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1.
Artigo em Inglês | MEDLINE | ID: mdl-34608267

RESUMO

Thalamocortical dysrhythmia (TCD) is a model characterized by abnormal resting-state thalamic oscillatory patterns where the alpha rhythm is replaced by cross-frequency coupling of low- and high-frequency rhythms. Although disrupted thalamic function is a suggested important pathophysiological mechanism underlying schizophrenia, knowledge regarding the TCD model in schizophrenia spectrum disorder (SSD) patients and individuals at clinical high risk (CHR) for psychosis is limited. A total of 169 SSD patients, 106 individuals at CHR for psychosis, and 105 healthy controls (HCs) underwent resting-state electroencephalography recordings. We performed mean global field power (MGFP) spectral analysis between 1 and 49 Hz as well as source-level theta phase-gamma amplitude coupling (TGC) analysis and compared resting-state oscillatory patterns across groups. Correlations between altered TGC values and psychotic symptom severity in the patient group were investigated. Spectral MGFP of low- and high-frequencies was larger in the SSD and CHR groups than in the HC group. The TGC of SSD patients was greater than that of HCs in the right frontal, right parietal, and left and right limbic lobes. Greater TGC in the right frontal and limbic lobes was associated with positive symptom severity in SSD patients. However, TGC in the CHR group was comparable to that in the HCs and was smaller than that in the SSD group in widespread cortical regions. The TCD pattern may be apparent after frank psychotic disorder onset in tandem with overt positive symptoms. A psychosis-risk state without overt psychotic symptoms could be characterized by abnormally increased low- and high-frequency activities with relatively preserved TGC.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34587050

RESUMO

Although we have seen a proliferation of algorithms for recommending visualizations, these algorithms are rarely compared with one another, making it difficult to ascertain which algorithm is best for a given visual analysis scenario. Though several formal frameworks have been proposed in response, we believe this issue persists because visualization recommendation algorithms are inadequately specified from an evaluation perspective. In this paper, we propose an evaluation-focused framework to contextualize and compare a broad range of visualization recommendation algorithms. We present the structure of our framework, where algorithms are specified using three components: (1) a graph representing the full space of possible visualization designs, (2) the method used to traverse the graph for potential candidates for recommendation, and (3) an oracle used to rank candidate designs. To demonstrate how our framework guides the formal comparison of algorithmic performance, we not only theoretically compare five existing representative recommendation algorithms, but also empirically compare four new algorithms generated based on our findings from the theoretical comparison. Our results show that these algorithms behave similarly in terms of user performance, highlighting the need for more rigorous formal comparisons of recommendation algorithms to further clarify their benefits in various analysis scenarios.

3.
Sci Rep ; 11(1): 18402, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526587

RESUMO

The symptoms of obsessive-compulsive disorder (OCD) are largely related to impaired executive functioning due to frontostriatal dysfunction. To better treat OCD, the development of biomarkers to bridge the gap between the symptomatic-cognitive phenotype and brain abnormalities is warranted. Therefore, we aimed to identify biomarkers of impaired organizational strategies during visual encoding processes in OCD patients by developing an eye tracking-based Rey-Osterrieth complex figure test (RCFT). In 104 OCD patients and 114 healthy controls (HCs), eye movements were recorded during memorization of the RCFT figure, and organizational scores were evaluated. Kullback-Leibler divergence (KLD) scores were calculated to evaluate the distance between a participant's eye gaze distribution and a hypothetical uniform distribution within the RCFT figure. Narrower gaze distributions within the RCFT figure, which yielded higher KLD scores, indicated that the participant was more obsessed with detail and had less organizational strategy. The OCD patients showed lower organizational scores than the HCs. Although no group differences in KLD scores were noted, KLD scores were significantly associated with organization T scores in the OCD group. The current study findings suggest that eye tracking biomarkers of visual memory encoding provide a rapidly determined index of executive functioning, such as organizational strategies, in OCD patients.

