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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3007-3010, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018638

RESUMO

Brain-machine interfaces (BMIs) allow individuals to communicate with computers using neural signals, and Kalman Filter (KF) are prevailingly used to decode movement directions from these neural signals. In this paper, we implemented a multi-layer long short-term memory (LSTM)based artificial neural network (ANN) for decoding BMI neural signals. We collected motor cortical neural signals from a nonhuman primate (NHP), implanted with microelectrode array (MEA) while performing a directional joystick task. Next, we compared the LSTM model in decoding the joystick trajectories from the neural signals against the prevailing KF model. The results showed that the LSTM model yielded significantly improved decoding accuracy measured by mean correlation coefficient (0.84, p < 10-7) than the KF model (0.72). In addition, using a principal component analysis (PCA)-based dimensionality reduction technique yielded slightly deteriorated accuracies for both the LSTM (0.80) and KF (0.70) models, but greatly reduced the computational complexity. The results showed that the LSTM decoding model holds promise to improve decoding in BMIs for paralyzed humans.


Assuntos
Interfaces Cérebro-Computador , Redes Neurais de Computação , Animais , Humanos , Macaca mulatta , Microeletrodos , Movimento
2.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3046-3049, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018647

RESUMO

In the design of brain-machine interface (BMI), as the number of electrodes used to collect neural spike signals declines slowly, it is important to be able to decode with fewer units. We tried to train a monkey to control a cursor to perform a two-dimensional (2D) center-out task smoothly with spiking activities only from two units (direct units). At the same time, we studied how the direct units did change their tuning to the preferred direction during BMI training and tried to explore the underlying mechanism of how the monkey learned to control the cursor with their neural signals. In this study, we observed that both direct units slowly changed their preferred directions during BMI learning. Although the initial angles between the preferred directions of 3 pairs units are different, the angle between their preferred directions approached 90 degrees at the end of the training. Our results imply that BMI learning made the two units independent of each other. To our knowledge, it is the first time to demonstrate that only two units could be used to control a 2D cursor movements. Meanwhile, orthogonalizing the activities of two units driven by BMI learning in this study implies that the plasticity of the motor cortex is capable of providing an efficient strategy for motor control.


Assuntos
Interfaces Cérebro-Computador , Córtex Motor , Animais , Macaca mulatta , Movimento , Neurônios
3.
Nat Commun ; 11(1): 4639, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934238

RESUMO

The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimologia , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Histona Desacetilases/metabolismo , Longevidade , Mitocôndrias/enzimologia , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Histona Desacetilases/genética , Macaca mulatta , Estresse Fisiológico , Resposta a Proteínas não Dobradas
4.
PLoS Pathog ; 16(8): e1008753, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866207

RESUMO

The induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several human-derived broadly neutralizing antibodies.


Assuntos
Vacinas contra a AIDS/imunologia , Mapeamento de Epitopos , Epitopos/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp41 do Envelope de HIV/imunologia , HIV-1/imunologia , Vacinas contra a AIDS/genética , Animais , Anticorpos Monoclonais Murinos/imunologia , Epitopos/genética , Anticorpos Anti-HIV/genética , Proteína gp41 do Envelope de HIV/genética , HIV-1/genética , Macaca mulatta , Multimerização Proteica/genética , Multimerização Proteica/imunologia
5.
Nat Commun ; 11(1): 4400, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879306

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmitted through the respiratory route, but potential extra-respiratory routes of SARS-CoV-2 transmission remain uncertain. Here we inoculated five rhesus macaques with 1 × 106 TCID50 of SARS-CoV-2 conjunctivally (CJ), intratracheally (IT), and intragastrically (IG). Nasal and throat swabs collected from CJ and IT had detectable viral RNA at 1-7 days post-inoculation (dpi). Viral RNA was detected in anal swabs from only the IT group at 1-7 dpi. Viral RNA was undetectable in tested swabs and tissues after intragastric inoculation. The CJ infected animal had a higher viral load in the nasolacrimal system than the IT infected animal but also showed mild interstitial pneumonia, suggesting distinct virus distributions. This study shows that infection via the conjunctival route is possible in non-human primates; further studies are necessary to compare the relative risk and pathogenesis of infection through these different routes in more detail.


