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1.
Methods Mol Biol ; 2567: 63-84, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36255695

RESUMO

The nonhuman primate (NHP) animal model is an important predictive preclinical model for developing gene and cell therapies. It is also an experimental animal model used to study hematopoietic stem and progenitor cell (HSPC) biology, with the capability of serving as a step for the translation of the basic research concepts from small animals to humans. Lentiviral vectors are currently the standard gene delivery vehicles for transduction of HSPCs in the clinical setting. They have proven to be less genotoxic and more efficient than the previously used murine γ-retroviruses. Transplantation of lentiviral vector-transduced HSPCs into autologous macaques has been well developed over the past two decades. In this chapter, we provide detailed methodologies for lentiviral vector transduction of rhesus macaque HSPCs, including production and titration of lentiviral vector, purification of CD34+ HSPCs, and lentiviral vector transduction and assessment.


Assuntos
Vetores Genéticos , Células-Tronco Hematopoéticas , Animais , Humanos , Camundongos , Antígenos CD34/genética , Vetores Genéticos/genética , Lentivirus/genética , Macaca mulatta , Transdução Genética
2.
Methods Mol Biol ; 2567: 87-98, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36255696

RESUMO

The preclinical development of hematopoietic stem cell (HSC) gene therapy/editing and transplantation protocols is frequently performed in large animal models such as nonhuman primates (NHPs). Similarity in physiology, size, and life expectation as well as cross-reactivity of most reagents and medications allows for the development of treatment strategies with rapid translation to clinical applications. Especially after the adverse events of HSC gene therapy observed in the late 1990s, the ability to perform autologous transplants and follow the animals long-term make the NHP a very attractive model to test the efficiency, feasibility, and safety of new HSC-mediated gene-transfer/editing and transplantation approaches.This protocol describes a method to phenotypically characterize functionally distinct NHP HSPC subsets within specimens or stem cell products from three different NHP species. Procedures are based on the flow-cytometric assessment of cell surface markers that are cross-reactive in between human and NHP to allow for immediate clinical translation. This protocol has been successfully used for the quality control of enriched, cultured, and gene-modified NHP CD34+ hematopoietic stem and progenitor cells (HSPCs) as well as sort-purified CD34 subsets for transplantation in the pig-tailed, cynomolgus, and rhesus macaque. It further allows the longitudinal assessment of primary specimens taken during the long-term follow-up post-transplantation in order to monitor homing, engraftment, and reconstitution of the bone marrow stem cell compartment.


Assuntos
Células-Tronco Hematopoéticas , Animais , Antígenos CD34/metabolismo , Edição de Genes , Macaca mulatta
3.
J Neurosci Res ; 101(1): 70-85, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36131680

RESUMO

Self-injurious behavior (SIB) can lead to serious injury and occurs in approximately 1%-4% of the adult population, with higher incidences in adolescent and institutionalized populations, as well as in children with developmental disorders such as Autism. SIB also spontaneously occurs in a low percentage of captive monkeys. Rhesus macaque (Macaca mulatta) monkeys are evolutionarily and physiologically similar to humans, share 93% genetic sequence similarity to humans, and have long been used as testing subjects for vaccine and clinical trials. Previous studies hypothesized that altered endogenous opioid expression occurs in the brains of individuals and animals that self-injure. We examined the regional mRNA expression of opioid signaling genes in sixteen rhesus macaques that exhibited SIB and eight sex- and age- matched controls. The brain regions examined are linked to reward reinforcement and stress adaptation including the hypothalamus, orbital frontal cortex, nucleus accumbens, hippocampus, caudate, and the amygdala. We found decreased µ-opioid receptor (OPRM1) in the amygdala of monkeys with SIB, and reduced prodynorphin (PDYN) in the hypothalamus. Our data suggest dysfunction in the regulation of opioid peptide precursors and calls for further investigation of the endogenous opioid system in SIB.