4.
Nat Commun ; 12(1): 4194, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234144

RESUMO

Photomorphogenesis, light-mediated development, is an essential feature of all terrestrial plants. While chloroplast development and brassinosteroid (BR) signaling are known players in photomorphogenesis, proteins that regulate both pathways have yet to be identified. Here we report that DE-ETIOLATION IN THE DARK AND YELLOWING IN THE LIGHT (DAY), a membrane protein containing DnaJ-like domain, plays a dual-role in photomorphogenesis by stabilizing the BR receptor, BRI1, as well as a key enzyme in chlorophyll biosynthesis, POR. DAY localizes to both the endomembrane and chloroplasts via its first transmembrane domain and chloroplast transit peptide, respectively, and interacts with BRI1 and POR in their respective subcellular compartments. Using genetic analysis, we show that DAY acts independently on BR signaling and chlorophyll biogenesis. Collectively, this work uncovers DAY as a factor that simultaneously regulates BR signaling and chloroplast development, revealing a key regulator of photomorphogenesis that acts across cell compartments.


Assuntos
Proteínas de Arabidopsis/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Membrana/metabolismo , Morfogênese/fisiologia , Proteínas Quinases/metabolismo , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Brassinosteroides/metabolismo , Clorofila/biossíntese , Cloroplastos/metabolismo , Estiolamento/fisiologia , Regulação da Expressão Gênica de Plantas/fisiologia , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/isolamento & purificação , Luz , Proteínas de Membrana/genética , Proteínas de Membrana/isolamento & purificação , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Morfogênese/efeitos da radiação , Mutação , Plantas Geneticamente Modificadas , Proteínas Quinases/genética , RNA-Seq , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Plântula/crescimento & desenvolvimento , Transdução de Sinais/fisiologia
5.
Zootaxa ; 4970(1): 131142, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34186905

RESUMO

Two new species, Diduga hastata sp. nov. and Diduga mucronata sp. nov. are described from Laos along with four newly recorded species, D. annulata Hampson, 1900, D. amoenusa Bucsek, 2012, D. allodubatolovi Bayarsaikhan, Li Bae, 2020 and D. luteogibbosa Bayarsaikhan, Li Bae, 2020. Illustrations of adults and genitalia of examined species from Laos are provided.


Assuntos
Mariposas/anatomia & histologia , Mariposas/classificação , Animais , Genitália , Laos
6.
Proc Natl Acad Sci U S A ; 118(25)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34161289

RESUMO

Receptor-like kinases (RLKs) are key cell signaling components. The rice ARBUSCULAR RECEPTOR-LIKE KINASE 1 (OsARK1) regulates the arbuscular mycorrhizal (AM) association postarbuscule development and belongs to an undefined subfamily of RLKs. Our phylogenetic analysis revealed that ARK1 has an ancient paralogue in spermatophytes, ARK2 Single ark2 and ark1/ark2 double mutants in rice showed a nonredundant AM symbiotic function for OsARK2 Global transcriptomics identified a set of genes coregulated by the two RLKs, suggesting that OsARK1 and OsARK2 orchestrate symbiosis in a common pathway. ARK lineage proteins harbor a newly identified SPARK domain in their extracellular regions, which underwent parallel losses in ARK1 and ARK2 in monocots. This protein domain has ancient origins in streptophyte algae and defines additional overlooked groups of putative cell surface receptors.

7.
Zootaxa ; 4990(3): 577-582, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34186742

RESUMO

A new species of the genus Palpita Hübner is described from Laos, which is very close to P. inusitata (Butler, 1879) found in Japan.


Assuntos
Mariposas/classificação , Animais , Laos
8.
Zootaxa ; 4915(4): zootaxa.4915.4.7, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33756555

RESUMO

The genus Agrisius Walker (1855) is reported for the first time in Cambodia, for the new species Agrisius nigripunctata sp. n. Additionally, Agrisius fuliginosus is reported for the first time in Laos, Myanmar, China, Thailand and Vietnam. Illustrations of the adult and genitalia of Agrisius nigripunctata sp. n. and A. fuliginosus Moore are presented.


Assuntos
Mariposas , Animais , Camboja
10.
Cancer Discov ; 11(6): 1542-1561, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33500244

RESUMO

Patients with acute myeloid leukemia (AML) frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA sequencing suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony-forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential. SIGNIFICANCE: Despite entering complete remission after chemotherapy, relapse occurs in many patients with AML. Thus, there is an urgent need to understand the relapse mechanism in AML and the development of targeted treatments to improve outcome. Here, we identified a senescence-like resilience phenotype through which AML cells can survive and repopulate leukemia.This article is highlighted in the In This Issue feature, p. 1307.