Assuntos
Betacoronavirus/fisiologia , Túnica Conjuntiva/virologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Pneumonia Viral/virologia , Animais , Anticorpos Antivirais , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Intestino Grosso/virologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino , Cavidade Nasal/virologia , Pandemias , Pneumonia Viral/patologia , RNA Viral/análise , RNA Viral/genética , Traqueia/virologia , Carga Viral , Replicação Viral
6.
PLoS Pathog ; 16(9): e1008764, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32881968

RESUMO

To augment HIV-1 pox-protein vaccine immunogenicity using a next generation adjuvant, a prime-boost strategy of recombinant modified vaccinia virus Ankara and multimeric Env gp145 was evaluated in macaques with either aluminum (alum) or a novel liposomal monophosphoryl lipid A (MPLA) formulation adsorbed to alum, ALFA. Binding antibody responses were robust and comparable between arms, while antibody-dependent neutrophil and monocyte phagocytotic responses were greatly enhanced by ALFA. Per-exposure vaccine efficacy against heterologous tier 2 SHIV mucosal challenge was 90% in ALFA-adjuvanted males (P = 0.002), while alum conferred no protection. Half of the ALFA-adjuvanted males remained uninfected after the full challenge series, which spanned seven months after the last vaccination. Antibody-dependent monocyte and neutrophil phagocytic responses both strongly correlated with protection. Significant sex differences in infection risk were observed, with much lower infection rates in females than males. In humans, MPLA-liposome-alum adjuvanted gp120 also increased HIV-1-specific phagocytic responses relative to alum. Thus, next-generation liposome-based adjuvants can drive vaccine elicited antibody effector activity towards potent phagocytic responses in both macaques and humans and these responses correlate with protection. Future protein vaccination strategies aiming to improve functional humoral responses may benefit from such adjuvants.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Vacinas contra a SAIDS/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Adolescente , Adulto , Animais , Anticorpos Neutralizantes/imunologia , Método Duplo-Cego , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Humanos , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/imunologia , Adulto Jovem
7.
Virology ; 550: 61-69, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32882638

RESUMO

The world is in the midst of a pandemic caused by a novel coronavirus and is desperately searching for possible treatments. The antiviral remdesivir has shown some effectiveness against SARS-CoV-2 in vitro and in a recent animal study. We use data from a study of remdesivir in rhesus macaques to fit a viral kinetics model in an effort to determine the most appropriate mathematical descripton of the effect of remdesivir. We find statistically significant differences in the viral decay rate and use this to inform a possible mathematical formulation of the effect of remdesivir. Unfortunately, this model formulation suggests that the application of remdesivir will lengthen SARS-CoV-2 infections, putting into question its potential clinical benefit.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Modelos Estatísticos , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/farmacocinética , Alanina/sangue , Alanina/farmacocinética , Animais , Antivirais/sangue , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/patogenicidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Esquema de Medicação , Humanos , Inflamação , Macaca mulatta , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia , Carga Viral , Replicação Viral
8.
PLoS One ; 15(9): e0236430, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956357

RESUMO

Rhesus macaques represent an important species for translational and pre-clinical research studies across a multitude of disease and injury models, including aging. Ketamine anesthesia is used in humans and non-human primates but may be associated with adverse effects, including neuromuscular reactions. The effects of aging on ketamine adverse effects is not well characterized. Urodynamic recordings and electromyography (EMG) studies were performed in aged (>20 years old) and adult (3.9-14.9 years old) female rhesus macaques under an equal and light plane of sedation by constant rate infusion (CRI) of ketamine. A total of 4 of 41 adult subjects (9.7%) showed clinical signs of ketamine-induced abnormal neuromuscular reactivity, whereas a larger portion of 14 of 26 aged subjects showed similar ketamine-induced neuromuscular reactivity (53.8%; P< 0.001). The ketamine CRI rate was 19.8±0.9 mg/kg/h in adults and lower in aged subjects at 16.5±1.4 mg/kg/h (P<0.05). The ketamine CRI rate was negatively correlated with age (r = -0.30, P<0.05, n = 64). The incidence of ketamine reactivity or CRI rate was not different between aged pre-and post-menopausal females. EMG recordings during neuromuscular reactivity showed coordinated activation of multiple muscles, suggesting a central nervous system (CNS) mechanism for ketamine-associated neuromuscular reactivity. The incidence of ketamine-induced neuromuscular reactivity is age related but not affected by the estrous cycle in female rhesus macaques. A coordinated activation of multiple muscles, innervated by different peripheral nerves, suggests that ketamine-induced neuromuscular reactivity originates in the CNS.


