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2.
Emerg Microbes Infect ; 10(1): 1881-1889, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34490832

RESUMO

SARS-CoV-2 has been the causative pathogen of the pandemic of COVID-19, resulting in catastrophic health issues globally. It is important to develop human-like animal models for investigating the mechanisms that SARS-CoV-2 uses to infect humans and cause COVID-19. Several studies demonstrated that the non-human primate (NHP) is permissive for SARS-CoV-2 infection to cause typical clinical symptoms including fever, cough, breathing difficulty, and other diagnostic abnormalities such as immunopathogenesis and hyperplastic lesions in the lung. These NHP models have been used for investigating the potential infection route and host immune response to SARS-CoV-2, as well as testing vaccines and drugs. This review aims to summarize the benefits and caveats of NHP models currently available for SARS-CoV-2, and to discuss key topics including model optimization, extended application, and clinical translation.


Assuntos
COVID-19/virologia , Modelos Animais de Doenças , Primatas/virologia , SARS-CoV-2/fisiologia , Animais , Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/patologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Humanos , Primatas/imunologia , SARS-CoV-2/genética
3.
Sci Transl Med ; 13(606)2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34285130

RESUMO

Multiple safe and effective vaccines that elicit immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary to respond to the ongoing coronavirus disease 2019 (COVID-19) pandemic. Here, we developed a protein subunit vaccine composed of spike ectodomain protein (StriFK) plus a nitrogen bisphosphonate-modified zinc-aluminum hybrid adjuvant (FH002C). StriFK-FH002C generated substantially higher neutralizing antibody titers in mice, hamsters, and cynomolgus monkeys than those observed in plasma isolated from COVID-19 convalescent individuals. StriFK-FH002C also induced both TH1- and TH2-polarized helper T cell responses in mice. In hamsters, StriFK-FH002C immunization protected animals against SARS-CoV-2 challenge, as shown by the absence of virus-induced weight loss, fewer symptoms of disease, and reduced lung pathology. Vaccination of hamsters with StriFK-FH002C also reduced within-cage virus transmission to unvaccinated, cohoused hamsters. In summary, StriFK-FH002C represents an effective, protein subunit-based SARS-CoV-2 vaccine candidate.


Assuntos
COVID-19 , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , Cricetinae , Humanos , Camundongos , Subunidades Proteicas , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética
4.
Theranostics ; 11(13): 6607-6615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995679

RESUMO

SARS-CoV-2 infection, which is responsible for the current COVID-19 pandemic, can cause life-threatening pneumonia, respiratory failure and even death. Characterizing SARS-CoV-2 pathogenesis in primary human target cells and tissues is crucial for developing vaccines and therapeutics. However, given the limited access to clinical samples from COVID-19 patients, there is a pressing need for in vitro/in vivo models to investigate authentic SARS-CoV-2 infection in primary human lung cells or tissues with mature structures. The present study was designed to evaluate a humanized mouse model carrying human lung xenografts for SARS-CoV-2 infection in vivo. Methods: Human fetal lung tissue surgically grafted under the dorsal skin of SCID mice were assessed for growth and development after 8 weeks. Following SARS-CoV-2 inoculation into the differentiated lung xenografts, viral replication, cell-type tropism and histopathology of SARS-CoV-2 infection, and local cytokine/chemokine expression were determined over a 6-day period. The effect of IFN-α treatment against SARS-CoV-2 infection was tested in the lung xenografts. Results: Human lung xenografts expanded and developed mature structures closely resembling normal human lung. SARS-CoV-2 replicated and spread efficiently in the lung xenografts with the epithelial cells as the main target, caused severe lung damage, and induced a robust pro-inflammatory response. IFN-α treatment effectively inhibited SARS-CoV-2 replication in the lung xenografts. Conclusions: These data support the human lung xenograft mouse model as a useful and biological relevant tool that should facilitate studies on the pathogenesis of SARS-CoV-2 lung infection and the evaluation of potential antiviral therapies.


