H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are prote...H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are protective and allow mass administration.Of note,these vaccines elicit undetectable H7N9-specific hemagglutination-inhibition(HI)but high IgG antibodies in chickens.However,the molecular basis and protective mechanism underlying this particular antibody immunity remain unclear.Herein,immunization with an NDV_(vec)H7N9 induced low anti-H7N9 HI and virus neutralization titers but high levels of hemagglutinin(HA)-binding IgG antibodies in chickens.Three residues(S150,G151 and S152)in HA of H7N9 virus were identified as the dominant epitopes recognized by the NDV_(vec)H7N9 immune serum.Passively transferred NDV_(vec)H7N9 immune serum conferred complete protection against H7N9 virus infection in chickens.The NDV_(vec)H7N9 immune serum can mediate a potent lysis of HA-expressing and H7N9 virus-infected cells and significantly suppress H7N9 virus infectivity.These activities of the serum were significantly impaired after heat-inactivation or treatment with complement inhibitor,suggesting the engagement of the complement system.Moreover,mutations in the 150-SGS-152 sites in HA resulted in significant reductions in cell lysis and virus neutralization mediated by the NDV_(vec)H7N9 immune serum,indicating the requirement of antibody-antigen binding for complement activity.Therefore,antibodies induced by the NDV_(vec)H7N9 can activate antibody-dependent complement-mediated lysis of H7N9 virus-infected cells and complement-mediated neutralization of H7N9 virus.Our findings unveiled a novel role of the complement in protection conferred by the NDV_(vec)H7N9,highlighting a potential benefit of engaging the complement system in H7N9 vaccine design.展开更多
Epilepsy is one of the most common neurological diseases worldwide with a high prevalence and unknown pathogenesis.Further,its control is challenging.It is generally accepted that an imbalance between the excitatory a...Epilepsy is one of the most common neurological diseases worldwide with a high prevalence and unknown pathogenesis.Further,its control is challenging.It is generally accepted that an imbalance between the excitatory and inhibitory properties of the central nervous system(CNS)leads to a large number of abnormally synchronized neuronal discharges in the brain.Transient receptor potential vanilloid protein type 1(TRPV1)is a non-selective cation channel that contributes to the regulation of the nervous system and influences the excitability of the nervous system.This includes the release of neurotransmitters,action potential generation due to alterations in ion channels,synaptic transmission,and the changes in glial cells.There is abundant evidence that TRPV1 is widely expressed in the central nervous system(including microglia)and is involved in the development of epilepsy through neuroinflammation.In conclusion,microglial TRPV1 participates in neuroinflammatory reactions and functions as a potential proinflammatory mediator.This presents a novel treatment approach to regulate seizures brought on by neuroinflammation.展开更多
Epilepsy is a clinical syndrome caused by highly synchronized abnormal discharges of neurons in the brain. It is a common disease of the nervous system. The pathogenesis of epilepsy has not been fully understood yet. ...Epilepsy is a clinical syndrome caused by highly synchronized abnormal discharges of neurons in the brain. It is a common disease of the nervous system. The pathogenesis of epilepsy has not been fully understood yet. The main pathological changes after seizures are programmed neuronal death and glial proliferation. Autophagy is a catabolic process. Moderate autophagy is critical to maintain the homeostasis and cell health, while abnormal autophagy can lead to disease. A number of studies have proved that abnormal autophagy mechanism can lead to epilepsy, and there are also literatures that autophagy induced by endoplasmic reticulum stress can reduce the neuronal damage triggered by epilepsy, thus playing a protective role in neurons. This article reviews the relationship between autophagy and epilepsy in order to provide basis for further study of autophagy pathway and pathophysiology of epilepsy.展开更多