Assuntos
Analgésicos Opioides , Comportamento Autodestrutivo , Animais , Criança , Humanos , Adolescente , Macaca mulatta/metabolismo , Peptídeos Opioides , Comportamento Autodestrutivo/genética , Núcleo Accumbens/metabolismo
4.
Parasitol Int ; 92: 102663, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36058466

RESUMO

Strongyloides is a genus of parasitic nematodes of vertebrates comprising approximately 50 documented species, each with various host ranges. Among these, three species (S. stercoralis, S. fuelleborni, and S. cebus) are known to infect primate hosts. S. fuelleborni typically infects non-human primates in the Old World. To complement the existing information on the global genetic structure of this species, we conducted a genotyping study of S. fuelleborni samples collected from rhesus macaques in Myanmar, Japanese macaques in Japan, and some zoo-kept primates. This study identified a novel haplotype group in isolates from the Myanmar rhesus macaques. Subsequently, we obtained the complete or nearly complete mitochondrial genome sequences of S. fuelleborni, S. cebus (Strongyloides of New World monkeys), and S. vituli (Strongyloides of cattle). Phylogenetic analysis based on concatenated mitochondrial protein sequences of various Strongyloides species indicated a close relationship between S. fuelleborni, S. vituli and S. papillosus (Strongyloides in sheep and cattle). S. cebus is quite distantly related to both S. fuelleborni and S. stercoralis, which led to the hypothesis that the three primate Strongyloides species evolved independently as parasites of primates.


Assuntos
Genoma Mitocondrial , Bovinos , Ovinos , Animais , Filogenia , Strongyloides/genética , Macaca mulatta , Cebus , Macaca fuscata , Genética Populacional
5.
Zool Res ; 44(1): 30-42, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36266933

RESUMO

Fluoxetine (Prozac™) is the only antidepressant approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) in children. Despite its considerable efficacy as a selective serotonin reuptake inhibitor, the possible long-term effects of fluoxetine on brain development in children are poorly understood. In the current study, we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques (Macaca mulatta) one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling. We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex (DLPFC) and cingulate cortex (CC) that correlated with impulsivity in animals, suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment. Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.


Assuntos
Transtorno Depressivo Maior , Fluoxetina , Estados Unidos , Animais , Fluoxetina/farmacologia , Macaca mulatta , Inibidores de Captação de Serotonina/farmacologia , Proteômica , Biomarcadores
6.
Life Sci Alliance ; 6(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36261226

RESUMO

Previously it was found that the neuroblastoma breakpoint family (NBPF) gene repeat units of ∼1.6 kb have an important role in human brain evolution and function. The higher order organization of these repeat units has been discovered by both methods, the higher order repeat (HOR)-searching method and the HLS searching method. Using the HOR searching method with global repeat map algorithm, here we identified the tandemly organized NBPF HORs in the human and nonhuman primate NCBI reference genomes. We identified 50 tandemly organized canonical 3mer NBPF HOR copies (Olduvai triplets), but none in nonhuman primates chimpanzee, gorilla, orangutan, and Rhesus macaque. This discontinuous jump in tandemly organized HOR copy number is in sharp contrast to the known gradual increase in the number of Olduvai domains (NBPF monomers) from nonhuman primates to human, especially from ∼138 in chimpanzee to ∼300 in human genome. Using the same global repeat map algorithm method we have also determined the 3mer tandems of canonical 3mer HOR copies in 20 randomly chosen human genomes (10 male and 10 female). In all cases, we found the same 3mer HOR copy numbers as in the case of the reference human genome, with no mutation. On the other hand, some point mutations with respect to reference genome are found for some NBPF monomers which are not tandemly organized in canonical HORs.


Assuntos
Neuroblastoma , Pan troglodytes , Animais , Humanos , Feminino , Masculino , Pan troglodytes/genética , Macaca mulatta/genética , Evolução Molecular , Genoma Humano/genética , Encéfalo
7.
Zool Res ; 43(6): 1041-1062, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36349357

RESUMO

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs. However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000 single-nucleus transcriptomes of the lung, liver, kidney, and cerebral cortex in rhesus macaques ( Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multi-organ dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019 (COVID-19). Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway, which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy (an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection, which may facilitate the development of therapeutic interventions for COVID-19.