Assuntos
COVID-19/imunologia , Modelos Animais de Doenças , Pulmão/patologia , Mucosa Respiratória/citologia , SARS-CoV-2/imunologia , Feto Abortado , Animais , COVID-19/patologia , COVID-19/virologia , Células Cultivadas , Células Epiteliais/virologia , Xenoenxertos , Humanos , Pulmão/imunologia , Pulmão/virologia , Transplante de Pulmão , Masculino , Camundongos , Camundongos SCID , Cultura Primária de Células , SARS-CoV-2/patogenicidade , Replicação Viral
5.
Signal Transduct Target Ther ; 6(1): 136, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790236

RESUMO

Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness. To experimentally demonstrate the epidemiological results, we performed animal studies to infect male and female Syrian hamsters with SARS-CoV-2. Remarkably, high viral titer in nasal washings was detectable in male hamsters who presented symptoms of weight loss, weakness, piloerection, hunched back and abdominal respiration, as well as severe pneumonia, pulmonary edema, consolidation, and fibrosis. In contrast with the males, the female hamsters showed much lower shedding viral titers, moderate symptoms, and relatively mild lung pathogenesis. The obvious differences in the susceptibility to SARS-CoV-2 and severity of lung pathogenesis between male and female hamsters provided experimental evidence that SARS-CoV-2 infection and the severity of COVID-19 are associated with gender.


Assuntos
COVID-19 , SARS-CoV-2/metabolismo , Caracteres Sexuais , Animais , COVID-19/metabolismo , COVID-19/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Masculino , Mesocricetus
6.
Influenza Other Respir Viruses ; 15(2): 235-244, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33108707

RESUMO

BACKGROUND: Influenza infection is often measured by a fourfold antibody titer increase over an influenza season (ie seroconversion). However, this approach may fail when influenza seasons are less distinct as it does not account for transient effects from recent infections. Here, we present a method to determine seroconversion for non-paired sera, adjusting for changes in individuals' antibody titers to influenza due to the transient impact of recent exposures, varied sampling times, and laboratory processes. METHODS: We applied our method using data for five H3N2 strains collected from 942 individuals, aged 2-90 years, during the first two study visits of the Fluscape cohort study (2009-2012) in Guangzhou, China. RESULTS: After adjustment, apparent seroconversion rates for non-circulating strains decreased while we observed a 20% increase in seroconversion rates to recently circulating strains. When examining seroconversion to the most recently circulating strain (A/Brisbane/20/2007) in our study, participants aged under 18, and over 64 had the highest seroconversion rates compared to other age groups. CONCLUSIONS: Our results highlight the need for improved methods when using antibody titers as an endpoint in settings where there is no clear influenza "off" season. Methods, like those presented here, that use titers from circulating and non-circulating strains may be key.

7.
Neurol Res ; 42(11): 973-979, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32693733

RESUMO

Objectives Hematoma expansion (HE) is an important factor of unfavorable outcome in patients with intracerebral hemorrhage (ICH). Imaging markers on noncontrast computed tomography (NCCT) provide increasing value in the prediction of HE due to fast and easy-to-use advantages; however, the accuracy of NCCT-based prediction of intracerebral HE remains unclear. We aimed to investigate the predictive accuracy of NCCT markers for the evaluation of HE using a well-characterized ICH cohort. Methods We retrospectively analyzed 414 patients with spontaneous ICH, who underwent baseline CT within 6 h after symptom onset and follow-up CT within 24 h after ICH. Hematoma volumes were measured on baseline and follow-up CT images, and imaging features that predicted HE were analyzed. The test characteristics for the NCCT predictors were calculated. Results Of the 414 patients investigated, 63 presented blend sign, 45 showed black hole sign, 36 had island sign and 34 had swirl sign. In the 414 patients, 88 presented HE, the incidence was 21.26%. Of the 88 patients with HE, 22 presented blend sign, 11 showed black hole sign, 8 had swirl sign and 7 had island sign. The blend sign showed highest sensitivity (25.00%) and swirl sign showed the highest specificity (92.02%) among the four predictors. We noted excellent interobserver agreement for the identification of HE. Conclusion The four NCCT markers can predict HE with limited sensitivity, high specificity and good accuracy. This may be useful for prompt identification of patients at high risk of active bleeding, and prevention of over-treatment associated with HE. Abbreviations HE, hematoma expansion; ICH, intracerebral hemorrhage; NCCT, noncontrast computed tomography.