11.
Methods Mol Biol ; 2200: 187-210, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33175379

RESUMO

Genome-wide association studies (GWAS) have proven effective at identifying genetic variants and genes that are associated with phenotypes in humans, animals, and plants. Since most phenotypes of plant species are complex traits regulated by many genes and their functional interactions, GWAS are increasing in popularity for genetic dissections of plant phenotypes. For the reference plant, Arabidopsis thaliana, detailed information on genetic variations became available with the completion of the 1001 Genomes Project, enabling highly resolved association mapping between chromosomal loci and complex traits. Improvements have been made in the statistical analysis methods for testing the significance of genotype-to-phenotype associations, thereby substantially reducing the confounding effects of population structures. Furthermore, there have been large efforts toward post-GWAS augmentation of signals via integration with other types of information to overcome the limited statistical power of GWAS. This chapter describes the stepwise procedure of GWAS in Arabidopsis, focusing on data analysis processes including preprocessing of genotype and phenotype data, statistical analysis to identify phenotype-associated chromosomal loci, identification of phenotype-associated genes based on the phenotype-associated loci, and finally network-based augmentation of GWAS signals to identify additional candidate genes for the phenotype.


Assuntos
Arabidopsis , Estudos de Associação Genética , Variação Genética , Característica Quantitativa Herdável , Arabidopsis/genética , Arabidopsis/metabolismo , Estudo de Associação Genômica Ampla
12.
PLoS One ; 15(10): e0240829, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33104722

RESUMO

Histone post-translational modifications (PTMs) create a powerful regulatory mechanism for maintaining chromosomal integrity in cells. Histone acetylation and methylation, the most widely studied histone PTMs, act in concert with chromatin-associated proteins to control access to genetic information during transcription. Alterations in cellular histone PTMs have been linked to disease states and have crucial biomarker and therapeutic potential. Traditional bottom-up mass spectrometry of histones requires large numbers of cells, typically one million or more. However, for some cell subtype-specific studies, it is difficult or impossible to obtain such large numbers of cells and quantification of rare histone PTMs is often unachievable. An established targeted LC-MS/MS method was used to quantify the abundance of histone PTMs from cell lines and primary human specimens. Sample preparation was modified by omitting nuclear isolation and reducing the rounds of histone derivatization to improve detection of histone peptides down to 1,000 cells. In the current study, we developed and validated a quantitative LC-MS/MS approach tailored for a targeted histone assay of 75 histone peptides with as few as 10,000 cells. Furthermore, we were able to detect and quantify 61 histone peptides from just 1,000 primary human stem cells. Detection of 37 histone peptides was possible from 1,000 acute myeloid leukemia patient cells. We anticipate that this revised method can be used in many applications where achieving large cell numbers is challenging, including rare human cell populations.


Assuntos
Histonas/genética , Histonas/metabolismo , Proteômica/métodos , Acetilação , Linhagem Celular , Cromatografia Líquida/métodos , Humanos , Metilação , Peptídeos/química , Processamento de Proteína Pós-Traducional/genética , Espectrometria de Massas em Tandem/métodos
13.
Zootaxa ; 4834(3): zootaxa.4834.3.2, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-33056113

RESUMO

The genus Leucinodella Strand (1918) is reported from Laos for the first time, with a new species, Leucinodella banthaensis n. sp., and one newly recorded species, Leucinodella leucostola (Hampson, 1896). A key to Leucinodella species in Laos is provided, with illustrations of adults and genitalia.


Assuntos
Mariposas , Animais , Genitália , Laos
14.
Zootaxa ; 4838(1): zootaxa.4838.1.6, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-33056835

RESUMO

Exoasota pursatensis Ko Bae, gen. nov. sp. nov. (Lepidoptera: Pyraloidea: Crambidae) is described from Indochina (Cambodia, Thailand, Vietnam, Myanmar). The new genus Exoasota is assigned to Spilomelinae on the basis of the morphological evidence, including the tympanal organs and genitalia. In addition, we provide comparisons with genera Epiparbattia Caradja (Crambidae, Pyraustinae) and Asota Hübner (Erebidae, Aganainae). Illustrations of adults, genitalia, and tympanal characters are provided.


Assuntos
Lepidópteros , Animais , Indochina
15.
Cell ; 182(2): 297-316.e27, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32619424

RESUMO

The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.


