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1.
N Engl J Med ; 381(15): 1477-1479, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597025
4.
Adv Gerontol ; 32(3): 316-324, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31512416

RESUMO

An increasing number of studies are devoted to the study of the relationship of mental disorders, such as depression and anxiety, with the risk of developing type 2 diabetes mellitus. However, in the literature there are practically no publications on the study of the relationship of the features of higher nervous activity, in particular, adaptive behavior, in healthy individuals with the risk of developing age-related dysfunction of the pancreatic islet apparatus (PIA). The purpose of this study was to investigate features of the functioning of the PIA during aging in individuals with normal standard behavior (SB), as well as anxiety- and depressive-like behavior (DAB) in experiments on nonhuman primates. 76 physically healthy young mature and old female rhesus monkeys with SB and DAB were used in the experiments. Old animals were divided into subgroups with normal (NW) and excess (EW) body weight. All young animals were characterized by NW. The function of PIA was assessed using a glucose tolerance test. Intergroup differences in the functioning of the PIA in young animals were revealed, which were characterized by signs of impaired early insulin response, apparently due to a decrease in the sensitivity of ß-cells of the pancreas to glucose. With aging, the function of the PIA was damaged in all animals, but the features of its changes depended on both the affiliation to a particular behavioral group and the animal's body weight. During aging in animals with SB, the development of relative insulin resistance of peripheral tissues was observed, accompanied by impaired glucose tolerance and a compensatory increase in the secretory activity of the PIA, which were more pronounced in animals with EW. Age-related dysfunction of the PIA in animals with DAB and NW was similar with age-related changes in the PIA function in animals with SB and NW. At the same time, with aging, animals with DAB and EW showed a more significant peak concentration of glucose than that of old animals with SB and EW, accompanied by a minimum «disappearance¼ rate of glucose from the circulation and significantly lower insulin secretion than this in animals with SB and EW. Thus, age-related dysfunctions of the PIA in primates with SB and DAB are unidirectional with the development of insulin resistance, impaired glucose tolerance and a compensatory increase in insulin secretion, which, however, in old animals with DAB and EW are accompanied by exhaustion of the PIA function, increasing the risk of developing type 2 diabetes mellitus.


Assuntos
Envelhecimento , Comportamento Animal , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Pâncreas , Primatas , Adaptação Psicológica , Animais , Comportamento Animal/fisiologia , Feminino , Insulina , Macaca mulatta , Pâncreas/fisiologia , Primatas/fisiologia
5.
Nat Neurosci ; 22(10): 1669-1676, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477898

RESUMO

Visual attention dramatically improves individuals' ability to see and modulates the responses of neurons in every known visual and oculomotor area, but whether such modulations can account for perceptual improvements is unclear. We measured the relationship between populations of visual neurons, oculomotor neurons and behavior during detection and discrimination tasks. We found that neither of the two prominent hypothesized neuronal mechanisms underlying attention (which concern changes in information coding and the way sensory information is read out) provide a satisfying account of the observed behavioral improvements. Instead, our results are more consistent with the hypothesis that attention reshapes the representation of attended stimuli to more effectively influence behavior. Our results suggest a path toward understanding the neural underpinnings of perception and cognition in health and disease by analyzing neuronal responses in ways that are constrained by behavior and interactions between brain areas.


Assuntos
Atenção/fisiologia , Neurônios/fisiologia , Animais , Tomada de Decisões/fisiologia , Discriminação (Psicologia)/fisiologia , Macaca mulatta , Masculino , Neurônios Motores/fisiologia , Rede Nervosa/fisiologia , Desempenho Psicomotor/fisiologia , Psicofísica
6.
Zool Res ; 40(5): 394-403, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31393096

RESUMO

Information flow between the prefrontal and visual cortices is critical for visual behaviors such as visual search. To investigate its mechanisms, we simultaneously recorded spike and local field potential (LFP) signals in the frontal eye field (FEF) and area V4 while monkeys performed a free-gaze visual search task. During free-gaze search, spike-LFP coherence between FEF and V4 was enhanced in the theta rhythm (4-8 Hz) but suppressed in the alpha rhythm (8-13 Hz). Cross-frequency couplings during the Cue period before the search phase were related to monkey performance, with higher FEF theta-V4 gamma coupling and lower FEF alpha-V4 gamma coupling associated with faster search. Finally, feature-based attention during search enhanced spike-LFP coherence between FEF and V4 in the gamma and beta rhythms, whereas overt spatial attention reduced coherence at frequencies up to 30 Hz. These results suggest that oscillatory coupling may play an important role in mediating interactions between the prefrontal and visual cortices during visual search.


