RESUMO
Zoonotic poxviruses such as mpox virus (MPXV) continue to threaten public health safety since the eradication of smallpox. Vaccinia virus (VACV), the prototypic poxvirus used as the vaccine strain for smallpox eradication, is the best-characterized member of the poxvirus family. VACV encodes a serine protease inhibitor 1 (SPI-1) conserved in all orthopoxviruses, which has been recognized as a host range factor for modified VACV Ankara (MVA), an approved smallpox vaccine and a promising vaccine vector. FAM111A (family with sequence similarity 111 member A), a nuclear protein that regulates host DNA replication, was shown to restrict the replication of a VACV SPI-1 deletion mutant (VACV-ΔSPI-1) in human cells. Nevertheless, the detailed antiviral mechanisms of FAM111A were unresolved. Here, we show that FAM111A is a potent restriction factor for VACV-ΔSPI-1 and MVA. Deletion of FAM111A rescued the replication of MVA and VACV-ΔSPI-1 and overexpression of FAM111A significantly reduced viral DNA replication and virus titers but did not affect viral early gene expression. The antiviral effect of FAM111A necessitated its trypsin-like protease domain and DNA-binding domain but not the PCNA-interacting motif. We further identified that FAM111A translocated into the cytoplasm upon VACV infection by degrading the nuclear pore complex via its protease activity, interacted with VACV DNA-binding protein I3, and promoted I3 degradation through autophagy. Moreover, SPI-1 from VACV, MPXV, or lumpy skin disease virus was able to antagonize FAM111A by prohibiting its nuclear export. Our findings reveal the detailed mechanism by which FAM111A inhibits VACV and provide explanations for the immune evasive function of VACV SPI-1.
Assuntos
Poxviridae , Varíola , Vacínia , Animais , Bovinos , Humanos , Vaccinia virus/genética , Inibidores de Serina Proteinase , Proteínas Virais/genética , Replicação do DNA , Especificidade de Hospedeiro , DNA Viral , Replicação Viral , Receptores ViraisRESUMO
The reoccurrence of successive waves of SARS-CoV-2 variants suggests the exploration of more vaccine alternatives is imperative. Modified vaccinia virus Ankara (MVA) is a virus vector exhibiting excellent safety as well as efficacy for vaccine development. Here, a series of recombinant MVAs (rMVAs) expressing monomerized or trimerized S proteins from different SARS-CoV-2 variants are engineered. Trimerized S expressed from rMVAs is found predominantly as trimers on the surface of infected cells. Remarkably, immunization of mice with rMVAs demonstrates that S expressed in trimer elicits higher levels of binding IgG and IgA, as well as neutralizing antibodies for matched and mismatched S proteins than S in the monomer. In addition, trimerized S expressed by rMVA induces enhanced cytotoxic T-cell responses than S in the monomer. Importantly, the rMVA vaccines expressing trimerized S exhibit superior protection against a lethal SARS-CoV-2 challenge as the immunized animals all survive without displaying any pathological conditions. This study suggests that opting for trimerized S may represent a more effective approach and highlights that the MVA platform serves as an ideal foundation to continuously advance SARS-CoV-2 vaccine development. IMPORTANCE: MVA is a promising vaccine vector and has been approved as a vaccine for smallpox and mpox. Our analyses suggested that recombinant MVA expressing S in trimer (rMVA-ST) elicited robust cellular and humoral immunity and was more effective than MVA-S-monomer. Importantly, the rMVA-ST vaccine was able to stimulate decent cross-reactive neutralization against pseudoviruses packaged using S from different sublineages, including Wuhan, Delta, and Omicron. Remarkably, mice immunized with rMVA-ST were completely protected from a lethal challenge of SARS-CoV-2 without displaying any pathological conditions. Our results demonstrated that an MVA vectored vaccine expressing trimerized S is a promising vaccine candidate for SARS-CoV-2 and the strategy might be adapted for future vaccine development for coronaviruses.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vaccinia virus , Animais , Vaccinia virus/genética , Vaccinia virus/imunologia , Camundongos , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Anticorpos Neutralizantes/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Feminino , Humanos , Camundongos Endogâmicos BALB C , Multimerização Proteica , Imunoglobulina G/imunologia , Linfócitos T Citotóxicos/imunologia , Imunoglobulina A/imunologia , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/genética , Vetores GenéticosRESUMO
The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon development have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS) by experiments using mouse and chick embryos. Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here, we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system.