Assuntos
Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/epidemiologia , Hematoma/diagnóstico , Hematoma/epidemiologia , Adulto , Idoso , Biomarcadores/análise , Hemorragia Cerebral/complicações , Estudos de Coortes , Progressão da Doença , Feminino , Hematoma/etiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
8.
PLoS Pathog ; 16(7): e1008635, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32702069

RESUMO

Complex exposure histories and immune mediated interactions between influenza strains contribute to the life course of human immunity to influenza. Antibody profiles can be generated by characterizing immune responses to multiple antigenically variant strains, but how these profiles vary across individuals and determine future responses is unclear. We used hemagglutination inhibition titers from 21 H3N2 strains to construct 777 paired antibody profiles from people aged 2 to 86, and developed novel metrics to capture features of these profiles. Total antibody titer per potential influenza exposure increases in early life, then decreases in middle age. Increased titers to one or more strains were seen in 97.8% of participants during a roughly four-year interval, suggesting widespread influenza exposure. While titer changes were seen to all strains, recently circulating strains exhibited the greatest titer rise. Higher pre-existing, homologous titers at baseline reduced the risk of seroconversion to recent strains. After adjusting for homologous titer, we also found an increased frequency of seroconversion against recent strains among those with higher immunity to older previously exposed strains. Including immunity to previously exposures also improved the deviance explained by the models. Our results suggest that a comprehensive quantitative description of immunity encompassing past exposures could lead to improved correlates of risk of influenza infection.


Assuntos
Anticorpos Antivirais/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Soroconversão/fisiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Nature ; 583(7815): 282-285, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32218527

RESUMO

The ongoing outbreak of viral pneumonia in China and across the world is associated with a new coronavirus, SARS-CoV-21. This outbreak has been tentatively associated with a seafood market in Wuhan, China, where the sale of wild animals may be the source of zoonotic infection2. Although bats are probable reservoir hosts for SARS-CoV-2, the identity of any intermediate host that may have facilitated transfer to humans is unknown. Here we report the identification of SARS-CoV-2-related coronaviruses in Malayan pangolins (Manis javanica) seized in anti-smuggling operations in southern China. Metagenomic sequencing identified pangolin-associated coronaviruses that belong to two sub-lineages of SARS-CoV-2-related coronaviruses, including one that exhibits strong similarity in the receptor-binding domain to SARS-CoV-2. The discovery of multiple lineages of pangolin coronavirus and their similarity to SARS-CoV-2 suggests that pangolins should be considered as possible hosts in the emergence of new coronaviruses and should be removed from wet markets to prevent zoonotic transmission.


Assuntos
Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Eutérios/virologia , Evolução Molecular , Genoma Viral/genética , Homologia de Sequência do Ácido Nucleico , Sequência de Aminoácidos , Animais , Betacoronavirus/química , Betacoronavirus/classificação , COVID-19 , China/epidemiologia , Quirópteros/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Reservatórios de Doenças/virologia , Genômica , Humanos , Malásia , Pandemias , Filogenia , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Recombinação Genética , SARS-CoV-2 , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Zoonoses/virologia
10.
PLoS Pathog ; 16(1): e1008191, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951644

RESUMO

Avian influenza viruses (AIVs) periodically cross species barriers and infect humans. The likelihood that an AIV will evolve mammalian transmissibility depends on acquiring and selecting mutations during spillover, but data from natural infection is limited. We analyze deep sequencing data from infected humans and domestic ducks in Cambodia to examine how H5N1 viruses evolve during spillover. Overall, viral populations in both species are predominated by low-frequency (<10%) variation shaped by purifying selection and genetic drift, and half of the variants detected within-host are never detected on the H5N1 virus phylogeny. However, we do detect a subset of mutations linked to human receptor binding and replication (PB2 E627K, HA A150V, and HA Q238L) that arose in multiple, independent humans. PB2 E627K and HA A150V were also enriched along phylogenetic branches leading to human infections, suggesting that they are likely human-adaptive. Our data show that H5N1 viruses generate putative human-adapting mutations during natural spillover infection, many of which are detected at >5% frequency within-host. However, short infection times, genetic drift, and purifying selection likely restrict their ability to evolve extensively during a single infection. Applying evolutionary methods to sequence data, we reveal a detailed view of H5N1 virus adaptive potential, and develop a foundation for studying host-adaptation in other zoonotic viruses.


