ix fc fusion protein (rfixfc) is a recombinant coagulation factor composed of a single molecule of recombinant factor ix (rfix) covalently fused to the fc domain of human immunoglobulin g1 (igg1) with no intervening sequence. an extensive nonclinical program was performed to support the clinical development of rfixfc for treatment of people with hemophilia b.201525840744
hiv specific responses induced in nonhuman primates with anrs hiv-lipo-5 vaccine combined with rmva-hiv prime or boost immunizations.we evaluated the immunogenicity of a prime/boost vaccine strategy combining 5 lipopeptides (hiv-lipo-5) and a recombinant modified vaccinia virus ankara (rmva-hiv) in cynomolgus macaques. both of these vaccine components deliver hiv lai gag, pol, and nef antigens. systemic and local safety was excellent in all groups. immunization with hiv-lipo-5 alone induced significant serum anti-hiv antibody titers which were not modified by rmva-hiv immunization. however, induction of t-cell responses, as m ...201525839103
electrophysiological signatures of spontaneous bold fluctuations in macaque prefrontal cortex.spontaneous brain activity is ubiquitous across brain structures and states. determining the role of these metabolically costly intrinsic events may be critical for understanding the brain's fundamental physiological principles that govern cognition and behavior. to date, most investigations of large-scale fluctuations and their coupling have been conducted using electro- or magneto-encephalography, modalities that are limited in their ability to spatially resolve the origin of the signals. inva ...201525837599
evaluation of crystallographic orientation of biological apatite in vertebral cortical bone in ovariectomized cynomolgus monkeys treated with minodronic acid and alendronate.quantitative analysis of the orientational distribution of biological apatite (bap) crystals is proposed as a new index of bone quality. this study aimed to analyze bap c-axis orientation in ovariectomized (ovx) monkeys treated with amino-bisphosphonates minodronic acid and alendronate as reference. sixty female monkeys aged 9-17 years were divided into five groups: one sham group and four ovx groups. the sham group and one ovx group were treated daily with vehicle for 17 months. the other three ...201625837430
pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration.intravenous enzyme replacement therapy with iduronate-2-sulfatase is an approved treatment for hunter syndrome, however, conventional intravenous delivery cannot treat the neurologic manifestations of the disease due to its limited central nervous system penetration. intrathecal administration of iduronate-2-sulfatase for delivery to the central nervous system is currently under investigation. the objective of this study was to evaluate the pharmacokinetics of idursulfase in the central nervous ...201525836678
live attenuated simian immunodeficiency virus vaccination confers superinfection resistance against macrophage-tropic and neurovirulent wild-type siv challenge.vaccination with live attenuated simian immunodeficiency virus (siv) in non-human primate species provides a means of characterizing the protective processes of retroviral superinfection and may lead to novel advances of human immunodeficiency virus (hiv)/aids vaccine design. the minimally attenuated sivmacc8 vaccine has been demonstrated to elicit early potent protection against pathogenic rechallenge with genetically diverse viral isolates in cynomolgus macaques (macaca fascicularis). in this ...201525834093
animal models and the molecular biology of hepadnavirus infection.australian antigen, the envelope protein of hepatitis b virus (hbv), was discovered in 1967 as a prevalent serum antigen in hepatitis b patients. early electron microscopy (em) studies showed that this antigen was present in 22-nm particles in patient sera, which were believed to be incomplete virus. complete virus, much less abundant than the 22-nm particles, was finally visualized in 1970. hbv was soon found to infect chimpanzees, gorillas, orangutans, gibbon apes, and, more recently, tree shr ...201525833941
the skint1-like gene is inactivated in hominoids but not in all primate species: implications for the origin of dendritic epidermal t cells.dendritic epidermal t cells, which express an invariant vγ5vδ1 t-cell receptor and account for 95% of all resident t cells in the mouse epidermis, play a critical role in skin immune surveillance. these γδ t cells are generated by positive selection in the fetal thymus, after which they migrate to the skin. the development of dendritic epidermal t cells is critically dependent on the skint1 gene expressed specifically in keratinocytes and thymic epithelial cells, suggesting an indispensable role ...201525830554