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Axônios , Cerebelo , Embrião de Galinha , Animais , Camundongos , Axônios/metabolismo , Cerebelo/metabolismo , Medula Espinal/metabolismo , Neurônios/metabolismo , Proteínas do Tecido Nervoso/genética , Precursores de Proteínas/metabolismoRESUMO
Adolescent development is characterized by an improvement in cognitive abilities, such as working memory. Neurophysiological recordings in a nonhuman primate model of adolescence have revealed changes in neural activity that mirror improvement in behavior, including higher firing rate during the delay intervals of working memory tasks. The laminar distribution of these changes is unknown. By some accounts, persistent activity is more pronounced in superficial layers, so we sought to determine whether changes are most pronounced there. We therefore analyzed neurophysiological recordings from the young and adult stage of male monkeys, at different cortical depths. Superficial layers exhibited an increased baseline firing rate in the adult stage. Unexpectedly, we also detected substantial increases in delay period activity in the middle layers after adolescence, which was confirmed even after excluding penetrations near sulci. Finally, improved discriminability around the saccade period was most evident in the deeper layers. These results reveal the laminar pattern of neural activity maturation that is associated with cognitive improvement.NEW & NOTEWORTHY Structural brain changes are evident during adolescent development particularly in the cortical thickness of the prefrontal cortex, at a time when working memory ability increases markedly. The depth distribution of neurophysiological changes during adolescence is not known. Here, we show that neurophysiological changes are not confined to superficial layers, which have most often been implicated in the maintenance of working memory. Contrary to expectations, substantial changes were evident in intermediate layers of the prefrontal cortex.
Assuntos
Desenvolvimento do Adolescente , Memória de Curto Prazo , Humanos , Animais , Masculino , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Neurônios/fisiologia , Cognição/fisiologiaRESUMO
Pigs are considered as important hosts or "mixing vessels" for the generation of pandemic influenza viruses. Systematic surveillance of influenza viruses in pigs is essential for early warning and preparedness for the next potential pandemic. Here, we report on an influenza virus surveillance of pigs from 2011 to 2018 in China, and identify a recently emerged genotype 4 (G4) reassortant Eurasian avian-like (EA) H1N1 virus, which bears 2009 pandemic (pdm/09) and triple-reassortant (TR)-derived internal genes and has been predominant in swine populations since 2016. Similar to pdm/09 virus, G4 viruses bind to human-type receptors, produce much higher progeny virus in human airway epithelial cells, and show efficient infectivity and aerosol transmission in ferrets. Moreover, low antigenic cross-reactivity of human influenza vaccine strains with G4 reassortant EA H1N1 virus indicates that preexisting population immunity does not provide protection against G4 viruses. Further serological surveillance among occupational exposure population showed that 10.4% (35/338) of swine workers were positive for G4 EA H1N1 virus, especially for participants 18 y to 35 y old, who had 20.5% (9/44) seropositive rates, indicating that the predominant G4 EA H1N1 virus has acquired increased human infectivity. Such infectivity greatly enhances the opportunity for virus adaptation in humans and raises concerns for the possible generation of pandemic viruses.