Assuntos
COVID-19 , Animais , COVID-19/genética , COVID-19/veterinária , Macaca mulatta , SARS-CoV-2 , Transcriptoma , Carga Viral/veterinária
8.
Proc Biol Sci ; 289(1986): 20220728, 2022 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-36350207

RESUMO

The greater male variability (GMV) hypothesis proposes that traits are more variable among males than females, and is supported by numerous empirical studies. Interestingly, GMV is also observed for human brain size and internal brain structure, a pattern which may have implications for sex-biased neurological and psychiatric conditions. A better understanding of neuroanatomical variability in non-human primates may illuminate whether certain species are appropriate models for these conditions. Here, we tested for sex differences in the variability of endocranial volume (ECV, a proxy for brain size) in a sample of 542 rhesus macaques (Macaca mulatta) from a large pedigreed free-ranging population. We also examined the components of phenotypic variance (additive genetic and residual variance) to tease apart the potential drivers of sex differences in variability. Our results suggest that males exhibit more variable ECVs, and that this pattern reflects either balancing/disruptive selection on male behaviour (associated with alternative male mating strategies) or sex chromosome effects (associated with mosaic patterns of X chromosome gene expression in females), rather than extended neurodevelopment among males. This represents evidence of GMV for brain size in a non-human primate species and highlights the potential of rhesus macaques as a model for sex-biased brain-based disorders.


Assuntos
Reprodução , Cromossomos Sexuais , Animais , Feminino , Masculino , Macaca mulatta/genética , Fenótipo , Caracteres Sexuais
9.
Front Immunol ; 13: 1001727, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389795

RESUMO

Despite advances in combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to experience gastrointestinal dysfunction. Infusions of anti-α4ß7 monoclonal antibodies (mAbs) have been proposed to increase virologic control during simian immunodeficiency virus (SIV) infection in macaques with mixed results. Recent evidences suggested that therapeutic efficacy of vedolizumab (a humanized anti-α4ß7 mAb), during inflammatory bowel diseases depends on microbiome composition, myeloid cell differentiation, and macrophage phenotype. We tested this hypothesis in SIV-infected, anti-α4ß7 mAb-treated macaques and provide flow cytometric and microscopic evidence that anti-α4ß7 administered to SIV-infected macaques increases the maturity of macrophage phenotypes typically lost in the small intestines during SIV disease progression. Further, this increase in mature macrophage phenotype was associated with tissue viral loads. These phenotypes were also associated with dysbiosis markers in the gut previously identified as predictors of HIV replication and immune activation in PLWH. These findings provide a novel model of anti-α4ß7 efficacy offering new avenues for targeting pathogenic mucosal immune response during HIV/SIV infection.


Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Macaca mulatta , Anticorpos/uso terapêutico , Macrófagos , Infecções por HIV/tratamento farmacológico
10.
Commun Biol ; 5(1): 1268, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36400843

RESUMO

Tissue stem cells maintain themselves through self-renewal while constantly supplying differentiating cells. Two distinct models have been proposed as mechanisms of stem cell homeostasis. According to the classical model, there is hierarchy among stem cells, and master stem cells produce stem cells by asymmetric division; whereas, according to the recent model, stem cells are equipotent and neutrally compete. However, the mechanism remains controversial in several tissues and species. Here, we developed a mathematical model linking the two models, named the hierarchical neutral competition (hNC) model. Our theoretical analysis showed that the combination of the hierarchy and neutral competition exhibited bursts in clonal expansion, which was consistent with experimental data of rhesus macaque hematopoiesis. Furthermore, the scaling law in clone size distribution, considered a unique characteristic of the recent model, was satisfied even in the hNC model. Based on the findings above, we proposed the criterion for distinguishing the three models based on experiments.


Assuntos
Hematopoese , Células-Tronco , Animais , Macaca mulatta , Homeostase , Células Cultivadas
11.
Nat Struct Mol Biol ; 29(11): 1080-1091, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36344847

RESUMO

Simian immunodeficiency viruses (SIVs) are lentiviruses that naturally infect non-human primates of African origin and seeded cross-species transmissions of HIV-1 and HIV-2. Here we report prefusion stabilization and cryo-EM structures of soluble envelope (Env) trimers from rhesus macaque SIV (SIVmac) in complex with neutralizing antibodies. These structures provide residue-level definition for SIV-specific disulfide-bonded variable loops (V1 and V2), which we used to delineate variable-loop coverage of the Env trimer. The defined variable loops enabled us to investigate assembled Env-glycan shields throughout SIV, which we found to comprise both N- and O-linked glycans, the latter emanating from V1 inserts, which bound the O-link-specific lectin jacalin. We also investigated in situ SIVmac-Env trimers on virions, determining cryo-electron tomography structures at subnanometer resolutions for an antibody-bound complex and a ligand-free state. Collectively, these structures define the prefusion-closed structure of the SIV-Env trimer and delineate variable-loop and glycan-shielding mechanisms of immune evasion conserved throughout SIV evolution.


