As an essential transcriptional activator,PDX1 plays a crucial role in pancreatic development andβ-cell function.Mutations in the PDX1 gene may lead to type 4 maturityonset diabetes of the young(MODY4)and neonatal di...As an essential transcriptional activator,PDX1 plays a crucial role in pancreatic development andβ-cell function.Mutations in the PDX1 gene may lead to type 4 maturityonset diabetes of the young(MODY4)and neonatal diabetes mellitus.However,the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models.In this study,three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology,all of which succumbed shortly postpartum,exhibiting pancreatic agenesis.Notably,one tri-allelic PDX1-mutant cynomolgus macaque(designated as M4)developed a pancreas,whereas the two monoallelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation.RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions,indicating developmental delay and PDX1haploinsufficiency.A marked change in m6A methylation was identified in the M4 pancreas,confirmed through cultured PDX1-mutantisletorganoids.Notably,overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids.This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.展开更多
Background:Viral pathogens belonging to the orderBunyavirales pose a continuous background threat to global health,but the fact remains that they are usually neglected and their distribution is still ambiguously known...Background:Viral pathogens belonging to the orderBunyavirales pose a continuous background threat to global health,but the fact remains that they are usually neglected and their distribution is still ambiguously known.We aim to map the geographical distribution ofBunyavirales viruses and assess the environmental suitability and transmission risk of majorBunyavirales viruses in China.Methods:We assembled data on allBunyavirales viruses detected in humans,animals and vectors from multiple sources,to update distribution maps of them across China.In addition,we predicted environmental suitability at the 10 km×10 km pixel level by applying boosted regression tree models for two importantBunyavirales viruses,including Crimean-Congo hemorrhagic fever virus(CCHFV)and Rift Valley fever virus(RVFV).Based on model-projected risks and air travel volume,the imported risk of RVFV was also estimated from its endemic areas to the cities in China.Results:Here we mapped all 89 species ofBunyavirales viruses in China from January 1951 to June 2021.Nineteen viruses were shown to infect humans,including ten species first reported as human infections.A total of 447,848 cases infected withBunyavirales viruses were reported,and hantaviruses,Dabie bandavirus and Crimean-Congo hemorrhagic fever virus(CCHFV)had the severest disease burden.Model-predicted maps showed that Xinjiang and southwestern Yunnan had the highest environmental suitability for CCHFV occurrence,mainly related toHyalomma asiaticum presence,while southern China had the highest environmental suitability for Rift Valley fever virus(RVFV)transmission all year round,mainly driven by livestock density,mean precipitation in the previous month.We further identified three cities including Guangzhou,Beijing and Shanghai,with the highest imported risk of RVFV potentially from Egypt,South Africa,Saudi Arabia and Kenya.Conclusions:A variety ofBunyavirales viruses are widely distributed in China,and the two major neglectedBunyavirales viruses including CCHFV and RVFV,both have the potential for outbreaks in local areas of China.Our study can help to promote the understanding of risk distribution and disease burden ofBunyavirales viruses in China,and the risk maps of CCHFV and RVFV occurrence are crucial to the targeted surveillance and control,especially in seasons and locations at high risk.展开更多
Background:The ongoing transmission of the Middle East respiratory syndrome coronavirus(MERS-CoV)in the Middle East and its expansion to other regions are raising concerns of a potential pandemic.An in-depth analysis ...Background:The ongoing transmission of the Middle East respiratory syndrome coronavirus(MERS-CoV)in the Middle East and its expansion to other regions are raising concerns of a potential pandemic.An in-depth analysis about both population and molecular epidemiology of this pathogen is needed.Methods:MERS cases reported globally as of June 2020 were collected mainly from World Health Organization official reports,supplemented by other reliable sources.Determinants for case fatality and spatial diffusion of MERS were assessed with Logistic regressions and Cox proportional hazard models,respectively.Phylogenetic and phylogeographic analyses were performed to examine the evolution and migration history of MERS-CoV.Results:A total of 2562 confirmed MERS cases with 150 case clusters were reported with a case fatality rate of 32.7%(95%Cl:30.9-34.6%).Saudi Arabia accounted for 83.6%of the cases.Age of>65 years old,underlying conditions and>5 days delay in diagnosis were independent risk factors for death.However,a history of animal contact was associated with a higher risk(adjusted OR=297,95%Cl:1」0-7.98)among female cases<65 years but with a lower risk(adjusted OR=0.31,95%Cl:0.18-0.51)among male cases>65 years old.Diffusion of the disease was fastest from its origin in Saudi Arabia to the east,and was primarily driven by the transportation network.The most recent subclade C5.1(since 2013)was associated with non-synonymous mutations and a higher mortality rate.Phylogeographic analyses pointed to Riyadh of Saudi Arabia and Abu Dhabi of the United Arab Emirates as the hubs for both local and international spread of MERS-CoV.Conclusions:MERS-CoV remains primarily locally transmitted in the Middle East,with opportunistic exportation to other continents and a potential of causing transmission clusters of human cases.Animal contact is associated with a higher risk of death,but the association differs by age and sex.Transportation network is the leading driver for the spatial diffusion ofthe disease.These findings how this pathogen spread are helpful for targeting public health surveillance and interventions to control endemics and to prevent a potential pandemic.展开更多
基金supported by the National Key R&D Program of China(2018YFA0801404,2023YFC3403400)National Natural Science Foundation of China(81941006,32371190,32370878)+2 种基金Guangdong Special Support Program(2019BT02Y276,2024A1515012868)Double First-Class Discipline Promotion Project(2023B10564003)Program for Scientific Research Start-up Funds of Guangdong Ocean University(060302052408)。
文摘As an essential transcriptional activator,PDX1 plays a crucial role in pancreatic development andβ-cell function.Mutations in the PDX1 gene may lead to type 4 maturityonset diabetes of the young(MODY4)and neonatal diabetes mellitus.However,the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models.In this study,three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology,all of which succumbed shortly postpartum,exhibiting pancreatic agenesis.Notably,one tri-allelic PDX1-mutant cynomolgus macaque(designated as M4)developed a pancreas,whereas the two monoallelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation.RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions,indicating developmental delay and PDX1haploinsufficiency.A marked change in m6A methylation was identified in the M4 pancreas,confirmed through cultured PDX1-mutantisletorganoids.Notably,overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids.This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.