Assuntos
Atenção , Lobo Frontal/fisiologia , Macaca mulatta/fisiologia , Córtex Visual/fisiologia , Potenciais de Ação , Animais , Masculino
7.
Immunogenetics ; 71(8-9): 545-559, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31384962

RESUMO

Butyrophilins (BTN), specifically BTN3A, play a central role in the modulation of γδ T cells, which are mainly present in gut and mucosal tissues. BTN3A1 is known, for example, to activate Vγ9Vδ2 T cells by means of a phosphoantigen interaction. In the extended HLA region, three genes are located, designated BTN3A1, BTN3A2 and BTN3A3, which were also defined in rhesus macaques. In contrast to humans, rhesus monkeys have an additional gene, BTN3A3Like, which has the features of a pseudogene. cDNA analysis of 32 Indian rhesus and 16 cynomolgus macaques originating from multiple-generation families revealed that all three genes are oligomorphic, and the deduced amino acids display limited variation. The macaque BTN3A alleles segregated together with MHC alleles, proving their location in the extended (Major Histocompatibility Complex) MHC. BTN3A nearly full-length transcripts of macaques and humans cluster tightly together in the phylogenetic tree, suggesting that the genes represent true orthologs of each other. Despite the limited level of polymorphism, 15 Mamu- and 14 Mafa-BTN3A haplotypes were defined, and, as in humans, all three BTN3A genes are transcribed in PBMCs and colon tissues. In addition to regular full-length transcripts, a high number of various alternative splicing (AS) products were observed for all BTN3A alleles, which may result in different isoforms. The comparable function of certain subsets of γδ T cells in human and non-human primates in concert with high levels of sequence conservation observed for the BTN3A transcripts presents the opportunity to study these not yet well understood molecules in macaques as a model species.


Assuntos
Antígenos CD/genética , Butirofilinas/genética , Antígenos de Histocompatibilidade/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Sequência de Aminoácidos , Animais , Butirofilinas/metabolismo , Sequência Conservada , Feminino , Haplótipos , Humanos , Macaca mulatta , Masculino , Filogenia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Homologia de Sequência , Linfócitos T/metabolismo
8.
Nat Neurosci ; 22(8): 1327-1335, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285613

RESUMO

During natural behavior, animals actively gather information that is relevant for learning or actions; however, the mechanisms of active sampling are rarely investigated. We tested parietal neurons involved in oculomotor control in a task in which monkeys made saccades to gather visual information relevant to a subsequent action. We show that the neurons encode, before the saccade, the information gain (reduction in decision uncertainty) that the saccade was expected to bring for the following action. Sensitivity to information gain correlates with the monkeys' efficiency at processing the information in the post-saccadic fixation, but is independent of neuronal reward sensitivity. Reward sensitivity, in turn, is unreliable across task contexts, inconsistent with the view that the cells encode economic utility. The findings suggest that parietal cells involved in oculomotor decisions show uncertainty-dependent boosts of neural gain that facilitate the implementation of active sampling policies, including the selection of relevant cues and the efficient use of the information delivered by these cues.


Assuntos
Tomada de Decisões/fisiologia , Neurônios/fisiologia , Lobo Parietal/citologia , Lobo Parietal/fisiologia , Incerteza , Animais , Sinais (Psicologia) , Discriminação (Psicologia)/fisiologia , Movimentos Oculares/fisiologia , Fixação Ocular , Macaca mulatta , Masculino , Recompensa , Movimentos Sacádicos/fisiologia
9.
Eur J Med Chem ; 180: 213-223, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306908