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Genes Virais , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/epidemiologia , Influenza Humana/virologia , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/virologia , Doenças dos Suínos/epidemiologia , Doenças dos Suínos/virologia , Animais , China , Reações Cruzadas , Células Epiteliais/virologia , Variação Genética , Genótipo , Humanos , Vírus da Influenza A Subtipo H1N1/classificação , Influenza Humana/imunologia , Influenza Humana/transmissão , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/transmissão , Pandemias , Filogenia , Prevalência , Vírus Reordenados/genética , Estudos Soroepidemiológicos , SuínosRESUMO
Avian influenza virus (AIV) can cross species barriers to infect humans and other mammals. However, these species-cross transmissions are most often dead-end infections due to host restriction. Current research about host restriction focuses mainly on the barriers of cell membrane, nuclear envelope, and host proteins; whether microRNAs (miRNAs) play a role in host restriction is largely unknown. In this study, we used porcine alveolar macrophage (PAM) cells as a model to elucidate the role of miRNAs in host range restriction. During AIV infection, 40 dysregulation expressed miRNAs were selected in PAM cells. Among them, two Sus scrofa (ssc; swine) miRNAs, ssc-miR-221-3p and ssc-miR-222, could inhibit the infection and replication of AIV in PAM cells by directly targeting viral genome and inducing cell apoptosis via inhibiting the expression of anti-apoptotic protein HMBOX1. Avian but not swine influenza virus caused upregulated expressions of ssc-miR-221-3p and ssc-miR-222 in PAM cells. We further found that NF-κB P65 was more effectively phosphorylated upon AIV infection and that P65 functioned as a transcription activator to regulate the AIV-induced expression of miR-221-3p/222 Importantly, we found that ssc-miR-221-3p and ssc-miR-222 could also be specifically upregulated upon AIV infection in newborn pig tracheal epithelial (NPTr) cells and also exerted anti-AIV function. In summary, our study indicated that miRNAs act as a host barrier during cross-species infection of influenza A virus.IMPORTANCE The host range of an influenza A virus is determined by species-specific interactions between virus and host cell factors. Host miRNAs can regulate influenza A virus replication; however, the role of miRNAs in host species specificity is unclear. Here, we show that the induced expression of ssc-miR-221-3p and ssc-miR-222 in swine cells is modulated by NF-κB P65 phosphorylation in response to AIV infection but not swine influenza virus infection. ssc-miR-221-3p and ssc-miR-222 exerted antiviral function via targeting viral RNAs and causing apoptosis by inhibiting the expression of HMBOX1 in host cells. These findings uncover miRNAs as a host range restriction factor that limits cross-species infection of influenza A virus.
Assuntos
Vírus da Influenza A/metabolismo , Influenza Aviária/metabolismo , MicroRNAs/metabolismo , Animais , Aves , Perfilação da Expressão Gênica , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Interações Hospedeiro-Patógeno/genética , Humanos , Vírus da Influenza A/patogenicidade , Influenza Aviária/genética , Influenza Aviária/virologia , Macrófagos Alveolares/virologia , MicroRNAs/genética , Suínos , Regulação para Cima , Replicação Viral/fisiologiaRESUMO
N 6-Methyladenosine (m6A) is a dynamic mRNA modification which regulates protein expression in various posttranscriptional levels. Functional studies of m6A in nervous system have focused on its writers and erasers so far, whether and how m6A readers mediate m6A functions through recognizing and binding their target mRNA remains poorly understood. Here, we find that the expression of axon guidance receptor Robo3.1 which plays important roles in midline crossing of spinal commissural axons is regulated precisely at translational level. The m6A reader YTHDF1 binds to and positively regulates translation of m6A-modified Robo3.1 mRNA. Either mutation of m6A sites in Robo3.1 mRNA or YTHDF1 knockdown or knockout leads to dramatic reduction of Robo3.1 protein without affecting Robo3.1 mRNA level. Specific ablation of Ythdf1 in spinal commissural neurons results in pre-crossing axon guidance defects. Our findings identify a mechanism that YTHDF1-mediated translation of m6A-modified Robo3.1 mRNA controls pre-crossing axon guidance in spinal cord.