基金National Key Research and Development Program of China(2021YFC2302004)National Science Foundation for Distinguished Young Scholars of China(81825019)。
文摘Background:Viral pathogens belonging to the orderBunyavirales pose a continuous background threat to global health,but the fact remains that they are usually neglected and their distribution is still ambiguously known.We aim to map the geographical distribution ofBunyavirales viruses and assess the environmental suitability and transmission risk of majorBunyavirales viruses in China.Methods:We assembled data on allBunyavirales viruses detected in humans,animals and vectors from multiple sources,to update distribution maps of them across China.In addition,we predicted environmental suitability at the 10 km×10 km pixel level by applying boosted regression tree models for two importantBunyavirales viruses,including Crimean-Congo hemorrhagic fever virus(CCHFV)and Rift Valley fever virus(RVFV).Based on model-projected risks and air travel volume,the imported risk of RVFV was also estimated from its endemic areas to the cities in China.Results:Here we mapped all 89 species ofBunyavirales viruses in China from January 1951 to June 2021.Nineteen viruses were shown to infect humans,including ten species first reported as human infections.A total of 447,848 cases infected withBunyavirales viruses were reported,and hantaviruses,Dabie bandavirus and Crimean-Congo hemorrhagic fever virus(CCHFV)had the severest disease burden.Model-predicted maps showed that Xinjiang and southwestern Yunnan had the highest environmental suitability for CCHFV occurrence,mainly related toHyalomma asiaticum presence,while southern China had the highest environmental suitability for Rift Valley fever virus(RVFV)transmission all year round,mainly driven by livestock density,mean precipitation in the previous month.We further identified three cities including Guangzhou,Beijing and Shanghai,with the highest imported risk of RVFV potentially from Egypt,South Africa,Saudi Arabia and Kenya.Conclusions:A variety ofBunyavirales viruses are widely distributed in China,and the two major neglectedBunyavirales viruses including CCHFV and RVFV,both have the potential for outbreaks in local areas of China.Our study can help to promote the understanding of risk distribution and disease burden ofBunyavirales viruses in China,and the risk maps of CCHFV and RVFV occurrence are crucial to the targeted surveillance and control,especially in seasons and locations at high risk.
基金supported by China Mega-Project on Infectious Disease Prevention(No.2017ZX10303401,2018ZX10713002,2018ZX10101003 and 2018ZX10201001)National Natural Science Foundation of China(No.81825019),and the National Institutes of Health of United States(R01 All 39761 and R01 AI116770)YY was supported by US National Institutes of Health grants R01 Al 139761 and R56 Al 148284.
文摘Background:The ongoing transmission of the Middle East respiratory syndrome coronavirus(MERS-CoV)in the Middle East and its expansion to other regions are raising concerns of a potential pandemic.An in-depth analysis about both population and molecular epidemiology of this pathogen is needed.Methods:MERS cases reported globally as of June 2020 were collected mainly from World Health Organization official reports,supplemented by other reliable sources.Determinants for case fatality and spatial diffusion of MERS were assessed with Logistic regressions and Cox proportional hazard models,respectively.Phylogenetic and phylogeographic analyses were performed to examine the evolution and migration history of MERS-CoV.Results:A total of 2562 confirmed MERS cases with 150 case clusters were reported with a case fatality rate of 32.7%(95%Cl:30.9-34.6%).Saudi Arabia accounted for 83.6%of the cases.Age of>65 years old,underlying conditions and>5 days delay in diagnosis were independent risk factors for death.However,a history of animal contact was associated with a higher risk(adjusted OR=297,95%Cl:1」0-7.98)among female cases<65 years but with a lower risk(adjusted OR=0.31,95%Cl:0.18-0.51)among male cases>65 years old.Diffusion of the disease was fastest from its origin in Saudi Arabia to the east,and was primarily driven by the transportation network.The most recent subclade C5.1(since 2013)was associated with non-synonymous mutations and a higher mortality rate.Phylogeographic analyses pointed to Riyadh of Saudi Arabia and Abu Dhabi of the United Arab Emirates as the hubs for both local and international spread of MERS-CoV.Conclusions:MERS-CoV remains primarily locally transmitted in the Middle East,with opportunistic exportation to other continents and a potential of causing transmission clusters of human cases.Animal contact is associated with a higher risk of death,but the association differs by age and sex.Transportation network is the leading driver for the spatial diffusion ofthe disease.These findings how this pathogen spread are helpful for targeting public health surveillance and interventions to control endemics and to prevent a potential pandemic.