MiRNAs are a family of small non-coding RNAs that control levels of multiple proteins by post-transcriptionally decreasing messenger RNA stability and translation. MiRNA is a part of the epigenetic machinery. In addit...MiRNAs are a family of small non-coding RNAs that control levels of multiple proteins by post-transcriptionally decreasing messenger RNA stability and translation. MiRNA is a part of the epigenetic machinery. In addition to post-transcriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of epilepsy. However, miRNA not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenetic and MiRNA, and any dysregulation of this complex system can result in various physiological and pathological conditions. Currently, there is an unmet need for antiepileptic drugs that truly prevent the development of epilepsy in high-risk populations. New findings in animal models and human brain tissue suggest that microRNAs play a crucial role in epileptogenesis and the pathophysiology of chronic epilepsy. Objectives: This paper focuses on the epigenetic role of miRNA in the development of epilepsy and potential targets for drug therapy. Methods: In this paper, through the keywords epilepsy, epigenetic, methylation, miRNA, non-coding RNA search in PubMed, SPIS, GeenMedical, Google Scholar and Web of Science, to study the potential application of miRNA epigenetic regulation in the treatment of epilepsy. Results: Future treatments that manipulate miRNA epigenetic processes, such as Anti-oligonucleotides, DNA methylation and Nucleic Acid Aptamers, to treat or prevent epilepsy. Conclusion: Overall, miRNA epigenetic drugs have become a new frontier target to achieve a cure for epilepsy.展开更多
Aiming at the difficulty of mining fault prognosis starting points and constructing prognostic models for remaining useful life(RUL)prediction of rolling bearings,a RUL prediction method is proposed based on health in...Aiming at the difficulty of mining fault prognosis starting points and constructing prognostic models for remaining useful life(RUL)prediction of rolling bearings,a RUL prediction method is proposed based on health indicator(HI)extraction and trajectory-enhanced particle filter(TE-PF).By extracting a HI that can accurately track the trending of bearing degradation and combining it with the early fault enhancement technology,early abnormal sample nodes can be mined to provide more samples with fault information for the construction and training of subsequent prediction models.Aiming at the problem that traditional degradation rate models based on PF are vulnerable to HI mutations,a TE-PF prediction method is proposed based on comprehensive utilization of historical degradation information to timely modify prediction model parameters.Results from a rolling bearing prognostic study show that prediction starting points can be accurately detected and a reasonable prediction model can be conveniently constructed by the RUL prediction method based on HI amplitude abnormal detection and TE-PF.Furthermore,aiming at the RUL prediction problem under the condition of HI mutation,RUL prediction with probability and statistics characteristics under a confidence interval can be obtained based on the method proposed.展开更多
Influenza A virus(IAV)continues to pose a pandemic threat to public health,resulting a high mortality rate annually and during pandemic years.Posttranslational modification of viral protein plays a substantial role in...Influenza A virus(IAV)continues to pose a pandemic threat to public health,resulting a high mortality rate annually and during pandemic years.Posttranslational modification of viral protein plays a substantial role in regulating IAV infection.Here,based on immunoprecipitation(IP)-based mass spectrometry(MS)and purified virus-coupled MS,a total of 89 phosphorylation sites distributed among 10 encoded viral proteins of IAV were identified,including 60 novel phosphorylation sites.Additionally,for the first time,we provide evidence that PB2 can also be acetylated at site K187.Notably,the PB2 S181 phosphorylation site was consistently identified in both IP-based MS and purified virus-based MS.Both S181 and K187 are exposed on the surface of the PB2 protein and are highly conserved in various IAV strains,suggesting their fundamental importance in the IAV life cycle.Bioinformatic analysis results demonstrated that S181E/A and K187Q/R mimic mutations do not significantly alter the PB2 protein structure.While continuous phosphorylation mimicked by the PB2 S181E mutation substantially decreases viral fitness in mice,PB2 K187Q mimetic acetylation slightly enhances viral virulence in mice.Mechanistically,PB2 S181E substantially impairs viral polymerase activity and viral replication,remarkably dampens protein stability and nuclear accumulation of PB2,and significantly weakens IAV-induced inflammatory responses.Therefore,our study further enriches the database of phosphorylation and acetylation sites of influenza viral proteins,laying a foundation for subsequent mechanistic studies.Meanwhile,the unraveled antiviral effect of PB2 S181E mimetic phosphorylation may provide a new target for the subsequent study of antiviral drugs.展开更多