Assuntos
Adenosina/análogos & derivados , Orientação de Axônios/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA/genética , Adenosina/genética , Animais , Axônios/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Camundongos , Camundongos Knockout , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/metabolismo , Neurônios/metabolismo , Ligação Proteica/genética , Receptores de Superfície Celular , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/metabolismoRESUMO
N6-methyladenosine (m6A) is a reversible modification in mRNA and has been shown to regulate processing, translation and decay of mRNA. However, the roles of m6A modification in neuronal development are still not known. Here, we found that the m6A eraser FTO is enriched in axons and can be locally translated. Axon-specific inhibition of FTO by rhein, or compartmentalized siRNA knockdown of Fto in axons led to increases of m6A levels. GAP-43 mRNA is modified by m6A and is a substrate of FTO in axons. Loss-of-function of this non-nuclear pool of FTO resulted in increased m6A modification and decreased local translation of axonal GAP-43 mRNA, which eventually repressed axon elongation. Mutation of a predicted m6A site in GAP-43 mRNA eliminated its m6A modification and exempted regulation of its local translation by axonal FTO. This work showed an example of dynamic internal m6A demethylation of non-nuclear localized mRNA by the demethylase FTO. Regulation of m6A modification of axonal mRNA by axonal FTO might be a general mechanism to control their local translation in neuronal development.
Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Axônios/metabolismo , Proteína GAP-43/genética , Gânglios Espinais/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/antagonistas & inibidores , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Animais , Antraquinonas/farmacologia , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Proteína GAP-43/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/crescimento & desenvolvimento , Gânglios Espinais/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Neurogênese/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Técnicas de Cultura de TecidosRESUMO
Segment reassortment and base mutagenesis of influenza A viruses are the primary routes to the rapid evolution of high-fitness virus genotypes. We recently described a predominant G57 genotype of avian H9N2 viruses that caused countrywide outbreaks in chickens in China during 2010 to 2013, which led to the zoonotic emergence of H7N9 viruses. One of the key features of the G57 genotype is the replacement of the earlier A/chicken/Beijing/1/1994 (BJ/94)-like M gene with the A/quail/Hong Kong/G1/1997 (G1)-like M gene of quail origin. We report here the functional significance of the G1-like M gene in H9N2 viruses in conferring increased infection severity and infectivity in primary chicken embryonic fibroblasts and chickens. H9N2 virus housing the G1-like M gene, in place of the BJ/94-like M gene, showed an early surge in viral mRNA and viral RNA (vRNA) transcription that was associated with enhanced viral protein production and with an early elevated release of progeny virus comprising largely spherical rather than filamentous virions. Importantly, H9N2 virus with the G1-like M gene conferred extrapulmonary virus spread in chickens. Five highly represented signature amino acid residues (37A, 95K, 224N, and 242N in the M1 protein and 21G in the M2 protein) encoded by the prevalent G1-like M gene were demonstrated to be prime contributors to enhanced infectivity. Therefore, the genetic evolution of the M gene in H9N2 virus increases reproductive virus fitness, indicating its contribution to the rising virus prevalence in chickens in China.IMPORTANCE We recently described the circulation of a dominant genotype (genotype G57) of H9N2 viruses in countrywide outbreaks in chickens in China, which was responsible, through reassortment, for the emergence of H7N9 viruses that cause severe human infections. A key feature of the genotype G57 H9N2 virus is the presence of the quail-origin G1-like M gene, which had replaced the earlier BJ/94-like M gene. We found that H9N2 virus with the G1-like M gene, but not the BJ/94-like M gene, showed an early surge in progeny virus production and more severe pathology and extrapulmonary virus spread in chickens. Five highly represented amino acid residues in the M1 and M2 proteins derived from the G1-like M gene were shown to mediate enhanced virus infectivity. These observations enhance what we currently know about the roles of reassortment and mutations in virus fitness and have implications for assessing the potential of variant influenza viruses that can cause a rising prevalence in chickens.