effects of long-term sertraline treatment and depression on coronary artery atherosclerosis in premenopausal female primates.major depressive disorder and coronary heart disease often co-occur in the same individuals. selective serotonin reuptake inhibitors (ssris) are widely prescribed for depression and other disorders, but their effects on coronary heart disease risk remain unclear. we determined the effects of an ssri on coronary artery atherosclerosis (caa) in an established nonhuman primate model used to clarify the association between depression and caa.201525829239
examining the species-specificity of rhesus macaque cytomegalovirus (rhcmv) in cynomolgus macaques.cytomegalovirus (cmv) is a highly species-specific virus that has co-evolved with its host over millions of years and thus restricting cross-species infection. to examine the extent to which host restriction may prevent cross-species research between closely related non-human primates, we evaluated experimental infection of cynomolgus macaques with a recombinant rhesus macaque-derived cmv (rhcmv-egfp). twelve cynomolgus macaques were randomly allocated to three groups: one experimental group (rh ...201525822981
[adenovirus vector-mediated short hairpin rna targeting nuclear factor-κb suppresses proliferation of endometrial cells of macaca fascicularis in vitro].to assess the effect of a high specific adenovirus vector-mediated shrna targeting nuclear factor-κb (nf-κb) on cell proliferation of the endometrium of macaca fascicularis.201525818787
lens capsule structure assessed with atomic force microscopy.to image the ultrastructure of the anterior lens capsule at the nanoscale level using atomic force microscopy (afm).201525814829
evaluation of cynomolgus monkeys for the identification of endogenous biomarkers for hepatic transporter inhibition and as a translatable model to predict pharmacokinetic interactions with statins in humans.inhibition of hepatic transporters such as organic anion transporting polypeptides (oatps) 1b can cause drug-drug interactions (ddis). determining the impact of perpetrator drugs on the plasma exposure of endogenous substrates for oatp1b could be valuable to assess the risk for ddis early in drug development. as oatp1b orthologs are well conserved between human and monkey, we assessed in cynomolgus monkeys the endogenous oatp1b substrates that are potentially suitable to assess ddi risk in human ...201525813937
large variation in brain exposure of reference cns drugs: a pet study in nonhuman primates.positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. the aim of the present study was to examine and compare the brain exposure of 12 commercially available cns drugs and one non-cns drug.201525813017
complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques.oncolytic viruses (ovs) have shown promising clinical activity when administered by direct intratumoral injection. however, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer ovs by the intravenous route. we demonstrate here that for a prototype of the clinical vaccinia virus based product pexa-vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune v ...201525807289
whole-genome sequencing of six mauritian cynomolgus macaques (macaca fascicularis) reveals a genome-wide pattern of polymorphisms under extreme population bottleneck.cynomolgus macaques (macaca fascicularis) were introduced to the island of mauritius by humans around the 16th century. the unique demographic history of the mauritian cynomolgus macaques provides the opportunity to not only examine the genetic background of well-established nonhuman primates for biomedical research but also understand the effect of an extreme population bottleneck on the pattern of polymorphisms in genomes. we sequenced the whole genomes of six mauritian cynomolgus macaques and ...201525805843
fluorescent image analysis of hiv-1 and hiv-2 uncoating kinetics in the presence of old world monkey trim5α.uncoating of human immunodeficiency virus type 1 (hiv-1) and type 2 (hiv-2) conical cores is an important early step for establishment of infection. in old world monkey (owm) cells, the trim5α cellular factor potently suppresses an early step of infection by hiv-1. previously, biochemical studies using whole cell lysates of infected cells revealed that owm trim5α accelerates the uncoating of hiv-1, leading to premature reverse transcription. in the present study, we re-evaluated uncoating kineti ...201525803716
slow r-warfarin 7-hydroxylation mediated by p450 2c19 genetic variants in cynomolgus monkeys in vivo.cynomolgus monkeys are widely used as non-human primate species in preclinical studies, due to their close evolutionary relationship to humans. monkey cytochrome p450 2c19 (formerly known as p450 2c75), highly homologous to human p450 2c19, has been identified to be r-warfarin 7-hydroxylase in cynomolgus monkeys. in the present study, the in vivo pharmacokinetics of stereoselective warfarin and metabolites at a dose of 1.0mg/kg were investigated after oral and intravenous administration of racem ...201525801008