Assuntos
Envelhecimento , Anestésicos Dissociativos/efeitos adversos , Ketamina/efeitos adversos , Macaca mulatta/fisiologia , Músculos/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Animais , Eletromiografia , Feminino , Músculos/inervação , Músculos/fisiologia
9.
PLoS One ; 15(9): e0237618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877413

RESUMO

Hepatitis E virus (HEV) genotype 1 (gt1) and gt3 infections have distinct epidemiologic characteristics and genotype-specific molecular mechanisms of pathogenesis are not well characterized. Previously, we showed differences in immune response-related gene expression profiles of HEV gt1 and gt3 infections using qPCR. We hypothesize that HEV gt1 and gt3 infections induce transcriptome modifications contributing to disease pathogenesis. RNAseq analysis was performed using liver biopsy samples of naïve (baseline), HEV gt1, or gt3-infected rhesus macaques, and nine anti-HEV positive rhesus macaques re-inoculated with HEV gt1. All 10 primary HEV gt1/gt3 infected animals exhibited the typical course of acute viral hepatitis and cleared the infection between 27 to 67 days after inoculation. Viremic stages of HEV infection were defined as early, peak, and decline based on HEV RNA titers in daily stool specimens. During early, peak, and decline phases of infection, HEV gt1 induced 415, 417, and 1769 differentially expressed genes, respectively, and 310, 678, and 388 genes were differentially expressed by HEV gt3, respectively (fold change ≥ 2.0, p-value ≤ 0.05). In the HEV gt1 infection, genes related to metabolic pathways were differentially expressed during the three phases of infection. In contrast, oxidative reduction (early phase), immune responses (peak phase), and T cell cytokine production (decline phase) were found to be regulated during HEV gt3 infection. In addition, FoxO and MAPK signaling pathways were differentially regulated in re-infected and protected animals against HEV gt1 reinfection, respectively. Significant differences of hepatic gene regulation exist between HEV gt1 and gt3 infections. These findings reveal a new link between molecular pathogenesis and epidemiological characteristics seen in HEV gt1 and gt3 infections.


Assuntos
Perfilação da Expressão Gênica , Vírus da Hepatite E/genética , Hepatite E/veterinária , Macaca mulatta/virologia , Animais , Biópsia , Ontologia Genética , Genótipo , Fígado/patologia , Análise de Sequência de RNA
10.
Nat Commun ; 11(1): 4560, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917899

RESUMO

The rhesus macaque is an important model species in several branches of science, including neuroscience, psychology, ethology, and medicine. The utility of the macaque model would be greatly enhanced by the ability to precisely measure behavior in freely moving conditions. Existing approaches do not provide sufficient tracking. Here, we describe OpenMonkeyStudio, a deep learning-based markerless motion capture system for estimating 3D pose in freely moving macaques in large unconstrained environments. Our system makes use of 62 machine vision cameras that encircle an open 2.45 m × 2.45 m × 2.75 m enclosure. The resulting multiview image streams allow for data augmentation via 3D-reconstruction of annotated images to train a robust view-invariant deep neural network. This view invariance represents an important advance over previous markerless 2D tracking approaches, and allows fully automatic pose inference on unconstrained natural motion. We show that OpenMonkeyStudio can be used to accurately recognize actions and track social interactions.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Macaca mulatta/fisiologia , Movimento (Física) , Algoritmos , Animais , Fenômenos Biomecânicos , Aprendizado Profundo , Masculino , Modelos Animais , Movimento , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Redes Neurais de Computação
11.
PLoS One ; 15(9): e0238614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936826

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated with severe respiratory illness emerged in Wuhan, China, in late 2019. The virus has been able to spread promptly across all continents in the world. The current pandemic has posed a great threat to public health concern and safety. Currently, there are no specific treatments or licensed vaccines available for COVID-19. We isolated SARS-CoV-2 from the nasopharyngeal sample of a patient in Turkey with confirmed COVID-19. We determined that the Vero E6 and MA-104 cell lines are suitable for supporting SARS-CoV-2 that supports viral replication, development of cytopathic effect (CPE) and subsequent cell death. Phylogenetic analyses of the whole genome sequences showed that the hCoV-19/Turkey/ERAGEM-001/2020 strain clustered with the strains primarily from Australia, Canada, England, Iran and Kuwait and that the cases in the nearby clusters were reported to have travel history to Iran and to share the common unique nucleotide substitutions.