Assuntos
Virus da Influenza A Subtipo H5N1/isolamento & purificação , Influenza Aviária/virologia , Influenza Humana/virologia , Animais , Camboja , Patos/virologia , Evolução Molecular , Humanos , Virus da Influenza A Subtipo H5N1/classificação , Virus da Influenza A Subtipo H5N1/genética , Mutação , Filogenia , Proteínas Virais/genética
11.
J Infect ; 80(3): 310-319, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31954742

RESUMO

OBJECTIVES: The long-term dynamics of antibody responses in patients with influenza A(H7N9) virus infection are not well understood. METHODS: We conducted a longitudinal serological follow-up study in patients who were hospitalized with A(H7N9) virus infection, during 2013-2018. A(H7N9) virus-specific antibody responses were assessed by hemagglutination inhibition (HAI) and neutralization (NT) assays. A random intercept model was used to fit a curve to HAI antibody responses over time. HAI antibody responses were compared by clinical severity. RESULTS: Of 67 patients with A(H7N9) virus infection, HAI antibody titers reached 40 on average 11 days after illness onset and peaked at a titer of 290 after three months, and average titers of ≥80 and ≥40 were present until 11 months and 22 months respectively. HAI antibody responses were significantly higher in patients who experienced severe disease, including respiratory failure and acute respiratory distress syndrome, compared with patients who experienced less severe illness. CONCLUSIONS: Patients with A(H7N9) virus infection who survived severe disease mounted higher antibody responses that persisted for longer periods compared with those that experienced moderate disease. Studies of convalescent plasma treatment for A(H7N9) patients should consider collection of donor plasma from survivors of severe disease between 1 and 11 months after illness onset.


Assuntos
Subtipo H7N9 do Vírus da Influenza A , Influenza Aviária , Influenza Humana , Animais , Anticorpos Antivirais , Formação de Anticorpos , Seguimentos , Humanos , Cinética
12.
Mol Biol Evol ; 37(2): 599-603, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633786

RESUMO

Phylogenetic trees and data are often stored in incompatible and inconsistent formats. The outputs of software tools that contain trees with analysis findings are often not compatible with each other, making it hard to integrate the results of different analyses in a comparative study. The treeio package is designed to connect phylogenetic tree input and output. It supports extracting phylogenetic trees as well as the outputs of commonly used analytical software. It can link external data to phylogenies and merge tree data obtained from different sources, enabling analyses of phylogeny-associated data from different disciplines in an evolutionary context. Treeio also supports export of a phylogenetic tree with heterogeneous-associated data to a single tree file, including BEAST compatible NEXUS and jtree formats; these facilitate data sharing as well as file format conversion for downstream analysis. The treeio package is designed to work with the tidytree and ggtree packages. Tree data can be processed using the tidy interface with tidytree and visualized by ggtree. The treeio package is released within the Bioconductor and rOpenSci projects. It is available at https://www.bioconductor.org/packages/treeio/.


Assuntos
Biologia Computacional/métodos , Mineração de Dados/métodos , Internet , Filogenia , Software
13.
Influenza Other Respir Viruses ; 13(6): 610-617, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31487118