translational development of an adamts-5 antibody for osteoarthritis disease modification.aggrecanase activity, most notably adamts-5, is implicated in pathogenic cartilage degradation. selective monoclonal antibodies (mabs) to both adamts-5 and adamts-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (oa).201525800415
homologous and heterologous protection of nonhuman primates by ebola and sudan virus-like particles.filoviruses cause hemorrhagic fever resulting in significant morbidity and mortality in humans. several vaccine platforms that include multiple virus-vectored approaches and virus-like particles (vlps) have shown efficacy in nonhuman primates. previous studies have shown protection of cynomolgus macaques against homologous infection for ebola virus (ebov) and marburg virus (marv) following a three-dose vaccine regimen of ebov or marv vlps, as well as heterologous protection against ravn virus (r ...201525793502
investigation of intrathecal transport of npt002, a prospective therapeutic based on phage m13, in nonhuman primates.presently, there are no effective treatments for conditions characterized by protein misfolding, such as alzheimer's, parkinson's, and other diseases involving cns. since misfolding occurs at the earliest stage of the disease, it is likely to be involved in subsequent pathological developments. it has been found that npt002 (bacteriophage m13) directly dissociates aggregates of misfolded proteins that form amyloid, including amyloid-β, tau and α-synuclein. for cns applications, npt002 requires d ...201225786868
safety evaluation of chronic intrathecal administration of heparan n-sulfatase in juvenile cynomolgus monkeys.an intrathecal (it) formulation of recombinant human heparan n-sulfatase (hns) is under development for the treatment of the neurological symptoms of mucopolysaccharidosis iiia (mps iiia; sanfilippo a disease), the defining clinical feature of this disorder. since the average age of mps iiia patients is 4.5 years, the pivotal toxicology studies for hns were conducted in juvenile cynomolgus monkeys to evaluate the effects on the developing brain. monkeys were implanted with an it-lumbar drug deli ...201225786866
molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques.the threat of radiation exposure requires a mechanistic understanding of radiation-induced immune injury and recovery. the study objective was to evaluate responses to ionizing radiation in ovariectomized (surgically post-menopausal) female cynomolgus macaques.201525786585
sequential monitoring and stability of ex vivo-expanded autologous and nonautologous regulatory t cells following infusion in nonhuman primates.ex vivo-expanded cynomolgus monkey cd4(+)cd25(+)cd127(-) regulatory t cells (treg) maintained foxp3 demethylation status at the treg-specific demethylation region, and potently suppressed t cell proliferation through three rounds of expansion. when carboxyfluorescein succinimidyl ester- or violet proliferation dye 450-labeled autologous (auto) and nonautologous (non-auto)-expanded treg were infused into monkeys, the number of labeled auto-treg in peripheral blood declined rapidly during the firs ...201525783759
macaques exhibit a naturally-occurring depression similar to humans.rodent models have dominated preclinical investigations into the mechanisms of depression. however, these models-which rely on subjecting individual rodents to physical stressors - do not realistically resemble the etiopathological development of depression, which occurs naturally in a social context. a non-human primate model that better reflects the social ethological aspects of depression would be more advantageous to investigating pathophysiological mechanisms and developing antidepressant t ...201525783476
small particle aerosol inoculation of cowpox brighton red in rhesus monkeys results in a severe respiratory disease.cowpox virus (cpxv) inoculation of nonhuman primates (nhps) has been suggested as an alternate model for smallpox (kramski et al., 2010, plos one, 5, e10412). previously, we have demonstrated that intrabronchial inoculation of cpxv-brighton red (cpxv-br) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (smith et al., 2011, j. gen. virol.). here we describe the course of disease after small particle aer ...201525776759
long-term effects of castration on the skeleton of male rhesus monkeys (macaca mulatta).while osteopenia (ope) and osteoporosis (opo) have been studied in various species of aging nonhuman primates and extensively in ovariectomized rhesus and cynomolgus macaques, there is virtually no information on the effects of castration on the skeleton of male nonhuman primates. most information on castrated male primates comes from a few studies on the skeletons of eunuchs. this report used a subset of the caribbean primate research center's (cprc) cayo santiago (cs) rhesus macaque skeletal c ...201625771746