Assuntos
Betacoronavirus/isolamento & purificação , Pandemias , Cultura de Vírus/métodos , Animais , Austrália , Betacoronavirus/genética , Betacoronavirus/fisiologia , Canadá , Linhagem Celular , Chlorocebus aethiops , Busca de Comunicante , Infecções por Coronavirus , Efeito Citopatogênico Viral , DNA Complementar/genética , DNA Viral/genética , Inglaterra , Genoma Viral , Células HeLa , Humanos , Irã (Geográfico) , Kuweit , Macaca mulatta , Nasofaringe/virologia , Filogenia , Pneumonia Viral , Análise de Sequência de DNA , Viagem , Turquia/epidemiologia , Células Vero , Replicação Viral
12.
Nat Commun ; 11(1): 4669, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938940

RESUMO

The prefrontal cortex and striatum form a recurrent network whose spiking activity encodes multiple types of learning-relevant information. This spike-encoded information is evident in average firing rates, but finer temporal coding might allow multiplexing and enhanced readout across the connected network. We tested this hypothesis in the fronto-striatal network of nonhuman primates during reversal learning of feature values. We found that populations of neurons encoding choice outcomes, outcome prediction errors, and outcome history in their firing rates also carry significant information in their phase-of-firing at a 10-25 Hz band-limited beta frequency at which they synchronize across lateral prefrontal cortex, anterior cingulate cortex and anterior striatum when outcomes were processed. The phase-of-firing code exceeds information that can be obtained from firing rates alone and is evident for inter-areal connections between anterior cingulate cortex, lateral prefrontal cortex and anterior striatum. For the majority of connections, the phase-of-firing information gain is maximal at phases of the beta cycle that were offset from the preferred spiking phase of neurons. Taken together, these findings document enhanced information of three important learning variables at specific phases of firing in the beta cycle at an inter-areally shared beta oscillation frequency during goal-directed behavior.


Assuntos
Corpo Estriado/fisiologia , Giro do Cíngulo/fisiologia , Aprendizagem/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Análise por Conglomerados , Corpo Estriado/citologia , Sincronização de Fases em Eletroencefalografia , Eletrofisiologia/métodos , Eletrofisiologia/estatística & dados numéricos , Giro do Cíngulo/citologia , Macaca mulatta , Masculino , Rede Nervosa , Córtex Pré-Frontal/citologia , Recompensa
13.
Nat Commun ; 11(1): 4207, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826924

RESUMO

The rapid spread of coronavirus SARS-CoV-2 greatly threatens global public health but no prophylactic vaccine is available. Here, we report the generation of a replication-incompetent recombinant serotype 5 adenovirus, Ad5-S-nb2, carrying a codon-optimized gene encoding Spike protein (S). In mice and rhesus macaques, intramuscular injection with Ad5-S-nb2 elicits systemic S-specific antibody and cell-mediated immune (CMI) responses. Intranasal inoculation elicits both systemic and pulmonary antibody responses but weaker CMI response. At 30 days after a single vaccination with Ad5-S-nb2 either intramuscularly or intranasally, macaques are protected against SARS-CoV-2 challenge. A subsequent challenge reveals that macaques vaccinated with a 10-fold lower vaccine dosage (1 × 1010 viral particles) are also protected, demonstrating the effectiveness of Ad5-S-nb2 and the possibility of offering more vaccine dosages within a shorter timeframe. Thus, Ad5-S-nb2 is a promising candidate vaccine and warrants further clinical evaluation.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/administração & dosagem , Adenoviridae/genética , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Infecções por Coronavirus/imunologia , Relação Dose-Resposta Imunológica , Feminino , Células HEK293 , Humanos , Imunidade Celular , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Viral/imunologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas/administração & dosagem
14.
Proc Natl Acad Sci U S A ; 117(33): 20274-20283, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747574