RESUMO

BACKGROUND: Avian influenza A (H7N9) remains circulating in China. For countries at risk of introduction of H7N9, such as Vietnam, early detection of H7N9 virus is essential for the early containment of the virus. Insulated isothermal reverse transcriptase PCR (iiRT-PCR) is a portable PCR system that can be deployed under field conditions to identify pathogens at the sampling site. Applying PCR at the sampling site will greatly reduce the time to obtain a diagnostic result which allows the veterinary authority to take immediate action to contain disease spreading. OBJECTIVE: To determine analytical and diagnostic sensitivity and specificity of the portable iiRT-PCR for H7N9 virus detection. METHODS: A panel of 59 virus isolates, including H7N9, avian influenza viruses of subtype H1 to H13, swine and human influenza viruses, Newcastle disease virus, and infectious bursal disease virus, were tested by H7 and N9 iiRT-PCR reagents, using probes and primers specific to H7 or N9, in comparison with laboratory-based real-time RT-PCR assays to determine analytical sensitivity and specificity. Fifty oropharyngeal samples from experimentally infected chicken and ducks with H7N9 and 50 non-infected control swabs were tested by the H7 iiRT-PCR to determine diagnostic sensitivity and specificity. RESULTS: The H7 and N9 iiRT-PCR reagents yielded comparable levels of analytical sensitivity and specificity with real-time RT-PCR for the detection of H7N9 virus. Diagnostic sensitivity and specificity of H7 iiRT-PCR were 98% and 100%, respectively. CONCLUSION: The observed high sensitivity and specificity of iiRT-PCR for H7N9 detection show its potential for early detection of H7N9 in risk-based surveillance.


Assuntos
Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Aviária/diagnóstico , Influenza Aviária/virologia , Técnicas de Diagnóstico Molecular/veterinária , Reação em Cadeia da Polimerase/veterinária , Animais , Galinhas , Patos , Subtipo H7N9 do Vírus da Influenza A/classificação , Subtipo H7N9 do Vírus da Influenza A/isolamento & purificação , Orofaringe/virologia , Testes Imediatos , Sensibilidade e Especificidade , Vietnã
14.
Vaccine ; 37(19): 2561-2568, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30955980

RESUMO

BACKGROUND: Influenza A/H7N9 viruses are undergoing antigenic drift since their emergence in 2013, and vaccination strategies are needed for pandemic preparedness. Two doses of adjuvanted monovalent inactivated influenza A/H7N9 vaccine (IIV1 A/H7N9) are needed for optimal serological responses. However, administering 2 doses in a pandemic setting might be challenging. We evaluated the immunogenicity of "boosting" with IIV1 A/H7N9 in subjects "primed" 8 years previously with IIV1 A/H7N7. METHODS: We administered 1 booster dose containing 45 mcg of IIV1 A/H7N9 hemagglutinin to 17 recipients of 2 prior doses of IIV1 A/H7N7, and to 10 influenza A/H7-naïve subjects. We tested their post-boosting sera for antibodies (Ab) against homologous influenza A/H7N9 using a hemagglutination inhibition assay; and compared their Ab titers to those in stored sera from recipients of AS03-adjuvanted IIV1 A/H7N9 against 9 strains of influenza A/H7N9 viruses. RESULTS: The percentage of subjects with Ab titers ≥40 on Days 9 and 29 post boosting, respectively, was 65% and 41% in primed subjects and 10% and 0% in unprimed subjects. The Ab titers in recipients of AS03-adjuvanted IIV1 A/H7N9 were higher than those in the prime-boost group against a panel of influenza A/H7N9 viruses, except for 2 highly pathogenic strains. CONCLUSIONS: Priming with IIV1 A/H7 results in serological responses following a delayed boost with 1 dose of unadjuvanted IIV1 A/H7N9, despite lack of antibody response after the prime. Optimizing prime-boost approaches would benefit pandemic preparedness. ClinicalTrials.gov identifier: NCT02586792.


Assuntos
Imunização Secundária , Imunogenicidade da Vacina , Vírus da Influenza A Subtipo H7N7/imunologia , Subtipo H7N9 do Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Vacinação , Fluxo de Trabalho
15.
Oncol Rep ; 41(2): 829-838, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535464