RESUMO

Reactions of Ni(II) and Pd(II) precursors with S-benzyl-N-(ferrocenyl)methylenedithiocarbazate (HFedtc) led to the formation of heterobimetallic complexes of the type [MII(Fedtc)2] (M = Ni and Pd). The characterization of the compounds involved the determination of melting point, FTIR, UV-Vis, 1H NMR, elemental analysis and electrochemical experiments. Furthermore, the crystalline structures of HFedtc and [NiII(Fedtc)2] were determined by single crystal X-ray diffraction. The compounds were evaluated against the intracellular form of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity assays were assessed using LLC-MK2 cells. The results showed that the coordination of HFedtc to Ni(II) or Pd(II) decreases the in vitro trypanocidal activity while the cytotoxicity against LLC-MK2 cells does not change significantly. [PdII(Fedtc)2] showed the greater potential between the two complexes studied, showing an SI value of 8.9. However, this value is not better than that of the free ligand with an SI of 40, a similar value to that of the standard drug benznidazole (SI = 48). Additionally, molecular docking simulations were performed with Trypanosoma cruzi Old Yellow Enzyme (TcOYE), which predicted that HFedtc binds to the protein, almost parallel to the flavin mononucleotide (FMN) prosthetic group, while the [NiII(Fedtc)2] complex was docked into the enzyme binding site in a significantly different manner. In order to confirm the hypothetical interaction, in vitro experiments of fluorescence quenching and enzymatic activity were performed which indicated that, although HFedtc was not processed by the enzyme, it was able to act as a competitive inhibitor, blocking the hydride transfer from the FMN prosthetic group of the enzyme to the menadione substrate.


Assuntos
Compostos de Benzil/farmacologia , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Metalocenos/farmacologia , NADPH Desidrogenase/antagonistas & inibidores , Níquel/farmacologia , Paládio/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Hidrazinas/química , Macaca mulatta , Metalocenos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , NADPH Desidrogenase/química , NADPH Desidrogenase/metabolismo , Níquel/química , Níquel/metabolismo , Paládio/química , Paládio/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/metabolismo , Trypanosoma cruzi/metabolismo
10.
Immunogenetics ; 71(8-9): 531-544, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31321455

RESUMO

Indian rhesus macaque major histocompatibility complex (MHC) variation can influence the outcomes of transplantation and infectious disease studies. Frequently, rhesus macaques are MHC genotyped to identify variants that could account for unexpected results. Since the MHC is only one region in the genome where variation could impact experimental outcomes, strategies for simultaneously profiling variation in the macaque MHC and the remainder of the protein coding genome would be useful. Here we determine MHC class I and class II genotypes using target-capture probes enriched for MHC sequences, a method we term macaque exome sequence (MES) genotyping. For a cohort of 27 Indian rhesus macaques, we describe two methods for obtaining MHC genotypes from MES data and demonstrate that the MHC class I and class II genotyping results obtained with these methods are 98.1% and 98.7% concordant, respectively, with expected MHC genotypes. In contrast, conventional MHC genotyping results obtained by deep sequencing of short multiplex PCR amplicons were only 92.6% concordant with expectations for this cohort.


Assuntos
Exoma/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Macaca mulatta/genética , Polimorfismo Genético , Animais , Haplótipos , Sequenciamento Completo do Exoma
11.
Nat Commun ; 10(1): 2898, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263112

RESUMO

The HIV-1 envelope (Env) is the target for neutralizing antibodies and exists on the surface of virions in open or closed conformations. Difficult-to-neutralize viruses (tier 2) express Env in a closed conformation antigenic for broadly neutralizing antibodies (bnAbs) but not for third variable region (V3) antibodies. Here we show that select V3 macaque antibodies elicited by Env vaccination can neutralize 26% of otherwise tier 2 HIV-1 isolates in standardized virus panels. The V3 antibodies only bound to Env in its open conformation. Thus, Envs on tier 2 viruses sample a state where the V3 loop is not in its closed conformation position. Envelope second variable region length, glycosylation sites and V3 amino acids were signatures of neutralization sensitivity. This study determined that open conformations of Env with V3 exposed are present on a subset of otherwise neutralization-resistant virions, therefore neutralization of tier 2 HIV-1 does not always indicate bnAb induction.