plasmalogen precursor analog treatment reduces levodopa-induced dyskinesias in parkinsonian monkeys.l-dopa-induced dyskinesias (lid) remain a serious obstacle in the treatment of parkinson's disease (pd). the objective of this study was to test a new target for treatment of dyskinesias, ethanolamine plasmalogens (plsetn). plsetn play critical roles in membrane structure mediated functions and as a storage depot of polyunsaturated fatty acids such as docosahexaenoic acid (dha, omega-3) known to reduce dyskinesias. the motor effect of a daily treatment for 12 days of 1-methyl-4-phenyl-1,2,3,6-te ...201525771209
social behavioral changes in mptp-treated monkey model of parkinson's disease.parkinsonian patients experience not only the physical discomfort of motor disorders but also the considerable psychological distress caused by cognitive deficits and behavioral disorders. these two factors can result in a disruption of social relationships during the symptomatic and even the presymptomatic motor states of the disease. however, it remains difficult, if not impossible, to evaluate social relationships in presymptomatic patients. the present study focused on the evaluation of soci ...201525767440
comparison of experimental respiratory tularemia in three nonhuman primate species.tularemia is a zoonotic disease caused by francisella tularensis, which is transmitted to humans most commonly by contact with infected animals, tick bites, or inhalation of aerosolized bacteria. f. tularensis is highly infectious via the aerosol route; inhalation of as few as 10-50 organisms can cause pneumonic tularemia. left untreated, the pneumonic form has more than >30% case-fatality rate but with early antibiotic intervention can be reduced to 3%. this study compared tularemia disease pro ...201525766142
tissue and species differences in the glucuronidation of glabridin with udp-glucuronosyltransferases.glabridin (ga) has gained wide application in the cosmetics and food industry. this study was performed to investigate its metabolic inactivation and elimination by glucuronidation by use of liver and intestine microsomes from humans (hlm and him) and rats (rlm and rim), and liver microsomes from cynomolgus monkeys and beagle dogs (cylm and dlm). both hydroxyl groups at the c2 and c4 positions of the b ring are conjugated to generate two mono-glucuronides (m1 and m2). him, rim and rlm showed the ...201525765239
generation and characterization of abt-981, a dual variable domain immunoglobulin (dvd-ig(tm)) molecule that specifically and potently neutralizes both il-1α and il-1β.interleukin-1 (il-1) cytokines such as il-1α, il-1β, and il-1ra contribute to immune regulation and inflammatory processes by exerting a wide range of cellular responses, including expression of cytokines and chemokines, matrix metalloproteinases, and nitric oxide synthetase. il-1α and il-1β bind to il-1r1 complexed to the il-1 receptor accessory protein and induce similar physiological effects. preclinical and clinical studies provide significant evidence for the role of il-1 in the pathogenesi ...201525764208
anti-bdca2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through fc-dependent and fc-independent mechanisms.type i interferons (ifn-i) are implicated in the pathogenesis of systemic lupus erythematosus (sle). in sle, immune complexes bind to the cd32a (fcγriia) receptor on the surface of plasmacytoid dendritic cells (pdcs) and stimulate the secretion of ifn-i from pdcs. bdca2 is a pdc-specific receptor that, when engaged, inhibits the production of ifn-i in human pdcs. bdca2 engagement, therefore, represents an attractive therapeutic target for inhibiting pdc-derived ifn-i and may be an effective ther ...201525762615
development and validation of a liquid chromatography tandem mass spectrometry assay for the quantitation of a protein therapeutic in cynomolgus monkey serum.we have developed and fully validated a fast and simple lc-ms/ms assay to quantitate a therapeutic protein bms-a in cynomolgus monkey serum. prior to trypsin digestion, a recently reported sample pretreatment method was applied to remove more than 95% of the total serum albumin and denature the proteins in the serum sample. the pretreatment procedure simplified the biological sample prior to digestion, improved digestion efficiency and reproducibility, and did not require reduction and alkylatio ...201525756208
potent neutralizing anti-cd1d antibody reduces lung cytokine release in primate asthma model.cd1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer t (nkt) cells, to release high levels of cytokines. nkt cells are implicated in asthma pathology and blockade of the cd1d/nkt cell pathway may have therapeutic potential. we developed a potent anti-human cd1d antibody (nib.2) that possesses high affinity for human and cynomolgus macaque cd1d (kd ∼100 pm) and strong neutralizing activity in human primary cell-based assays (ic50 typi ...201525751125
cuprizone does not induce cns demyelination in nonhuman primates.cognitive decline is a common symptom in multiple sclerosis patients, with profound effects on the quality of life. a nonhuman primate model of multiple sclerosis would be best suited to test the effects of demyelination on complex cognitive functions such as learning and reasoning. cuprizone has been shown to reliably induce brain demyelination in mice. to establish a nonhuman primate model of multiple sclerosis, young adult cynomolgus monkeys were administered cuprizone per os as a dietary sup ...201525750925