Assuntos
Anticorpos Neutralizantes , HIV-1 , Animais , Microscopia Crioeletrônica , Macaca mulatta/metabolismo , HIV-1/metabolismo , Tomografia com Microscopia Eletrônica , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Anticorpos Anti-HIV
12.
Commun Biol ; 5(1): 1204, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352100

RESUMO

Despite increasing evidence that uveitis is common and consequential in survivors of Ebola virus disease (EVD), the host-pathogen determinants of the clinical phenotype are undefined, including the pathogenetic role of persistent viral antigen, ocular tissue-specific immune responses, and histopathologic characterization. Absent sampling of human intraocular fluids and tissues, these questions might be investigated in animal models of disease; however, challenges intrinsic to the nonhuman primate model and the animal biosafety level 4 setting have historically limited inquiry. In a rhesus monkey survivor of experimental Ebola virus (EBOV) infection, we observed and documented the clinical, virologic, immunologic, and histopathologic features of severe uveitis. Here we show the clinical natural history, resultant ocular pathology, intraocular antigen-specific antibody detection, and persistent intraocular EBOV RNA detected long after clinical resolution. The association of persistent EBOV RNA as a potential driver of severe immunopathology has pathophysiologic implications for understanding, preventing, and mitigating vision-threatening uveitis in EVD survivors.


Assuntos
Ebolavirus , Doença pelo Vírus Ebola , Uveíte , Animais , Humanos , Doença pelo Vírus Ebola/complicações , Ebolavirus/fisiologia , Macaca mulatta , Uveíte/complicações , Uveíte/diagnóstico , RNA
13.
Hum Gene Ther ; 33(21-22): 1174-1186, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36375122

RESUMO

Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 1013 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.


Assuntos
Neuropatias Amiloides Familiares , Dependovirus , Humanos , Camundongos , Animais , Dependovirus/genética , Dependovirus/metabolismo , Macaca mulatta/genética , Macaca mulatta/metabolismo , Neuropatias Amiloides Familiares/terapia , Neuropatias Amiloides Familiares/tratamento farmacológico , Pré-Albumina/genética , Pré-Albumina/metabolismo , Pré-Albumina/uso terapêutico , RNA/uso terapêutico
14.
Sci Rep ; 12(1): 20260, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36424495

RESUMO

Cannabis use in pregnancy is associated with adverse perinatal outcomes, which are likely mediated by the placenta. However, the underlying mechanisms and specific vasoactive effects of cannabis on the placenta are unknown. Our objective was to determine the impact of chronic prenatal delta-tetrahydrocannabinol (THC, main psychoactive component of cannabis) exposure on placental function and development in a rhesus macaque model using advanced imaging. Animals were divided into two groups, control (CON, n = 5) and THC-exposed (THC, n = 5). THC-exposed animals received a THC edible daily pre-conception and throughout pregnancy. Animals underwent serial ultrasound and MRI at gestational days 85 (G85), G110, G135 and G155 (full term is ~ G168). Animals underwent cesarean delivery and placental collection at G155 for histologic and RNA-Seq analysis. THC-exposed pregnancies had significantly decreased amniotic fluid volume (p < 0.001), placental perfusion (p < 0.05), and fetal oxygen availability (p < 0.05), all indicators of placental insufficiency. Placental histological analysis demonstrated evidence of ischemic injury with microinfarctions present in THC-exposed animals only. Bulk RNA-seq demonstrated that THC alters the placental transcriptome and pathway analysis suggests dysregulated vasculature development and angiogenesis pathways. The longer-term consequences of these adverse placental findings are unknown, but they suggest that use of THC during pregnancy may deleteriously impact offspring development.