RESUMO

In cancer research, autophagy acts as a double­edged sword: it increases cell viability or induces cell apoptosis depending upon the cell context and functional status. Recent studies have shown that adenosine (Ado) has cytotoxic effects in many tumors. However, the role of autophagy in Ado­induced apoptosis is still poorly understood. In the present study, Ado­induced apoptotic death and autophagy in hepatoblastoma HepG2 cells was investigated and the relationship between autophagy and apoptosis was identified. In the present study, it was demonstrated that Ado inhibited HepG2 cell growth in a time­ and concentration­dependent manner and activated endoplasmic reticulum (ER) stress, as indicated by G0/G1 cell cycle arrest, the increased mRNA and protein levels of GRP78/BiP, PERK, ATF4, CHOP, cleaved caspase­3, cytochrome c and the loss of mitochon-drial membrane potential (ΔΨm). Ado also induced autophagic flux, revealed by the increased expression of the autophagy marker microtubule­associated protein 1 light chain 3­II (LC3­II), Beclin­1, autophagosomes, and the degradation of p62, as revealed by western blot analysis and macrophage­derived chemokine (MDC) staining. Blocking autophagy using LY294002 notably entrenched Ado­induced growth inhibition and cell apoptosis, as demonstrated with the increased expression of cytochrome c and p62, and the decreased expression of LC3­II. Conversely, the autophagy inducer rapamycin alleviated Ado­induced apoptosis and markedly increased the ΔΨm. Moreover, knockdown of AMPK with si­AMPK partially abolished Ado­induced ULK1 activation and mTOR inhibition, and thus reinforced CHOP expression and Ado­induced apoptosis. These results indicated that Ado­induced ER stress resulted in apoptosis and autophagy concurrently. The AMPK/mTOR/ULK1 signaling pathway played a protective role in the apoptotic procession. Inhibition of autophagy may effectively enhance the anticancer effect of Ado in human hepatoblastoma HepG2 cells.


Assuntos
Adenosina/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hepatoblastoma/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adenosina/uso terapêutico , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células Hep G2 , Hepatoblastoma/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/patologia , Morfolinas/farmacologia , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo
16.
Mol Biol Evol ; 35(12): 3041-3043, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30351396

RESUMO

Ggtree is a comprehensive R package for visualizing and annotating phylogenetic trees with associated data. It can also map and visualize associated external data on phylogenies with two general methods. Method 1 allows external data to be mapped on the tree structure and used as visual characteristic in tree and data visualization. Method 2 plots the data with the tree side by side using different geometric functions after reordering the data based on the tree structure. These two methods integrate data with phylogeny for further exploration and comparison in the evolutionary biology context. Ggtree is available from http://www.bioconductor.org/packages/ggtree.


Assuntos
Técnicas Genéticas , Filogenia , Software
17.
Emerg Infect Dis ; 24(6): 965-971, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29774862

RESUMO

The ferret transmission model is extensively used to assess the pandemic potential of emerging influenza viruses, yet experimental conditions and reported results vary among laboratories. Such variation can be a critical consideration when contextualizing results from independent risk-assessment studies of novel and emerging influenza viruses. To streamline interpretation of data generated in different laboratories, we provide a consensus on experimental parameters that define risk-assessment experiments of influenza virus transmissibility, including disclosure of variables known or suspected to contribute to experimental variability in this model, and advocate adoption of more standardized practices. We also discuss current limitations of the ferret transmission model and highlight continued refinements and advances to this model ongoing in laboratories. Understanding, disclosing, and standardizing the critical parameters of ferret transmission studies will improve the comparability and reproducibility of pandemic influenza risk assessment and increase the statistical power and, perhaps, accuracy of this model.


Assuntos
Furões , Influenza Humana/epidemiologia , Influenza Humana/transmissão , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/transmissão , Orthomyxoviridae/fisiologia , Animais , Modelos Animais de Doenças , Humanos , Vigilância em Saúde Pública , Medição de Risco
18.
J Infect Dis ; 217(3): 438-442, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28973317

RESUMO

Pregnancy has been associated with severe influenza, an association highlighted during the 2009 pandemic of influenza A(H1N1) virus (A[H1N1]pdm09) infection. To assess the underlying mechanism, we infected pregnant and non-pregnant ferrets with A(H1N1) pdm09 virus. A(H1N1)pdm09-infected pregnant ferrets also had higher levels of inflammatory cytokines in their pulmonary tracts. Systemically, total CD8+ T cell counts and A(H1N1)pdm09-specific B-cell responses in blood were significantly lower in pregnant ferrets. This model predicts that the poorer outcome for pregnant women during the A(H1N1)pdm09 pandemic was due to an elevated level of viral replication and to a cytokine imbalance that led to a less effective immune response.