emergence of infectious malignant thrombocytopenia in japanese macaques (macaca fuscata) by srv-4 after transmission to a novel host.we discovered a lethal hemorrhagic syndrome arising from severe thrombocytopenia in japanese macaques kept at the primate research institute, kyoto university. extensive investigation identified that simian retrovirus type 4 (srv-4) was the causative agent of the disease. srv-4 had previously been isolated only from cynomolgus macaques in which it is usually asymptomatic. we consider that the srv-4 crossed the so-called species barrier between cynomolgus and japanese macaques, leading to extreme ...201525743183
evaluation of rosuvastatin as an organic anion transporting polypeptide (oatp) probe substrate: in vitro transport and in vivo disposition in cynomolgus monkeys.organic anion transporting polypeptides (oatps) mediate hepatic drug uptake and serve as the loci of drug-drug interactions (ddis). consequently, there is a major need to develop animal models and refine in vitro-in vivo extrapolations. therefore, the in vivo disposition of a model oatp substrate, [(3)h]rosuvastatin (rsv), was studied in the cynomolgus monkey and reported for the first time. after monkeys had received a 3-mg/kg oral dose, mass balance was achieved after bile duct cannulation (me ...201525740896
pharmacokinetics and immunogenicity investigation of a human anti-interleukin-17 monoclonal antibody in non-naïve cynomolgus monkeys.the pharmacokinetics (pk) of biologic therapeutics, especially monoclonal antibodies (mabs), in monkeys generally presents the most relevant predictive pk information for humans. however, human mabs, xenogeneic proteins to monkeys, are likely to be immunogenic. monkeys previously treated with a human mab (non-naïve) may have developed antidrug antibodies (adas) that cross-react with another test mab in subsequent studies. unlike pk studies for small-molecule therapeutics, in which animals may be ...201525739974
molecular attributes of conjugate antigen influence function of antibodies induced by anti-nicotine vaccine in mice and non-human primates.anti-nicotine vaccines aim to prevent nicotine entering the brain, and thus reduce or eliminate the reward that drives nicotine addiction. those tested in humans to date have failed to improve quit rates over placebo, possibly because antibody (ab) responses were insufficient to sequester enough nicotine in the blood in the majority of subjects. we have previously shown in mice that the carrier, hapten and linker used in the nicotine conjugate antigen each influence the function (nicotine-bindin ...201525737198
generation, cryopreservation, function and in vivo persistence of ex vivo expanded cynomolgus monkey regulatory t cells.we expanded flow-sorted foxp3(+) cynomolgus monkey regulatory t cells (treg) >1000-fold after three rounds of stimulation with anti-cd3 mab-loaded artificial antigen-presenting cells, rapamycin (first round only) and il-2. the expanded treg maintained their expression of treg signature markers, cd25, cd27, cd39, foxp3, helios, and ctla-4, as well as cxcr3, which plays an important role in t cell migration to sites of inflammation. in contrast to expanded effector t cells (teff), expanded treg pr ...201525732601
successful function of autologous ipsc-derived dopamine neurons following transplantation in a non-human primate model of parkinson's disease.autologous transplantation of patient-specific induced pluripotent stem cell (ipsc)-derived neurons is a potential clinical approach for treatment of neurological disease. preclinical demonstration of long-term efficacy, feasibility, and safety of ipsc-derived dopamine neurons in non-human primate models will be an important step in clinical development of cell therapy. here, we analyzed cynomolgus monkey (cm) ipsc-derived midbrain dopamine neurons for up to 2 years following autologous transpla ...201525732245
detection and quantification of male-specific fetal dna in the serum of pregnant cynomolgus monkeys (macaca fascicularis).because of their developmental similarities to humans, nonhuman primates are often used as a model to study fetal development for potential clinical applications in humans. the detection of fetal dna in maternal plasma or serum offers a source of fetal genetic material for prenatal diagnosis. however, no such data have been reported for cynomolgus monkeys (macaca fascicularis), an important model in biomedical research. we have developed a specific, highly sensitive pcr system for detecting and ...201525730760