Pulmonary Hypertension(PH)is a global health problem that affects about 1%of the global population.Animal models of PH play a vital role in unraveling the pathophysiological mechanisms of the disease.The present study...Pulmonary Hypertension(PH)is a global health problem that affects about 1%of the global population.Animal models of PH play a vital role in unraveling the pathophysiological mechanisms of the disease.The present study proposes a Kernel Extreme Learning Machine(KELM)model based on an improved Whale Optimization Algorithm(WOA)for predicting PH mouse models.The experimental results showed that the selected blood indicators,including Haemoglobin(HGB),Hematocrit(HCT),Mean,Platelet Volume(MPV),Platelet distribution width(PDW),and Platelet–Large Cell Ratio(P-LCR),were essential for identifying PH mouse models using the feature selection method proposed in this paper.Remarkably,the method achieved 100.0%accuracy and 100.0%specificity in classification,demonstrating that our method has great potential to be used for evaluating and identifying mouse PH models.展开更多
Decades have passed since the first discovery of H10-subtype avian influenza virus(AIV) in chickens in 1949,and it has been detected in many species including mammals such as minks,pigs,seals and humans.Cases of human...Decades have passed since the first discovery of H10-subtype avian influenza virus(AIV) in chickens in 1949,and it has been detected in many species including mammals such as minks,pigs,seals and humans.Cases of human infections with H10N8viruses identified in China in 2013 have raised widespread attention.Two novel reassortant H10N3 viruses were isolated from chickens in December 2019 in eastern China during routine surveillance for AIVs.The internal genes of these viruses were derived from genotype S(G57) H9N2 and were consistent with H5N6,H7N9 and H10N8,which cause fatal infections in humans.Their viral pathogenicity and transmissibility were further studied in different animal models.The two H10N3 isolates had low pathogenicity in chickens and were transmitted between chickens via direct contact.These viruses were highly pathogenic in mice and could be transmitted between guinea pigs via direct contact and respiratory droplets.More importantly,these viruses can bind to both human-type SAα-2,6-Gal receptors and avian-type SAα-2,3-Gal receptors.Asymptomatic shedding in chickens and good adaptability to mammals of these H10N3 isolates would make it easier to transmit to humans and pose a threat to public health.展开更多
基金supported by the earmarked fund for China Agriculture Research System(CARS-40)the Key Research and Development Project of Yangzhou(Modern Agriculture),China(YZ2022052)the‘‘High-end Talent Support Program’’of Yangzhou University,China。
文摘H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are protective and allow mass administration.Of note,these vaccines elicit undetectable H7N9-specific hemagglutination-inhibition(HI)but high IgG antibodies in chickens.However,the molecular basis and protective mechanism underlying this particular antibody immunity remain unclear.Herein,immunization with an NDV_(vec)H7N9 induced low anti-H7N9 HI and virus neutralization titers but high levels of hemagglutinin(HA)-binding IgG antibodies in chickens.Three residues(S150,G151 and S152)in HA of H7N9 virus were identified as the dominant epitopes recognized by the NDV_(vec)H7N9 immune serum.Passively transferred NDV_(vec)H7N9 immune serum conferred complete protection against H7N9 virus infection in chickens.The NDV_(vec)H7N9 immune serum can mediate a potent lysis of HA-expressing and H7N9 virus-infected cells and significantly suppress H7N9 virus infectivity.These activities of the serum were significantly impaired after heat-inactivation or treatment with complement inhibitor,suggesting the engagement of the complement system.Moreover,mutations in the 150-SGS-152 sites in HA resulted in significant reductions in cell lysis and virus neutralization mediated by the NDV_(vec)H7N9 immune serum,indicating the requirement of antibody-antigen binding for complement activity.Therefore,antibodies induced by the NDV_(vec)H7N9 can activate antibody-dependent complement-mediated lysis of H7N9 virus-infected cells and complement-mediated neutralization of H7N9 virus.Our findings unveiled a novel role of the complement in protection conferred by the NDV_(vec)H7N9,highlighting a potential benefit of engaging the complement system in H7N9 vaccine design.