RESUMO

Episodic memory is believed to be intimately related to our experience of the passage of time. Indeed, neurons in the hippocampus and other brain regions critical to episodic memory code for the passage of time at a range of timescales. The origin of this temporal signal, however, remains unclear. Here, we examined temporal responses in the entorhinal cortex of macaque monkeys as they viewed complex images. Many neurons in the entorhinal cortex were responsive to image onset, showing large deviations from baseline firing shortly after image onset but relaxing back to baseline at different rates. This range of relaxation rates allowed for the time since image onset to be decoded on the scale of seconds. Further, these neurons carried information about image content, suggesting that neurons in the entorhinal cortex carry information about not only when an event took place but also, the identity of that event. Taken together, these findings suggest that the primate entorhinal cortex uses a spectrum of time constants to construct a temporal record of the past in support of episodic memory.


Assuntos
Córtex Entorrinal/fisiologia , Memória Episódica , Animais , Comportamento Animal , Macaca mulatta , Masculino , Neurônios/fisiologia , Fatores de Tempo
15.
Cell ; 182(3): 713-721.e9, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32778225

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health. The development of a vaccine is urgently needed for the prevention and control of COVID-19. Here, we report the pilot-scale production of an inactivated SARS-CoV-2 vaccine candidate (BBIBP-CorV) that induces high levels of neutralizing antibodies titers in mice, rats, guinea pigs, rabbits, and nonhuman primates (cynomolgus monkeys and rhesus macaques) to provide protection against SARS-CoV-2. Two-dose immunizations using 2 µg/dose of BBIBP-CorV provided highly efficient protection against SARS-CoV-2 intratracheal challenge in rhesus macaques, without detectable antibody-dependent enhancement of infection. In addition, BBIBP-CorV exhibits efficient productivity and good genetic stability for vaccine manufacture. These results support the further evaluation of BBIBP-CorV in a clinical trial.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Avaliação Pré-Clínica de Medicamentos/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas de Produtos Inativados/uso terapêutico , Vacinas Virais/uso terapêutico , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/genética , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Feminino , Cobaias , Imunogenicidade da Vacina , Macaca fascicularis , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Filogenia , Pneumonia Viral/virologia , Coelhos , Ratos , Ratos Wistar , Vacinas de Produtos Inativados/efeitos adversos , Células Vero , Vacinas Virais/efeitos adversos
16.
PLoS Comput Biol ; 16(8): e1008064, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817614

RESUMO

Antiretroviral therapy (ART) for HIV-1 infection is life-long. Stopping therapy typically leads to the reignition of infection and progressive disease. In a major breakthrough, recent studies have shown that early initiation of ART can lead to sustained post-treatment control of viremia, raising hopes of long-term HIV-1 remission. ART, however, elicits post-treatment control in a small fraction of individuals treated. Strikingly, passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 early in infection was found recently to elicit long-term control in a majority of SHIV-infected macaques, suggesting that HIV-1 remission may be more widely achievable. The mechanisms underlying the control elicited by bNAb therapy, however, remain unclear. Untreated infection typically leads to progressive disease. We hypothesized that viremic control represents an alternative but rarely realized outcome of the infection and that early bNAb therapy triggers a dynamical switch to this outcome. To test this hypothesis, we constructed a model of viral dynamics with bNAb therapy and applied it to analyse clinical data. The model fit quantitatively the complex longitudinal viral load data from macaques that achieved lasting control. The model predicted, consistently with our hypothesis, that the underlying system exhibited bistability, indicating two potential outcomes of infection. The first had high viremia, weak cytotoxic effector responses, and high effector exhaustion, marking progressive disease. The second had low viremia, strong effector responses, and low effector exhaustion, indicating lasting viremic control. Further, model predictions suggest that early bNAb therapy elicited lasting control via pleiotropic effects. bNAb therapy lowers viremia, which would also limit immune exhaustion. Simultaneously, it can improve effector stimulation via cross-presentation. Consequently, viremia may resurge post-therapy, but would encounter a primed effector population and eventually get controlled. ART suppresses viremia but does not enhance effector stimulation, explaining its limited ability to elicit post-treatment control relative to bNAb therapy.


Assuntos
Anticorpos Amplamente Neutralizantes/imunologia , Infecções por HIV/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Animais , Infecções por HIV/virologia , Humanos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Carga Viral , Viremia/imunologia
17.
Zool Res ; 41(5): 503-516, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32772513

RESUMO

As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques ( Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b + and CD8 + cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b + cells, and persistent infiltration of CD8 + cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.