use of genome-wide heterospecific single-nucleotide polymorphisms to estimate linkage disequilibrium in rhesus and cynomolgus macaques.rhesus and cynomolgus macaques are frequently used in biomedical research, and the availability of their reference genomes now provides for their use in genome-wide association studies. however, little is known about linkage disequilibrium (ld) in their genomes, which can affect the design and success of such studies. here we studied ld by using 1781 conserved single-nucleotide polymorphisms (snps) in 183 rhesus macaques (macaca mulatta), including 97 purebred chinese and 86 purebred indian anim ...201525730759
en face optical coherence tomography of foveal microstructure in full-thickness macular hole: a model to study perifoveal müller cells.to characterize perifoveal intraretinal cavities observed around full-thickness macular holes (mh) using en face optical coherence tomography and to establish correlations with histology of human and primate maculae.201525728860
development of rapid multistep carbon-11 radiosynthesis of the myeloperoxidase inhibitor azd3241 to assess brain exposure by pet microdosing.the myeloperoxidase inhibitor azd3241 has been selected as a candidate drug currently being developed to delay progression in patients with neurodegenerative brain disorders. part of the decision tree for translation of azd3241 into clinical studies included the need for assessment of brain exposure in non-human primates by pet microdosing. for that purpose a rapid multistep method for (11)c-labeling of azd3241 was developed.201525726760
isolation and characterization of arylacetamide deacetylase in cynomolgus macaques.arylacetamide deacetylase (aadac), a microsomal serine esterase, hydrolyzes drugs, such as flutamide, phenacetin and rifampicin. because aadac has not been fully investigated at molecular levels in cynomolgus macaques, the non-human primate species widely used in drug metabolism studies, cynomolgus aadac cdna was isolated and characterized. the deduced amino acid sequence, highly homologous (92%) to human aadac, was more closely clustered with human aadac than the dog, rat or mouse ortholog in a ...201525715734
complementary patterns of direct amygdala and hippocampal projections to the macaque prefrontal cortex.the projections from the amygdala and hippocampus (including subiculum and presubiculum) to prefrontal cortex were compared using anterograde tracers injected into macaque monkeys (macaca fascicularis, macaca mulatta). almost all prefrontal areas were found to receive some amygdala inputs. these connections, which predominantly arose from the intermediate and magnocellular basal nucleus, were particularly dense in parts of the medial and orbital prefrontal cortex. contralateral inputs were not, ...201525715284
analysis of full-length mitochondrial dna d-loop sequences from macaca fascicularis of different geographical origin reveals novel haplotypes.cynomolgus macaques are indigenous to asia occupying a range of geographical areas. a non-indigenous population established on mauritius approximately 500 years ago. mauritian cynomolgus macaques are recognised as having low genetic diversity compared to indonesian macaques, from which they originated. as cynomolgus macaques are widely used as a biomedical model, there have been many studies of their genetic relationships. however, population diversity and relationships have only been assessed t ...201525707924
immunology studies in non-human primate models of tuberculosis.non-human primates, primarily macaques, have been used to study tuberculosis for decades. however, in the last 15 years, this model has been refined substantially to allow careful investigations of the immune response and host-pathogen interactions in mycobacterium tuberculosis infection. low-dose challenge with fully virulent strains in cynomolgus macaques result in the full clinical spectrum seen in humans, including latent and active infection. reagents from humans are usually cross-reactive ...201525703552
preclinical pharmacokinetics, pharmacodynamics, and efficacy of rg7116: a novel humanized, glycoengineered anti-her3 antibody.rg7116 is a novel anti-her3 therapeutic antibody that inhibits her3 signalling and induces antibody-dependent cellular cytotoxicity of tumor cells due to a glycoengineered antibody fc moiety. we investigated the efficacy and pharmacokinetic/pharmacodynamic properties of her3 signal inhibition by rg7116 in a murine xenograft model of human head and neck cancer.201525702049
selection of igg variants with increased fcrn binding using random and directed mutagenesis: impact on effector functions.despite the reasonably long half-life of immunoglogulin g (iggs), market pressure for higher patient convenience while conserving efficacy continues to drive igg half-life improvement. igg half-life is dependent on the neonatal fc receptor (fcrn), which among other functions, protects igg from catabolism. fcrn binds the fc domain of igg at an acidic ph ensuring that endocytosed igg will not be degraded in lysosomal compartments and will then be released into the bloodstream. consistent with this ...201525699055