文摘Epilepsy is one of the most common neurological diseases worldwide with a high prevalence and unknown pathogenesis.Further,its control is challenging.It is generally accepted that an imbalance between the excitatory and inhibitory properties of the central nervous system(CNS)leads to a large number of abnormally synchronized neuronal discharges in the brain.Transient receptor potential vanilloid protein type 1(TRPV1)is a non-selective cation channel that contributes to the regulation of the nervous system and influences the excitability of the nervous system.This includes the release of neurotransmitters,action potential generation due to alterations in ion channels,synaptic transmission,and the changes in glial cells.There is abundant evidence that TRPV1 is widely expressed in the central nervous system(including microglia)and is involved in the development of epilepsy through neuroinflammation.In conclusion,microglial TRPV1 participates in neuroinflammatory reactions and functions as a potential proinflammatory mediator.This presents a novel treatment approach to regulate seizures brought on by neuroinflammation.
文摘Epilepsy is a clinical syndrome caused by highly synchronized abnormal discharges of neurons in the brain. It is a common disease of the nervous system. The pathogenesis of epilepsy has not been fully understood yet. The main pathological changes after seizures are programmed neuronal death and glial proliferation. Autophagy is a catabolic process. Moderate autophagy is critical to maintain the homeostasis and cell health, while abnormal autophagy can lead to disease. A number of studies have proved that abnormal autophagy mechanism can lead to epilepsy, and there are also literatures that autophagy induced by endoplasmic reticulum stress can reduce the neuronal damage triggered by epilepsy, thus playing a protective role in neurons. This article reviews the relationship between autophagy and epilepsy in order to provide basis for further study of autophagy pathway and pathophysiology of epilepsy.
文摘MiRNAs are a family of small non-coding RNAs that control levels of multiple proteins by post-transcriptionally decreasing messenger RNA stability and translation. MiRNA is a part of the epigenetic machinery. In addition to post-transcriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of epilepsy. However, miRNA not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenetic and MiRNA, and any dysregulation of this complex system can result in various physiological and pathological conditions. Currently, there is an unmet need for antiepileptic drugs that truly prevent the development of epilepsy in high-risk populations. New findings in animal models and human brain tissue suggest that microRNAs play a crucial role in epileptogenesis and the pathophysiology of chronic epilepsy. Objectives: This paper focuses on the epigenetic role of miRNA in the development of epilepsy and potential targets for drug therapy. Methods: In this paper, through the keywords epilepsy, epigenetic, methylation, miRNA, non-coding RNA search in PubMed, SPIS, GeenMedical, Google Scholar and Web of Science, to study the potential application of miRNA epigenetic regulation in the treatment of epilepsy. Results: Future treatments that manipulate miRNA epigenetic processes, such as Anti-oligonucleotides, DNA methylation and Nucleic Acid Aptamers, to treat or prevent epilepsy. Conclusion: Overall, miRNA epigenetic drugs have become a new frontier target to achieve a cure for epilepsy.
基金supported by the National Key Research and Development Program of China (No.2018YFB1702401)National Natural Science Foundation of China (Grant No.51975576,51475463).
文摘Aiming at the difficulty of mining fault prognosis starting points and constructing prognostic models for remaining useful life(RUL)prediction of rolling bearings,a RUL prediction method is proposed based on health indicator(HI)extraction and trajectory-enhanced particle filter(TE-PF).By extracting a HI that can accurately track the trending of bearing degradation and combining it with the early fault enhancement technology,early abnormal sample nodes can be mined to provide more samples with fault information for the construction and training of subsequent prediction models.Aiming at the problem that traditional degradation rate models based on PF are vulnerable to HI mutations,a TE-PF prediction method is proposed based on comprehensive utilization of historical degradation information to timely modify prediction model parameters.Results from a rolling bearing prognostic study show that prediction starting points can be accurately detected and a reasonable prediction model can be conveniently constructed by the RUL prediction method based on HI amplitude abnormal detection and TE-PF.Furthermore,aiming at the RUL prediction problem under the condition of HI mutation,RUL prediction with probability and statistics characteristics under a confidence interval can be obtained based on the method proposed.