Assuntos
Citocinas/metabolismo , Vírus da Influenza A Subtipo H1N1/imunologia , Infecções por Orthomyxoviridae/patologia , Complicações Infecciosas na Gravidez/patologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Furões , Pulmão/patologia , Pulmão/virologia , Infecções por Orthomyxoviridae/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia
19.
Proc Biol Sci ; 284(1868)2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-29212718

RESUMO

Multiple subtypes of avian influenza (AI) and novel reassortants are frequently isolated from live bird markets (LBMs). However, our understanding of the drivers of persistence of multiple AI subtypes is limited. We propose a stochastic model of AI transmission within an LBM that incorporates market size, turnover rate and the balance of direct versus environmental transmissibility. We investigate the relationship between these factors and the critical community size (CCS) for the persistence of single and multiple AI strains within an LBM. We fit different models of seeding from farms to two-strain surveillance data collected from Shantou, China. For a single strain and plausible estimates for continuous turnover rates and transmissibility, the CCS was approximately 11 800 birds, only a 4.2% increase in this estimate was needed to ensure persistence of the co-infecting strains (two strains in a single host). Precise values of CCS estimates were sensitive to changes in market turnover rate and duration of the latent period. Assuming a gradual daily sell rate of birds the estimated CCS was higher than when an instantaneous selling rate was assumed. We were able to reproduce prevalence dynamics similar to observations from a single market in China with infection seeded every 5-15 days, and a maximum non-seeding duration of 80 days. Our findings suggest that persistence of co-infections is more likely to be owing to sequential infection of single strains rather than ongoing transmission of both strains concurrently. In any given system for a fixed set of ecological and epidemiological conditions, there is an LBM size below which the risk of sustained co-circulation is low and which may suggest a clear policy opportunity to reduce the frequency of influenza co-infection in poultry.


Assuntos
Aves , Vírus da Influenza A/fisiologia , Influenza Aviária/epidemiologia , Animais , China/epidemiologia , Comércio , Influenza Aviária/virologia , Modelos Teóricos , Prevalência
20.
BMJ Open ; 7(10): e017503, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29092901

RESUMO

PURPOSE: This study was established to provide direct evidence on the incidence of laboratory-confirmed influenza virus and respiratory syncytial virus (RSV) infections in older adults in two cities in Jiangsu Province, China, and the potential impact of acute respiratory infections on frailty. PARTICIPANTS: The cohort was enrolled in Suzhou and Yancheng, two cities in Jiangsu Province in Eastern China. Between November 2015 and March 2016, we enrolled 1532 adults who were 60-89 years of age, and collected blood samples along with baseline data on demographics, general health, chronic diseases, functional status and cognitive function through face-to-face interviews using a standardised questionnaire. Participants are being followed weekly throughout the year to identify acute respiratory illnesses. We schedule home visits to ill participants to collect mid-turbinate nasal and oropharyngeal swabs for laboratory testing and detailed symptom information for the acute illness. Regular follow-up including face-to-face interviews and further blood draws will take place every 6-12 months. FINDINGS TO DATE: As of 3 September 2016, we had identified 339 qualifying acute respiratory illness events and 1463 (95%) participants remained in the study. Laboratory testing is ongoing. FUTURE PLANS: We plan to conduct laboratory testing to estimate the incidence of influenza virus and RSV infections in older adults. We plan to investigate the impact of these infections on frailty and functional status to determine the association of pre-existing immune status with protection against influenza and RSV infection in unvaccinated older adults, and to assess the exposure to avian influenza viruses in this population.


Assuntos
Influenza Humana/epidemiologia , Orthomyxoviridae , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sinciciais Respiratórios , Infecções Respiratórias/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Animais , China/epidemiologia , Feminino , Fragilidade , Humanos , Incidência , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Nariz/virologia , Orofaringe/virologia , Orthomyxoviridae/crescimento & desenvolvimento , Estudos Prospectivos , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/crescimento & desenvolvimento , Infecções Respiratórias/virologia , Inquéritos e Questionários , População Urbana
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