the zonules selectively alter the shape of the lens during accommodation based on the location of their anchorage points.to determine the role of anterior and posterior zonular tension on the optomechanical lens response during accommodation simulation.201525698707
deep subconjunctival injection of gentamicin for the treatment of bacterial conjunctivitis in macaques (macaca mulatta and macaca fascicularis).infectious conjunctivitis occurs in a number of domestic and laboratory animal species and is usually treated topically with eye drops or eye ointments, which must be administered several times a day and sometimes for a prolonged period of time. in aggressive nonhuman primates or other large laboratory animal species, this may require the use of anesthesia or physical restraint before each treatment, which can be stressful to the animals and demanding for personnel. the authors describe a techni ...201525693106
prediction of clinical pharmacokinetics of amg 181, a human anti-α 4 β 7 monoclonal antibody for treating inflammatory bowel diseases.the purpose of this study was to predict a safe starting dose of amg 181, a human anti-α 4 β 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (pk) and pharmacodynamic (pd) data. a two-compartment model with parallel linear and target-mediated drug disposition for amg 181 pk in cynomolgus monkey was developed. the estimated parameters were allometrically scaled to predict human pk. an e max pd model was used to relate amg 181 concentration and free α ...201525692016
daily application of alprostadil topical cream (vitaros) does not impact vaginal ph, flora, or histology in female cynomolgus monkeys.topical alprostadil cream (vitaros) is approved in canada and europe for the treatment of erectile dysfunction. to determine the effects on the female urogenital tract with repeated administration of the entire dose (300 μg alprostadil containing 2.5% dodecyl-2-n,n-dimethylaminopropionate hydrochloride), the vaginal ph, flora, and histology were assessed as a model for 100% transference from male to the female during unprotected sexual intercourse. female cynomolgus monkeys were administered the ...201525691520
estrogen promotes luteolysis by redistributing prostaglandin f2α receptors within primate luteal cells.prostaglandin f2α (pgf2α) has been proposed as a functional luteolysin in primates. however, administration of pgf2α or prostaglandin synthesis inhibitors in vivo both initiate luteolysis. these contradictory findings may reflect changes in pgf2α receptors (ptgfrs) or responsiveness to pgf2α at a critical point during the life span of the corpus luteum. the current study addressed this question using ovarian cells and tissues from female cynomolgus monkeys and luteinizing granulosa cells from he ...201525687410
sustained modeling-based bone formation during adulthood in cynomolgus monkeys may contribute to continuous bmd gains with denosumab.denosumab (dmab) administration to postmenopausal women with osteoporosis is associated with continued bone mineral density (bmd) increases and low fracture incidence through 8 years, despite persistently reduced bone turnover markers and limited fluorochrome labeling in iliac crest bone biopsies. bmd increases were hypothesized to result from additional accrual of bone matrix via modeling-based bone formation-a hypothesis that was tested by examining fluorochrome labeling patterns in sections f ...201525684625
non-clinical pharmacokinetics, prediction of human pharmacokinetics and first-in-human dose selection for cnto 5825, an anti-interleukin-13 monoclonal antibody.cnto 5825 is a human anti-interleukin-13 (il-13) monoclonal antibody (mab) that inhibits binding of human il-13 to il-13rα1 and il-13rα2. the purpose of this investigation was to predict human pharmacokinetics (pk) of cnto 5825 using different allometric approaches and non-clinical pk data in order to select the right and safe doses for first-in-human (fih) study. after intravenous (iv) administration of cnto 5825, clearance (cl) ranged from 9.98 to 11.49 ml/day/kg in rats and from 5.78 to 7.19  ...201525683750
expression of recipient cytomegalovirus in immunosuppressed and xenotransplanted macaca fascicularis may be related to more severe gastrointestinal lesions.xenotransplantation is a potential answer to the current organ shortage, but the risk of infections related to overimmunosuppression is an important parameter that may predict the recipient's long-term survival. cytomegalovirus (cmv) in xenotransplanted and immunosuppressed primates is a well-known cause of disease particularly affecting the gastrointestinal (gi) tract and a zoonotic concern.201625683577
antimicrobial resistance in campylobacter coli and campylobacter jejuni in cynomolgus monkeys (macaca fascicularis) and eradication regimens.campylobacter spp. are zoonotic pathogens, however, knowledge about their presence and antimicrobial resistance in nonhuman primates is limited. our animal facility purchased cynomolgus monkeys (macaca fascicularis) from various asian countries: china, cambodia, indonesia, the philippines, and vietnam.201725683191