Assuntos
Memória Imunológica/fisiologia , Linfoma Difuso de Grandes Células B/patologia , Proteínas Nucleares/genética , Células Precursoras de Linfócitos B/imunologia , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Cromatina/química , Cromatina/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Histona Desacetilases/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutagênese Sítio-Dirigida , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Correpressor 2 de Receptor Nuclear/química , Correpressor 2 de Receptor Nuclear/metabolismo , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Transcrição Genética
16.
PLoS Pathog ; 16(6): e1008611, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511263

RESUMO

Human infection with avian influenza A (H5N1) and (H7N9) viruses causes severe respiratory diseases. PB1-F2 protein is a critical virulence factor that suppresses early type I interferon response, but the mechanism of its action in relation to high pathogenicity is not well understood. Here we show that PB1-F2 protein of H7N9 virus is a particularly potent suppressor of antiviral signaling through formation of protein aggregates on mitochondria and inhibition of TRIM31-MAVS interaction, leading to prevention of K63-polyubiquitination and aggregation of MAVS. Unaggregated MAVS accumulated on fragmented mitochondria is prone to degradation by both proteasomal and lysosomal pathways. These properties are proprietary to PB1-F2 of H7N9 virus but not shared by its counterpart in WSN virus. A recombinant virus deficient of PB1-F2 of H7N9 induces more interferon ß in infected cells. Our findings reveal a subtype-specific mechanism for destabilization of MAVS and suppression of interferon response by PB1-F2 of H7N9 virus.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Subtipo H7N9 do Vírus da Influenza A/metabolismo , Influenza Humana/metabolismo , Agregação Patológica de Proteínas/metabolismo , Transdução de Sinais , Proteínas Virais/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Cães , Células HEK293 , Humanos , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/genética , Influenza Humana/patologia , Interferon beta/genética , Interferon beta/metabolismo , Células Madin Darby de Rim Canino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Agregação Patológica de Proteínas/genética , Células THP-1 , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/genética
17.
Asian Pac J Allergy Immunol ; 38(2): 78-90, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32563233

RESUMO

BACKGROUND: Elucidation of the critical immune pathways involved in allergic inflammation has identified, apart from IgE, therapeutic targets in the cytokine network suitable for intervention by biological therapies. OBJECTIVE: The drugs that target the cytokine networks pertinent to asthma and allergic diseases are reviewed and some illustrative case histories presented. The overview proposes a framework to use when deciding which monoclonal antibody (mAb) to select for treatment of severe asthma based on total IgE concentration, peripheral blood eosinophil count, induced sputum analysis and measurement of fractional exhaled nitric oxide (FENO). METHODS: Internet-based literature search including PubMed for studies on biological therapies targeting IgE and the cytokine network in allergic inflammation focusing on asthma with and without rhinosinusitis and nasal polyposis, eczema, urticaria and food allergies. Lists of pivotal trials published in the peer reviewed literature and pertaining to their own mAb products were also provided by GSK, AstraZeneca and Sanofi. Therapeutic agents licensed or in advanced stages of development (Phase 2b and 3) were selected for discussion. RESULTS: The survey identifies a number of mAbs with substantial potential for the future targeted treatment of asthma with and without rhinosinusitis and nasal polyposis, eczema, urticaria and food allergies uncontrolled by existing therapies. A pragmatic framework is proposed for selecting the optimal mAb for initial use in individual patients with severe asthma. CONCLUSIONS: Launch of these new biologicals may revolutionise the treatment of allergic diseases if employed in an endotype-specific fashion, heralding an unprecedented era of personalised medicine.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Terapia Biológica/métodos , Hipersensibilidade/tratamento farmacológico , Animais , Humanos , Medicina de Precisão
18.
Nat Commun ; 11(1): 2114, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355217

RESUMO

Most plants associate with beneficial arbuscular mycorrhizal (AM) fungi that facilitate soil nutrient acquisition. Prior to contact, partner recognition triggers reciprocal genetic remodelling to enable colonisation. The plant Dwarf14-Like (D14L) receptor conditions pre-symbiotic perception of AM fungi, and also detects the smoke constituent karrikin. D14L-dependent signalling mechanisms, underpinning AM symbiosis are unknown. Here, we present the identification of a negative regulator from rice, which operates downstream of the D14L receptor, corresponding to the homologue of the Arabidopsis thaliana Suppressor of MAX2-1 (AtSMAX1) that functions in karrikin signalling. We demonstrate that rice SMAX1 is a suppressor of AM symbiosis, negatively regulating fungal colonisation and transcription of crucial signalling components and conserved symbiosis genes. Similarly, rice SMAX1 negatively controls strigolactone biosynthesis, demonstrating an unexpected crosstalk between the strigolactone and karrikin signalling pathways. We conclude that removal of SMAX1, resulting from D14L signalling activation, de-represses essential symbiotic programmes and increases strigolactone hormone production.