Assuntos
Fibroblastos/virologia , Vírus da Influenza A Subtipo H9N2/fisiologia , Influenza Aviária/patologia , Vírus Reordenados/fisiologia , Proteínas da Matriz Viral/genética , Fatores de Virulência/genética , Replicação Viral , Animais , Galinhas , Análise Mutacional de DNA , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Influenza A Subtipo H9N2/patogenicidade , Vírus da Influenza A Subtipo H9N2/ultraestrutura , Influenza Aviária/virologia , Vírus Reordenados/genética , Vírion/ultraestrutura , VirulênciaRESUMO
The electromagnetic enhancement by a metallic nanowire optical antenna on metallic substrate is investigated theoretically. By considering the excitation and multiple scattering of surface plasmon polaritons in the nanogap between the antenna and the substrate, we build up an intuitive and comprehensive model that provides semianalytical expressions for the electromagnetic field in the nanogap to achieve an understanding of the mechanism of electromagnetic enhancement. Our results show that antennas with short lengths that support the lowest order of resonance can achieve a high electric-field enhancement factor over a large range of incidence angles. Two phase-matching conditions are derived from the model for predicting the antenna lengths at resonance. Excitation of symmetric or antisymmetric localized surface plasmon resonance is further explained with the model. The model also shows superior computational efficiency compared to the full-wave numerical method when scanning the antenna length, the incidence angle, or the wavelength.
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Here, we report perturbative approaches to overcome the recently reported nonconvergence of the Fourier modal method (FMM) and the coordinate transformation method (C method) caused by the field hypersingularities (also called irregular field singularities) at lossless metal-dielectric arbitrary-angle edges. For the example of triangular gratings, we replace the sharp edge with a rounded edge to remove the hypersingularities at the edge. With such profile perturbations, we observe the convergence of the C method. The converged values of the diffraction efficiency are tested by the finite element method. However, with the radius of the rounded edge approaching zero, the converged values of the diffraction efficiency cannot approach a fixed value. For the example of parallelogram gratings, we smooth the sharp lamellar boundaries with a medium having a gradually varied refractive index to remove the hypersingularities. With the decrease of the width of the perturbative medium, the converged values of the diffraction efficiency can approach a fixed value for some numerical examples but cannot for other examples. For parallelogram gratings with a period much smaller than the wavelength, we surprisingly find that the FMM tends to converge despite the existence of hypersingularities, and the converged value consists well with the theoretical value given by the effective medium theory.
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In recent years, acoustic emission (AE) sensors and AE-based techniques have been developed and tested for gearbox fault diagnosis. In general, AE-based techniques require much higher sampling rates than vibration analysis-based techniques for gearbox fault diagnosis. Therefore, it is questionable whether an AE-based technique would give a better or at least the same performance as the vibration analysis-based techniques using the same sampling rate. To answer the question, this paper presents a comparative study for gearbox tooth damage level diagnostics using AE and vibration measurements, the first known attempt to compare the gearbox fault diagnostic performance of AE- and vibration analysis-based approaches using the same sampling rate. Partial tooth cut faults are seeded in a gearbox test rig and experimentally tested in a laboratory. Results have shown that the AE-based approach has the potential to differentiate gear tooth damage levels in comparison with the vibration-based approach. While vibration signals are easily affected by mechanical resonance, the AE signals show more stable performance.
Assuntos
Acústica , Doenças Dentárias/diagnóstico , Vibração , Humanos , Doenças Dentárias/patologiaRESUMO
The ability to suppress inappropriate actions and respond rapidly to appropriate ones matures late in life, after puberty. We investigated the development of this capability in monkeys trained to look away from a lone, bright stimulus (antisaccade task). We evaluated behavioral performance and recorded neural activity in the prefrontal cortex both before and after the transition from puberty to adulthood. Compared to when young, adult monkeys processed the stimulus more rapidly, resisted more effectively the involuntary urge to look at it, and adhered to the task rule more consistently. The spatially selective visuomotor neurons in the prefrontal cortex provided neural correlates of these behavioral changes indicative of a faster transition from stimulus-driven (exogenous) to goal-driven (endogenous) control within the time course of each trial. The results reveal parallel signatures of cognitive maturation in behavior and prefrontal activity that are consistent with improvements in attentional allocation after adolescence.