Assuntos
Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Motivos de Aminoácidos , Animais , Anticorpos Neutralizantes/imunologia , Glicosilação , Infecções por HIV/virologia , HIV-1/química , HIV-1/genética , Humanos , Macaca mulatta , Testes de Neutralização , Conformação Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/química
12.
Anim Cogn ; 22(5): 883-895, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31256340

RESUMO

Numerosity illusions emerge when the stimuli in one set are overestimated or underestimated relative to the number (or quantity) of stimuli in another set. In the case of multi-item arrays, individual items that form a better Gestalt are more readily grouped, leading to overestimation by human adults and children. As an example, the Solitaire illusion emerges when dots forming a central cluster (cross-pattern) are overestimated relative to the same number of dots on the periphery of the array. Although this illusion is robustly experienced by human adults, previous studies have produced weaker illusory results for young children, chimpanzees, rhesus macaques, capuchin monkeys, and guppies. In the current study, we presented nonhuman primates with other linear arrangements of stimuli from Frith and Frith's (Percept Psychoph 11:409-410, 1972) original paper with human participants that included the Solitaire illusion. Capuchin monkeys, rhesus macaques, and human adults learned to quantify black and white dots that were presented within intermingled arrays, responding on the basis of the more numerous dot colors. Humans perceived the various illusions similar to the original findings of Frith and Frith (1972), validating the current comparative design; however, there was no evidence of illusory susceptibility in either species of monkey. These results are considered in light of illusion susceptibility among primates as well as considering the role of numerical discrimination abilities and perceptual processing mode on illusion emergence.


Assuntos
Cebus , Ilusões , Aprendizagem , Macaca mulatta , Pan troglodytes , Animais , Cor , Feminino , Humanos , Masculino , Aves Canoras
13.
Neuron ; 103(3): 533-545.e5, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31196672

RESUMO

The explore-exploit dilemma refers to the challenge of deciding when to forego immediate rewards and explore new opportunities that could lead to greater rewards in the future. While motivational neural circuits facilitate learning based on past choices and outcomes, it is unclear whether they also support computations relevant for deciding when to explore. We recorded neural activity in the amygdala and ventral striatum of rhesus macaques as they solved a task that required them to balance novelty-driven exploration with exploitation of what they had already learned. Using a partially observable Markov decision process (POMDP) model to quantify explore-exploit trade-offs, we identified that the ventral striatum and amygdala differ in how they represent the immediate value of exploitative choices and the future value of exploratory choices. These findings show that subcortical motivational circuits are important in guiding explore-exploit decisions.


Assuntos
Tonsila do Cerebelo/fisiologia , Comportamento de Escolha/fisiologia , Tomada de Decisões/fisiologia , Desvalorização pelo Atraso/fisiologia , Comportamento Exploratório/fisiologia , Motivação/fisiologia , Estriado Ventral/fisiologia , Animais , Simulação por Computador , Condicionamento Operante/fisiologia , Macaca mulatta , Masculino , Cadeias de Markov , Modelos Neurológicos , Recompensa
14.
Neuron ; 103(4): 658-672.e6, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227309

RESUMO

The functions of the diverse retinal ganglion cell types in primates and the parallel visual pathways they initiate remain poorly understood. Here, unusual physiological and computational properties of the ON and OFF smooth monostratified ganglion cells are explored. Large-scale multi-electrode recordings from 48 macaque retinas revealed that these cells exhibit irregular receptive field structure composed of spatially segregated hotspots, quite different from the classic center-surround model of retinal receptive fields. Surprisingly, visual stimulation of different hotspots in the same cell produced spikes with subtly different spatiotemporal voltage signatures, consistent with a dendritic contribution to hotspot structure. Targeted visual stimulation and computational inference demonstrated strong nonlinear subunit properties associated with each hotspot, supporting a model in which the hotspots apply nonlinearities at a larger spatial scale than bipolar cells. These findings reveal a previously unreported nonlinear mechanism in the output of the primate retina that contributes to signaling spatial information.