Assuntos
Proteínas de Arabidopsis/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Micorrizas/fisiologia , Oryza/microbiologia , Proteínas de Plantas/fisiologia , Simbiose , Arabidopsis/genética , Arabidopsis/microbiologia , Proteínas de Arabidopsis/genética , Furanos/metabolismo , Regulação da Expressão Gênica de Plantas , Germinação , Compostos Heterocíclicos com 3 Anéis/metabolismo , Homozigoto , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lactonas/metabolismo , Família Multigênica , Oryza/genética , Filogenia , Proteínas de Plantas/genética , Raízes de Plantas/microbiologia , Piranos/metabolismo , RNA-Seq , Transdução de Sinais
19.
J Leukoc Biol ; 108(5): 1655-1663, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32386456

RESUMO

Infection with seasonal as well as highly pathogenic avian influenza A virus (IAV) causes significant morbidity and mortality worldwide. As a major virulence factor, PB1-F2 protein of IAV affects the severity of disease through multiple mechanisms including perturbation of host innate immune response. Macrophages are known to phagocytose extracellular PB1-F2 protein aggregate, leading to hyperactivation of NLRP3 inflammasome and excessive production of IL-1ß and IL-18. On the other hand, when expressed intracellularly PB1-F2 suppresses NLRP3 inflammasome maturation. How extracellular and intracellular PB1-F2 orchestrates to drive viral pathogenesis remains unclear. In this study, we demonstrated the suppression of NLRP3 inflammasome activation and IL-1ß secretion by PB1-F2 of highly pathogenic influenza A (H7N9) virus in infected human monocyte-derived macrophages. Mechanistically, H7N9 PB1-F2 selectively mitigated RNA-induced NLRP3 inflammasome activation by inhibiting the interaction between NLRP3 and MAVS. Intracellular PB1-F2 of H7N9 virus did not affect extracellular PB1-F2-induced NLRP3 inflammasome maturation. In contrast, PB1-F2 of WSN laboratory strain of human IAV effectively suppressed IL-1ß processing and secretion induced by various stimuli including NLRP3, AIM2, and pro-IL-1ß. This subtype-specific effect of PB1-F2 on inflammasome activation correlates with the induction of a proinflammatory cytokine storm by H7N9 but not WSN virus. Our findings on selective suppression of MAVS-dependent activation of NLRP3 inflammasome by H7N9 PB1-F2 have implications in viral pathogenesis and antiviral development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Inflamassomos/imunologia , Subtipo H7N9 do Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , RNA Viral/imunologia , Proteínas Virais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Células HEK293 , Humanos , Inflamassomos/genética , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/genética , Influenza Humana/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas Virais/genética
20.
J Leukoc Biol ; 107(5): 763-771, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32323899

RESUMO

Influenza A virus (IAV) causes not only seasonal respiratory illness, but also outbreaks of more severe disease and pandemics when novel strains emerge as a result of reassortment or interspecies transmission. PB1-F2 is an IAV protein expressed from the second open reading frame of PB1 gene. Small as it is, PB1-F2 is a critical virulence factor. Multiple key amino acid residues and motifs of PB1-F2 have been shown to influence the virulence of IAV in a strain- and host-specific manner, plausibly through the induction of apoptotic cell death, modulation of type I IFN response, activation of inflammasome, and facilitation of secondary bacterial infection. However, the exact role of PB1-F2 in IAV pathogenesis remains unexplained. Through reanalysis of the current literature, we redefine PB1-F2 as an ambivalent innate immune modulator that determines IAV infection outcome through induction of immune cell death, differential modulation of early- and late-type I IFN response, and promotion of pathogenic inflammation. PB1-F2 functions both intracellularly and extracellularly. Further investigations of the mechanistic details of PB1-F2 action will shed new light on immunopathogenesis of IAV infection.


Assuntos
Imunidade Inata/imunologia , Vírus da Influenza A/patogenicidade , Influenza Humana/imunologia , Proteínas Virais/imunologia , Fatores de Virulência/imunologia , Humanos , Virulência/imunologia
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