Assuntos
Envelhecimento/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Macaca mulatta/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Fatores Etários , Envelhecimento/metabolismo , Animais , Betacoronavirus/fisiologia , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/veterinária , Inflamação/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta/virologia , Doenças dos Macacos/imunologia , Doenças dos Macacos/virologia , Pandemias/veterinária , Pneumonia Viral/veterinária , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/veterinária , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Carga Viral/imunologia , Carga Viral/veterinária , Replicação Viral/imunologia
18.
PLoS One ; 15(8): e0236285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841250

RESUMO

Characterizing meiotic recombination rates across the genomes of nonhuman primates is important for understanding the genetics of primate populations, performing genetic analyses of phenotypic variation and reconstructing the evolution of human recombination. Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primates in biomedical research. We constructed a high-resolution genetic map of the rhesus genome based on whole genome sequence data from Indian-origin rhesus macaques. The genetic markers used were approximately 18 million SNPs, with marker density 6.93 per kb across the autosomes. We report that the genome-wide recombination rate in rhesus macaques is significantly lower than rates observed in apes or humans, while the distribution of recombination across the macaque genome is more uniform. These observations provide new comparative information regarding the evolution of recombination in primates.


Assuntos
Evolução Molecular , Macaca mulatta/genética , Meiose/genética , Recombinação Genética , Animais , Mapeamento Cromossômico , Marcadores Genéticos , Variação Genética , Genoma , Humanos , Polimorfismo de Nucleotídeo Único , Especificidade da Espécie , Sequenciamento Completo do Genoma
19.
Math Biosci ; 328: 108438, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32771304

RESUMO

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading and causing the global coronavirus pandemic. The viral dynamics of SARS-CoV-2 infection have not been quantitatively investigated. In this paper, we use mathematical models to study the pathogenic features of SARS-CoV-2 infection by examining the interaction between the virus, cells and immune responses. Models are fit to the data of SARS-CoV-2 infection in patients and non-human primates. Data fitting and numerical simulation show that viral dynamics of SARS-CoV-2 infection have a few distinct stages. In the initial stage, viral load increases rapidly and reaches the peak, followed by a plateau phase possibly generated by lymphocytes as a secondary target of infection. In the last stage, viral load declines due to the emergence of adaptive immune responses. When the initiation of seroconversion is late or slow, the model predicts viral rebound and prolonged viral persistence, consistent with the observation in non-human primates. Using the model we also evaluate the effect of several potential therapeutic interventions for SARS-CoV-2 infection. Model simulation shows that anti-inflammatory treatments or antiviral drugs combined with interferon are effective in reducing the duration of the viral plateau phase and diminishing the time to recovery. These results provide insights for understanding the infection dynamics and might help develop treatment strategies against COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/virologia , Modelos Biológicos , Pneumonia Viral/virologia , Imunidade Adaptativa , Animais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Macaca mulatta , Conceitos Matemáticos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , RNA Viral/análise , RNA Viral/genética , Carga Viral
20.
Nat Commun ; 11(1): 3886, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753603

RESUMO

The ability to recognize written letter strings is foundational to human reading, but the underlying neuronal mechanisms remain largely unknown. Recent behavioral research in baboons suggests that non-human primates may provide an opportunity to investigate this question. We recorded the activity of hundreds of neurons in V4 and the inferior temporal cortex (IT) while naïve macaque monkeys passively viewed images of letters, English words and non-word strings, and tested the capacity of those neuronal representations to support a battery of orthographic processing tasks. We found that simple linear read-outs of IT (but not V4) population responses achieved high performance on all tested tasks, even matching the performance and error patterns of baboons on word classification. These results show that the IT cortex of untrained primates can serve as a precursor of orthographic processing, suggesting that the acquisition of reading in humans relies on the recycling of a brain network evolved for other visual functions.


Assuntos
Evolução Biológica , Macaca mulatta/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Lobo Temporal/fisiologia , Animais , Mapeamento Encefálico , Tomada de Decisões , Imagem por Ressonância Magnética , Masculino , Estimulação Luminosa/métodos , Leitura , Lobo Temporal/diagnóstico por imagem
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