cyp2d44 polymorphisms in cynomolgus and rhesus macaques.macaques, including cynomolgus and rhesus macaques, are important animal species used in drug metabolism studies. cyp2d44 is expressed in cynomolgus macaque liver and encodes a functional drug metabolizing enzyme, metabolizing typical human cyp2d substrates such as bufuralol and dextromethorphan. cyp2d44 is highly homologous to human cyp2d6 that is known to be polymorphic with a large inter-individual variation in metabolic activities, however, genetic polymorphisms have not been investigated in ...201525682269
hydroxypropyl-β-cyclodextrin spikes local inflammation that induces th2 cell and t follicular helper cell responses to the coadministered antigen.cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. in this study, we reprofiled hydroxypropyl-β-cyclodextrin (hp-β-cd) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. hp-β-cd triggered the innate immune response at the injection site ...201525681338
inducible nitric oxide synthase (inos) regulatory region variation in non-human primates.inducible nitric oxide synthase (inos) is an enzyme that plays a key role in intracellular immune response against respiratory infections. since various species of nonhuman primates exhibit different levels of susceptibility to infectious respiratory diseases, and since variation in regulatory regions of genes is thought to play a key role in expression levels of genes, two candidate regulatory regions of inos were mapped, sequenced, and compared across five species of nonhuman primates: african ...201525675838
diabetes mellitus accelerates aβ pathology in brain accompanied by enhanced gaβ generation in nonhuman primates.growing evidence suggests that diabetes mellitus (dm) is one of the strongest risk factors for developing alzheimer's disease (ad). however, it remains unclear why dm accelerates ad pathology. in cynomolgus monkeys older than 25 years, senile plaques (sps) are spontaneously and consistently observed in their brains, and neurofibrillary tangles are present at 32 years of age and older. in laboratory-housed monkeys, obesity is occasionally observed and frequently leads to development of type 2 dm. ...201525675436
development of antifertility vaccine using sperm specific proteins.sperm proteins are known to be associated with normal fertilization as auto- or iso-antibodies to these proteins may cause infertility. therefore, sperm proteins have been considered to be the potential candidate for the development of antifertility vaccine. some of the sperm proteins proved to be promising antigens for contraceptive vaccine includes lactate dehydrogenase (ldh-c4), protein hyaluronidase (ph-20), and eppin. immunization with ldh-c4 reduced fertility in female baboons but not in f ...201425673547
changes in monkey crystalline lens spherical aberration during simulated accommodation in a lens stretcher.the purpose of this study was to quantify accommodation-induced changes in the spherical aberration of cynomolgus monkey lenses.201525670492
nanogel-based pneumococcal surface protein a nasal vaccine induces microrna-associated th17 cell responses with neutralizing antibodies against streptococcus pneumoniae in macaques.we previously established a nanosized nasal vaccine delivery system by using a cationic cholesteryl group-bearing pullulan nanogel (cchp nanogel), which is a universal protein-based antigen-delivery vehicle for adjuvant-free nasal vaccination. in the present study, we examined the central nervous system safety and efficacy of nasal vaccination with our developed cchp nanogel containing pneumococcal surface protein a (pspa-nanogel) against pneumococcal infection in nonhuman primates. when [(18)f] ...201525669148
an fda oncology analysis of antibody-drug conjugates.antibody-drug conjugates (adcs) are complex molecules composed of monoclonal antibodies conjugated to potent cytotoxic agents through chemical linkers. because of this complexity, sponsors have used different approaches for the design of nonclinical studies to support the safety evaluation of adcs and first-in-human (fih) dose selection. we analyzed this data with the goal of describing the relationship between nonclinical study results and phase 1 study outcomes. we summarized the following dat ...201525661711
nicotinic receptors in non-human primates: analysis of genetic and functional conservation with humans.nicotinic acetylcholine receptors (nachrs) are highly conserved between humans and non-human primates. conservation exists at the level of genomic structure, protein structure and epigenetics. overall homology of nachrs at the protein level is 98% in macaques versus 89% in mice, which is highly relevant for evaluating subtype-specific ligands that have different affinities in humans versus rodents. in addition to conservation at the protein level, there is high conservation of genomic structure ...201525661700
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