Assuntos
Dronabinol , Alucinógenos , Animais , Feminino , Gravidez , Macaca mulatta , Dronabinol/farmacologia , Placenta , Feto/metabolismo , Alucinógenos/metabolismo , Agonistas de Receptores de Canabinoides/metabolismo
15.
Invest Ophthalmol Vis Sci ; 63(12): 6, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36326726

RESUMO

Purpose: Pattern strabismus is characterized by a horizontal misalignment of the eyes that varies with vertical eye position. This disorder has traditionally been described, and treated, as overaction or underaction of the oblique muscles. In recent years, evidence has accumulated that indicate that the disorder is associated with abnormal cross-talk between brainstem pathways that contribute to the horizontal and vertical components of eye movements. The present study was designed to investigate the hypothesis that the key abnormalities are at the level of, or downstream from, the interstitial nucleus of Cajal (INC). Methods: Microstimulation was applied to the INC in two mature rhesus monkeys with "A" pattern strabismus that was experimentally induced in infancy. We asked whether the evoked movements would be vertical and conjugate, as has been previously reported in normal monkeys, or would be directionally disconjugate (i.e. with oblique or horizontal movement observed for at least one eye). Results: Evoked movements were conjugate and vertical for a minority of sites but, for most sites, the evoked movements were directionally disconjugate. Moreover, there was typically a convergent change in horizontal strabismus when the evoked movements were upward and a divergent change when the evoked movements were downward. Conclusions: Microstimulation of INC in monkeys with A-pattern strabismus evokes movements with the expected directional disconjugacies, implying that the key neural abnormalities are within, or downstream from, this structure. High site-to-site variability in the conjugacy/disconjugacy of evoked movements rules out the hypothesis that the abnormalities are solely peripheral.


Assuntos
Transtornos da Motilidade Ocular , Estrabismo , Animais , Movimentos Oculares , Movimentos Sacádicos , Tegmento Mesencefálico , Macaca mulatta
16.
PLoS One ; 17(11): e0276866, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36318529

RESUMO

Extracting life history information from mineralized hard tissues of extant and extinct species is an ongoing challenge in evolutionary and conservation studies. Primary lamellar bone is a mineralized tissue with multidien periodicity that begins deposition prenatally and continues until adulthood albeit with concurrent resorption, thus maintaining a record spanning several years of an individual's life. Here, we use field-emission scanning electron microscopy and energy-dispersive X-ray analysis to measure the relative concentrations of calcium, phosphorous, oxygen, magnesium and sodium in the femora of seven rhesus macaque with known medical and life-history information. We find that the concentration of these elements distinguishes parous from nulliparous females; that in females calcium and phosphorus are lower in bone formed during reproductive events; and that significant differences in relative magnesium concentration correlate with breastfeeding in infants.


Assuntos
Cálcio , Magnésio , Animais , Feminino , Magnésio/análise , Macaca mulatta , Cálcio/análise , Fósforo/análise , Sódio/análise
17.
Sci Data ; 9(1): 722, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36433985

RESUMO

Plasmodium cynomolgi causes zoonotic malarial infections in Southeast Asia and this parasite species is important as a model for Plasmodium vivax and Plasmodium ovale. Each of these species produces hypnozoites in the liver, which can cause relapsing infections in the blood. Here we present methods and data generated from iterative longitudinal systems biology infection experiments designed and performed by the Malaria Host-Pathogen Interaction Center (MaHPIC) to delve deeper into the biology, pathogenesis, and immune responses of P. cynomolgi in the Macaca mulatta host. Infections were initiated by sporozoite inoculation. Blood and bone marrow samples were collected at defined timepoints for biological and computational experiments and integrative analyses revolving around primary illness, relapse illness, and subsequent disease and immune response patterns. Parasitological, clinical, haematological, immune response, and -omic datasets (transcriptomics, proteomics, metabolomics, and lipidomics) including metadata and computational results have been deposited in public repositories. The scope and depth of these datasets are unprecedented in studies of malaria, and they are projected to be a F.A.I.R., reliable data resource for decades.