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Cognitive abilities of primates, including humans, continue to improve through adolescence 1,2. While a range of changes in brain structure and connectivity have been documented 3,4, how they affect neuronal activity that ultimately determines performance of cognitive functions remains unknown. Here, we conducted a multilevel longitudinal study of monkey adolescent neurocognitive development. The developmental trajectory of neural activity in the prefrontal cortex accounted remarkably well for working memory improvements. While complex aspects of activity changed progressively during adolescence, such as the rotation of stimulus representation in multidimensional neuronal space, which has been implicated in cognitive flexibility, even simpler attributes, such as the baseline firing rate in the period preceding a stimulus appearance had predictive power over behavior. Unexpectedly, decreases in brain volume and thickness, which are widely thought to underlie cognitive changes in humans 5 did not predict well the trajectory of neural activity or cognitive performance changes. Whole brain cortical volume in particular, exhibited an increase and reached a local maximum in late adolescence, at a time of rapid behavioral improvement. Maturation of long-distance white matter tracts linking the frontal lobe with areas of the association cortex and subcortical regions best predicted changes in neuronal activity and behavior. Our results provide evidence that optimization of neural activity depending on widely distributed circuitry effects cognitive development in adolescence.
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Lumpy skin disease virus (LSDV) is a poxvirus that mainly affects cattle and can lead to symptoms such as severe reduction in milk production as well as infertility and mortality, which has resulted in dramatic economic loss in affected countries in Africa, Europe, and Asia. In this study, we successfully isolated two strains of LSDV from different geographical regions in China. Comparative genomic analyses were performed by incorporating additional LSDV whole genome sequences reported in other areas of Asia. Our analyses revealed that LSDV exhibited an 'open' pan-genome. Phylogenetic analysis unveiled distinct branches of LSDV evolution, signifying the prevalence of multiple lineages of LSDV across various regions in Asia. In addition, a reporter LSDV expressing eGFP directed by a synthetic poxvirus promoter was generated and used to evaluate the cell tropism of LSDV in various mammalian and avian cell lines. Our results demonstrated that LSDV replicated efficiently in several mammalian cell lines, including human A549 cells. In conclusion, our results underscore the necessity for strengthening LSD outbreak control measures and continuous epidemiological surveillance.
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Adolescent development is characterized by an improvement in cognitive abilities, such as working memory. Neurophysiological recordings in a non-human primate model of adolescence have revealed changes in neural activity that mirror improvement in behavior, including higher firing rate during the delay intervals of working memory tasks. The laminar distribution of these changes is unknown. By some accounts, persistent activity is more pronounced in superficial layers, so we sought to determine whether changes are most pronounced there. We therefore analyzed neurophysiological recordings from neurons recorded in the young and adult stage, at different cortical depths. Superficial layers exhibited increased baseline firing rate in the adult stage. Unexpectedly, changes in persistent activity were most pronounced in the middle layers. Finally, improved discriminability of stimulus location was most evident in the deeper layers. These results reveal the laminar pattern of neural activity maturation that is associated with cognitive improvement. NEW AND NOTEWORTHY: Structural brain changes are evident during adolescent development particularly in the cortical thickness of the prefrontal cortex, at a time when working memory ability increases markedly. The depth distribution of neurophysiological changes during adolescence is not known. Here we show that neurophysiological changes are not confined to superficial layers, which have most often been implicated in the maintenance of working memory. Contrary to expectations, greatest changes were evident in intermediate layers of the prefrontal cortex.
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Regulated cell death (RCD) is a strategy employed by host cells to defend invasions of pathogens, such as viruses and bacteria. Ferroptosis is a type of RCD characterized by excessive accumulation of iron and lipid peroxidation. While ferroptosis is primarily considered as a mechanism associated with tumorigenesis, emerging evidence begin to suggest that it may play essential role during virus infections. Recent studies illustrated that activation of ferroptosis could either induce or prohibit various types of RCDs to facilitate virus replication or evade host surveillance. More experimental evidence has demonstrated how viruses regulate ferroptosis to influence replication, transmission, and pathogenesis. This review summarizes ferroptosis-related metabolism, including iron metabolism, lipid peroxidation, and antioxidant metabolism. Furthermore, we discuss the interplay between viral infections and host ferroptosis process, with a focus on the mechanism of how viruses exploit ferroptosis for its own replication. Understanding how ferroptosis impacts virus infection can offer valuable insights into the development of effective therapeutic strategies to combat virus infections.