基金supported by the National Natural Science Foundation of China(32072832,32372976)by the National Key Research and Development Project of China(2021YFD1800202)+3 种基金by Jiangsu Province Agricultural Science&Technology Independent Innovation Funds[CX(21)3141]by the Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_3553 and KYCX21_3277)by the Earmarked Fund for China Agriculture Research System(CARS-40)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Influenza A virus(IAV)continues to pose a pandemic threat to public health,resulting a high mortality rate annually and during pandemic years.Posttranslational modification of viral protein plays a substantial role in regulating IAV infection.Here,based on immunoprecipitation(IP)-based mass spectrometry(MS)and purified virus-coupled MS,a total of 89 phosphorylation sites distributed among 10 encoded viral proteins of IAV were identified,including 60 novel phosphorylation sites.Additionally,for the first time,we provide evidence that PB2 can also be acetylated at site K187.Notably,the PB2 S181 phosphorylation site was consistently identified in both IP-based MS and purified virus-based MS.Both S181 and K187 are exposed on the surface of the PB2 protein and are highly conserved in various IAV strains,suggesting their fundamental importance in the IAV life cycle.Bioinformatic analysis results demonstrated that S181E/A and K187Q/R mimic mutations do not significantly alter the PB2 protein structure.While continuous phosphorylation mimicked by the PB2 S181E mutation substantially decreases viral fitness in mice,PB2 K187Q mimetic acetylation slightly enhances viral virulence in mice.Mechanistically,PB2 S181E substantially impairs viral polymerase activity and viral replication,remarkably dampens protein stability and nuclear accumulation of PB2,and significantly weakens IAV-induced inflammatory responses.Therefore,our study further enriches the database of phosphorylation and acetylation sites of influenza viral proteins,laying a foundation for subsequent mechanistic studies.Meanwhile,the unraveled antiviral effect of PB2 S181E mimetic phosphorylation may provide a new target for the subsequent study of antiviral drugs.
基金the National Natural Science Foundation of China(82003831,62076185 and U1809209)the Project of Health Commission of Zhejiang Province(2020KY177)+2 种基金the Wenzhou Technology Foundation(Y2020002)the Natural Science Foundation of Zhejiang Province(LZ22F020005)the First Affiliated Hospital of Wenzhou Medical University Youth Excellence Project(QNYC114).
文摘Pulmonary Hypertension(PH)is a global health problem that affects about 1%of the global population.Animal models of PH play a vital role in unraveling the pathophysiological mechanisms of the disease.The present study proposes a Kernel Extreme Learning Machine(KELM)model based on an improved Whale Optimization Algorithm(WOA)for predicting PH mouse models.The experimental results showed that the selected blood indicators,including Haemoglobin(HGB),Hematocrit(HCT),Mean,Platelet Volume(MPV),Platelet distribution width(PDW),and Platelet–Large Cell Ratio(P-LCR),were essential for identifying PH mouse models using the feature selection method proposed in this paper.Remarkably,the method achieved 100.0%accuracy and 100.0%specificity in classification,demonstrating that our method has great potential to be used for evaluating and identifying mouse PH models.
基金supported by the National Key Research and Development Project of China (2016YFD0500202-1,2016YFD0501601)the National Natural Science Foundation of China(31772755)+3 种基金Jiangsu Provincial Natural Science Fund for Excellent Young Scholars (BK20170068)the Earmarked Fund For China Agriculture Research System (CARS-40)the Open Project Program of Jiangsu Key Laboratory of Zoonosis (R1808)the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)。
文摘Decades have passed since the first discovery of H10-subtype avian influenza virus(AIV) in chickens in 1949,and it has been detected in many species including mammals such as minks,pigs,seals and humans.Cases of human infections with H10N8viruses identified in China in 2013 have raised widespread attention.Two novel reassortant H10N3 viruses were isolated from chickens in December 2019 in eastern China during routine surveillance for AIVs.The internal genes of these viruses were derived from genotype S(G57) H9N2 and were consistent with H5N6,H7N9 and H10N8,which cause fatal infections in humans.Their viral pathogenicity and transmissibility were further studied in different animal models.The two H10N3 isolates had low pathogenicity in chickens and were transmitted between chickens via direct contact.These viruses were highly pathogenic in mice and could be transmitted between guinea pigs via direct contact and respiratory droplets.More importantly,these viruses can bind to both human-type SAα-2,6-Gal receptors and avian-type SAα-2,3-Gal receptors.Asymptomatic shedding in chickens and good adaptability to mammals of these H10N3 isolates would make it easier to transmit to humans and pose a threat to public health.