Assuntos
Malária , Plasmodium cynomolgi , Animais , Interações Hospedeiro-Patógeno , Macaca mulatta , Plasmodium cynomolgi/fisiologia , Esporozoítos , Biologia de Sistemas , Zoonoses
18.
Sci Prog ; 105(4): 368504221141660, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36443989

RESUMO

Numbers are one of the three basic concepts of human abstract thinking. When human beings count, they often point to things, one by one, and read numbers in a positive integer column. The prefrontal cortex plays a wide range of roles in executive functions, including active maintenance and achievement of goals, adaptive coding and exertion of general intelligence, and completion of time complexity events. Nonhuman animals do not use number names, such as "one, two, three," or numerals, such as "1, 2, 3" to "count" in the same way as humans do. Our previous study established an animal model of counting in monkeys. Here, we used this model to determine whether the prefrontal cortex participates in counting in monkeys. Two 5-year-old female rhesus monkeys (macaques), weighing 5.0 kg and 5.5 kg, were selected to train in a counting task, counting from 1 to 5. When their counting task performance stabilized, we performed surgery on the prefrontal cortex to implant drug delivery tubes. After allowing the monkeys' physical condition and counting performance to recover, we injected either muscimol or normal saline into their dorsal and ventral prefrontal cortex. Thereafter, we observed their counting task performance and analyzed the error types and reaction time during the counting task. The monkeys' performance in the counting task decreased significantly after muscimol injection into the ventral prefrontal cortex; however, it was not affected after saline injection into the ventral prefrontal cortex, or after muscimol or saline injection into the dorsal prefrontal cortex. The ventral prefrontal cortex of the monkey is necessary for counting performance.


Assuntos
Função Executiva , Córtex Pré-Frontal , Animais , Feminino , Humanos , Adulto , Macaca mulatta , Muscimol/farmacologia , Modelos Animais de Doenças
19.
Nat Commun ; 13(1): 6787, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36351907

RESUMO

Although the presence of face patches in primate inferotemporal (IT) cortex is well established, the functional and causal relationships among these patches remain elusive. In two monkeys, muscimol was infused sequentially into each patch or pair of patches to assess their respective influence on the remaining IT face network and the amygdala, as determined using fMRI. The results revealed that anterior face patches required input from middle face patches for their responses to both faces and objects, while the face selectivity in middle face patches arose, in part, from top-down input from anterior face patches. Moreover, we uncovered a parallel fundal-lateral functional organization in the IT face network, supporting dual routes (dorsal-ventral) in face processing within IT cortex as well as between IT cortex and the amygdala. Our findings of the causal relationship among the face patches demonstrate that the IT face circuit is organized into multiple functional compartments.


Assuntos
Mapeamento Encefálico , Imageamento por Ressonância Magnética , Animais , Estimulação Luminosa/métodos , Macaca mulatta , Córtex Cerebral/fisiologia , Reconhecimento Visual de Modelos/fisiologia
20.
Viruses ; 14(11)2022 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-36423122

RESUMO

With the development of NK cell-directed therapeutic strategies, the actual effect of NK cells on the cellular SIV DNA levels of the virus in SIV-infected macaques in vivo remains unclear. In this study, five chronically SIVmac239-infected, treatment-naïve rhesus macaques were euthanized, and the blood, spleen, pararectal/paracolonic lymph nodes (PaLNs), and axillary lymph nodes (ALNs) were collected. The distributional, phenotypic, and functional profiles of NK cells were detected by flow cytometry. The highest frequency of NK cells was found in PBMC, followed by the spleen, while only 0~0.5% were found in LNs. Peripheral NK cells also exhibited higher cytotoxic potential (CD56- CD16+ NK subsets) and IFN-γ-producing capacity but low PD-1 and Tim-3 levels than those in the spleen and LNs. Our results demonstrated a significant positive correlation between the frequency of NK cells and the ratios of cellular SIV DNA/RNA in HLADR- CD4+ T cells (r = 0.6806, p < 0.001) in SIV-infected macaques, despite no discrepancies in the cellular SIV DNA or RNA levels that were found among the blood, spleen, and LNs. These findings showed a profile of NK cell frequencies and NK cytotoxicity levels in different immune organs from chronically SIVmac239-infected, treatment-naïve rhesus macaques. It was suggested that NK cell frequencies could be closely related to SIV DNA/RNA levels, which could affect the transcriptional activity of SIV proviruses. However, the cytotoxicity effect of NK cells on the latent SIV viral load in LNs could be limited due to the sparse abundance of NK cells in LNs. The development of NK cell-directed treatment approaches aiming for HIV clearance remains challenging.


Assuntos
Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Macaca mulatta , RNA , Linfócitos T/patologia , Leucócitos Mononucleares/patologia , Células Matadoras Naturais , DNA , Linfócitos T CD4-Positivos
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