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Since 2014, highly pathogenic avian influenza H5N6 viruses have been responsible for outbreaks in poultry. In this study, four H5N6 virus strains were isolated from faecal samples of sick white ducks and dead chickens in Shandong in 2019. These H5N6 viruses were triple-reassortant viruses that have not been previously characterized. Their HA genes were derived from the H5 viruses and were closely related to the vaccine strain Re-11. Their NA genes all fell into the N6-like lineage and the internal gene were derived from H5N1 and H9N2 viruses. They all showed high pathogenicity in mice and caused lethal infection with high rates of transmission in chickens. Moreover, the SPF chickens inoculated with the currently used H5 (Re-11 and Re-12 strains)/H7 (H7-Re-2 strain) trivalent inactivated vaccines in China were completely protected from these four H5N6 viruses. Our study indicated the necessity of continued surveillance for H5 influenza A viruses and the importance of timely update of vaccine strains in poultry industry.
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Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A Subtipo H9N2 , Vacinas contra Influenza , Influenza Aviária , Doenças dos Roedores , Animais , Galinhas , Virus da Influenza A Subtipo H5N1/genética , Camundongos , Filogenia , Aves Domésticas , Vacinas de Produtos InativadosRESUMO
Splicing of influenza A virus (IAV) RNA is an essential process in the viral life cycle that involves the co-opting of host factors. Here, it is demonstrated that induction of host serine and arginine-rich splicing factor 5 (SRSF5) by IAV facilitated viral replication by enhancing viral M mRNA splicing. Mechanistically, SRSF5 with its RRM2 domain directly bounds M mRNA at conserved sites (M mRNA position 163, 709, and 712), and interacts with U1 small nuclear ribonucleoprotein (snRNP) to promote M mRNA splicing and M2 production. Mutations introduced to the three binding sites, without changing amino acid code, significantly attenuates virus replication and pathogenesis in vivo. Likewise, SRSF5 conditional knockout in the lung protects mice against lethal IAV challenge. Furthermore, anidulafungin, an approved antifungal drug, is identified as an inhibitor of SRSF5 that effectively blocks IAV replication in vitro and in vivo. In conclusion, SRSF5 as an activator of M mRNA splicing promotes IAV replication and is a host-derived antiviral target.
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Vírus da Influenza A , Infecções por Orthomyxoviridae , Animais , Camundongos , Processamento Alternativo , RNA Mensageiro , Replicação ViralRESUMO
The H1N1 influenza virus of swine-origin was responsible for the H1N1 pandemic in 2009 (pdm/09 H1N1), where the virus was transmitted to humans and then spread between people, and its continued circulation has resulted in it becoming a seasonal human flu virus. Since 2016, the matrix (M) gene of pdm/09 H1N1 has been involved in the reassortment of swine influenza viruses (SIVs) in China and has gradually become a dominant genotype in pigs. However, whether M gene substitution will influence the fitness of emerging SIVs remains unclear. Here, we analyzed the biological characteristics of SIVs with the M gene from Eurasian avian-like (EA) SIV or pdm/09 H1N1 in mammals and found that SIVs containing the pdm/09-M gene exhibit stronger virulence in mice, more efficient respiratory droplet transmission between ferrets, and increased transcription of viral genes in A549 cells compared with those containing EA-M. We also determined the functional significance of the pdm/09-M gene in conferring an elevated release of progeny viruses comprised of largely filamentous virions rather than spherical virions. Our study suggests that pdm/09-M plays a crucial role in the genesis of emerging SIVs in terms of the potential prevalence in the population.