Assuntos
Células Ganglionares da Retina/classificação , Potenciais de Ação , Animais , Contagem de Células , Eletrofisiologia/métodos , Macaca fascicularis , Macaca mulatta , Modelos Neurológicos , Dinâmica não Linear , Técnicas de Patch-Clamp , Estimulação Luminosa , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/efeitos da radiação , Visão Ocular/fisiologia
15.
Neuron ; 103(3): 520-532.e5, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31230761

RESUMO

In economic decisions, we make a good-based choice first, then we transform the outcome into an action to obtain the good. To elucidate the network mechanisms for such transformation, we constructed a neural circuit model consisting of modules representing choice, integration of choice with target locations, and the final action plan. We examined three scenarios regarding how the final action plan could emerge in the neural circuit and compared their implications with experimental data. Our model with heterogeneous connectivity predicts the coexistence of three types of neurons with distinct functions, confirmed by analyzing the neural activity in the lateral prefrontal cortex (LPFC) of behaving monkeys. We obtained a much more distinct classification of functional neuron types in the ventral than the dorsal region of LPFC, suggesting that the action plan is initially generated in ventral LPFC. Our model offers a biologically plausible neural circuit architecture that implements good-to-action transformation during economic choice.


Assuntos
Comportamento de Escolha/fisiologia , Tomada de Decisões/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Feminino , Fixação Ocular/fisiologia , Macaca mulatta , Masculino , Memória de Curto Prazo/fisiologia , Movimentos Sacádicos/fisiologia
16.
Nat Neurosci ; 22(8): 1269-1275, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31235933

RESUMO

Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades inhibitory chondroitin sulfate proteoglycans and improves axonal sprouting and functional recovery after spinal cord injury in rodents. We evaluated the effects of Chase in rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, we administered multiple intraparenchymal Chase injections below the lesion, targeting spinal cord circuits that control hand function. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in spinal cord injury.


Assuntos
Condroitinases e Condroitim Liases/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Axônios/patologia , Condroitinases e Condroitim Liases/administração & dosagem , Condroitinases e Condroitim Liases/efeitos adversos , Substância Cinzenta/patologia , Mãos/inervação , Mãos/fisiopatologia , Injeções Intralesionais , Macaca mulatta , Masculino , Microglia/patologia , Neurônios Motores/patologia , Desempenho Psicomotor , Tratos Piramidais/patologia , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/fisiopatologia , Suínos , Sinapses/patologia , Resultado do Tratamento
17.
Nature ; 571(7766): 510-514, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31243368

RESUMO

Although many long noncoding RNAs (lncRNAs) have been identified in human and other mammalian genomes, there has been limited systematic functional characterization of these elements. In particular, the contribution of lncRNAs to organ development remains largely unexplored. Here we analyse the expression patterns of lncRNAs across developmental time points in seven major organs, from early organogenesis to adulthood, in seven species (human, rhesus macaque, mouse, rat, rabbit, opossum and chicken). Our analyses identified approximately 15,000 to 35,000 candidate lncRNAs in each species, most of which show species specificity. We characterized the expression patterns of lncRNAs across developmental stages, and found many with dynamic expression patterns across time that show signatures of enrichment for functionality. During development, there is a transition from broadly expressed and conserved lncRNAs towards an increasing number of lineage- and organ-specific lncRNAs. Our study provides a resource of candidate lncRNAs and their patterns of expression and evolutionary conservation across mammalian organ development.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Especificidade de Órgãos/genética , Organogênese/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Especificidade da Espécie , Animais , Atlas como Assunto , Galinhas/genética , Evolução Molecular , Feminino , Humanos , Macaca mulatta/genética , Masculino , Camundongos , Gambás/genética , Proteínas/genética , RNA Longo não Codificante/análise , Coelhos , Ratos
18.
Neuron ; 103(2): 277-291.e4, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31151774

RESUMO

Neocortical circuits are sensitive to experience, showing both anatomical and electrophysiological changes in response to altered sensory input. We examined input- and cell-type-specific changes in thalamo- and intracortical pathways during learning using an automated, home-cage sensory association training (SAT) paradigm coupling multi-whisker stimulation to a water reward. We found that the posterior medial nucleus (POm) but not the ventral posterior medial (VPM) nucleus of the thalamus drives increased cortical activity after 24 h of SAT, when behavioral evidence of learning first emerges. Synaptic strengthening within the POm thalamocortical pathway was first observed at thalamic inputs to L5 and was not generated by sensory stimulation alone. Synaptic changes in L2 were delayed relative to L5, requiring 48 h of SAT to drive synaptic plasticity at thalamic and intracortical inputs onto L2 Pyr neurons. These data identify the POm thalamocortical circuit as a site of rapid synaptic plasticity during learning and suggest a temporal sequence to learning-evoked synaptic changes in the sensory cortex.


Assuntos
Vias Aferentes/fisiologia , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Células Receptoras Sensoriais/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Animais , Macaca mulatta , Masculino , Modelos Neurológicos , Dinâmica não Linear , Amplitude de Movimento Articular/fisiologia , Vibrissas/inervação
19.
Radiat Res ; 192(2): 121-134, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31161966

RESUMO

Radiation-induced fibrosis (RIF) is a common delayed effect of acute ionizing radiation exposure (DEARE) affecting diverse tissues including the heart, lungs, liver and skin, leading to reduced tissue function and increased morbidity. Monocytes, which may be classified into classical (CD14++, CD16-), intermediate (CD14++, CD16+) and non-classical (CD14+/low, CD16++) subtypes in humans and non-human primates (NHPs), and monocyte-derived macrophages may play an integral role in the pathogenesis of RIF. We tested the hypothesis that moderate to high levels of total-body exposure to radiation would alter monocyte polarization and produce phenotypes that could promote multi-organ fibrosis in a wellestablished NHP model of DEARE. Subjects were 16 young adult male rhesus macaques, ten of which were exposed to high-energy, 4 Gy X-ray total-body irradiation (TBI) and six that received sham irradiation (control). Total monocytes assessed by complete blood counts were 89% depleted in TBI animals by day 9 postirradiation (P < 0.05), but recovered by day 30 postirradiation and did not differ from control levels thereafter. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) and sorted into classical, intermediate and non-classical subsets using fluorescence-activated cell sorting (FACS) prior to and at 6 months post-TBI. At 6 months postirradiation, monocyte polarization shifted towards lower classical (92% → 86%) and higher intermediate (7% → 12%) and non-classical monocyte subsets (0.6% → 2%) (all P < 0.05) in TBI animals compared to baseline. No change in monocyte subsets was observed in control animals. Transcriptional profiles in classical and intermediate monocyte subsets were assessed using RNAseq. Classical monocyte gene expression did not change significantly over time or differ cross-sectionally between TBI and control groups. In contrast, significant numbers of differentially expressed genes (DEGs) were detected in intermediate monocyte comparisons between the TBI animals and all animals at baseline (304 DEGs), and in the TBI versus control animals at 6 months postirradiation (67 DEGs). Intermediate monocytes also differed between baseline and 6 months in control animals (147 DEGs). Pathway analysis was used to identify genes within significant canonical pathways, yielding 52 DEGs that were specific to irradiated intermediate monocytes. These DEGs and significant canonical pathways were associated with pro-fibrotic and anti-inflammatory signaling pathways that have been noted to induce M2 macrophage polarization. These findings support the hypothesis that TBI may alter monocyte programming and polarization towards a profibrotic phenotype, providing a novel target opportunity for therapies to inhibit or prevent RIF.


Assuntos
Monócitos/citologia , Monócitos/efeitos da radiação , Irradiação Corporal Total/efeitos adversos , Animais , Polaridade Celular/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Macaca mulatta , Masculino , Monócitos/metabolismo , Fatores de Tempo , Transcrição Genética/efeitos da radiação
20.
Nat Neurosci ; 22(7): 1057-1060, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182868

RESUMO

We report a difference between humans and macaque monkeys in the functional organization of cortical regions implicated in pitch perception. Humans but not macaques showed regions with a strong preference for harmonic sounds compared to noise, measured with both synthetic tones and macaque vocalizations. In contrast, frequency-selective tonotopic maps were similar between the two species. This species difference may be driven by the unique demands of speech and music perception in humans.


Assuntos
Córtex Auditivo/fisiologia , Nível de Percepção Sonora/fisiologia , Percepção da Fala/fisiologia , Estimulação Acústica , Adulto , Animais , Córtex Auditivo/anatomia & histologia , Mapeamento Encefálico , Feminino , Humanos , Macaca mulatta , Imagem por Ressonância Magnética , Masculino , Música , Especificidade da Espécie , Vocalização Animal
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