Objective Non-suicidal self-injury(NSSI)has a higher prevalence in adolescents with depressive disorders than in community adolescents.This study examined the differences in NSSI behaviors between adolescents with uni...Objective Non-suicidal self-injury(NSSI)has a higher prevalence in adolescents with depressive disorders than in community adolescents.This study examined the differences in NSSI behaviors between adolescents with unipolar depression(UD)and those with bipolar depression(BD).Methods Adolescents with UD or BD were recruited from 20 general or psychiatric hospitals across China.The methods,frequency,and function of NSSI were assessed by Functional Assessment of Self-Mutilation.The Beck Suicide Ideation Scale was used to evaluate adolescents’suicidal ideation,and the 10-item Kessler Psychological Distress Scale to estimate the anxiety and depression symptoms.Results The UD group had higher levels of depression(19.16 vs.17.37,F=15.23,P<0.001)and anxiety symptoms(17.73 vs.16.70,F=5.00,P=0.026)than the BD group.Adolescents with BD had a longer course of NSSI than those with UD(2.00 vs.1.00 year,Z=−3.39,P=0.001).There were no statistical differences in the frequency and the number of methods of NSSI between the UD and BD groups.Depression(r=0.408,P<0.01)and anxiety(r=0.391,P<0.01)were significantly and positively related to NSSI frequency.Conclusion Adolescents with BD had a longer course of NSSI than those with UD.More importantly,NSSI frequency were positively and strongly correlated with depression and anxiety symptoms,indicating the importance of adequate treatment of depression and anxiety in preventing and intervening adolescents’NSSI behaviors.展开更多
The long-term consequences of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,known as the post-acute sequelae of COVID-19(PASC),have been a growing concern.A significant proportion of COVID-19 pa...The long-term consequences of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,known as the post-acute sequelae of COVID-19(PASC),have been a growing concern.A significant proportion of COVID-19 patients experience persistent health issues even six to twelve months after recovering from acute infection[1],[2],[3],[4].Therefore,understanding the immune reconstitution process and identifying the molecular and cellular mechanisms underlying PASC is crucial.展开更多
Dear Editor,Different from normal differentiated cells,metabolic reprogramming was spotted in cancer cells,due to increased demand for energy and macromolecule synthesis during their rapid proliferation(Hanahan and We...Dear Editor,Different from normal differentiated cells,metabolic reprogramming was spotted in cancer cells,due to increased demand for energy and macromolecule synthesis during their rapid proliferation(Hanahan and Weinberg,2011;Pavlova and Thompson,2016).Most cancer cells prefer anaerobic glycolysis even with oxygen in the environment due to its higher speed to produce macromolecular materials required for biosynthesis(Vander Heiden et al.,2009;DeBerardinis and Chandel,2016).But to compensate for the lower efficiency of anaerobic glycolysis in producing ATP,these cancer cells demand much higher glucose supply(Warburg,1956;Vander Heiden et al.,2009).These metabolic characteristics point to the huge demand of cancer cells for carbohydrate substrates,which creates the possibility of treating tumors by exploiting this feature(Patra et al.,2013;DeBerardinis and Chandel,2016).展开更多
Mosquito-borne viruses(MBVs)are a large class of viruses transmitted mainly through mosquito bites,including dengue virus,Zika virus,Japanese encephalitis virus,West Nile virus,and chikungunya virus,which pose a major...Mosquito-borne viruses(MBVs)are a large class of viruses transmitted mainly through mosquito bites,including dengue virus,Zika virus,Japanese encephalitis virus,West Nile virus,and chikungunya virus,which pose a major threat to the health of people around the world.With global warming and extended human activities,the incidence of many MBVs has increased significantly.Mosquito saliva contains a variety of bioactive protein components.These not only enable blood feeding but also play a crucial role in regulating local infection at the bite site and the remote dissemination of MBVs as well as in remodeling the innate and adaptive immune responses of host vertebrates.Here,we review the physiological functions of mosquito salivary proteins(MSPs)in detail,the influence and the underlying mechanism of MSPs on the transmission of MBVs,and the current progress and issues that urgently need to be addressed in the research and development of MSP-based MBV transmission blocking vaccines.展开更多
Dear Editor,Despite myriad successful applications of gene editing in plant functional genomics research and precision breeding,many challenges persist around the efficiency of gene-editing tools for many plant specie...Dear Editor,Despite myriad successful applications of gene editing in plant functional genomics research and precision breeding,many challenges persist around the efficiency of gene-editing tools for many plant species.For instance,soybean(Glycine max)is a major crop providing oil and protein to human diets and feedstock,but its gene-editing efficiency remains relatively low(Bai et al.,2019).展开更多
A common approach in therapeutic protein development involves employing synthetic ligands with multivalency,enabling sophisticated control of signal transduction.Leveraging the emerging concept of liquid-liquid phase ...A common approach in therapeutic protein development involves employing synthetic ligands with multivalency,enabling sophisticated control of signal transduction.Leveraging the emerging concept of liquid-liquid phase separation(LLPS)and its ability to organize cell surface receptors into functional compartments,we herein have designed modular ligands with phase-separation modalities to engineer programmable interreceptor communications and precise control of signal pathways,thus inducing the rapid,potent,and specific apoptosis of tumor cells.Despite their simplicity,these“triggers”,named phase-separated Tumor Killers(hereafter referred to as psTK),are sufficient to yield interreceptor clustering of death receptors(represented by DR5)and tumor-associated receptors,with notable features:LLPSmediated robust high-order organization,well-choreographed conditional activation,and broad-spectrum capacity to potently induce apoptosis in tumor cells.The development of novel therapeutic proteins with phase-separation modalities showcases the power of spatially reorganizing signal transduction.This approach facilitates the diversification of cell fate and holds promising potential for targeted therapies against challenging tumors.展开更多
Stimulator of interferon genes(STING),also known as MITA,ERIS,MPYS or TMEM173,is a key player in innate immunity,specifically in the typeⅠinterferon response[1-3].It is also involved in a range of non-canonical biolo...Stimulator of interferon genes(STING),also known as MITA,ERIS,MPYS or TMEM173,is a key player in innate immunity,specifically in the typeⅠinterferon response[1-3].It is also involved in a range of non-canonical biological functions,including autophagy,cellular metabolism,translation,and DNA repair,and has implications in many diseases[4-9].After activation by its ligands,STING translocates from endoplasmic reticulum(ER),via ERGIC,Golgi apparatus and endosomes,finally to lysosomes for degradation[4-9].However,the mechanisms by which STING is delivered to lysosomes and whether this delivery process regulates STING activity remain elusive.展开更多
To the Editor:The global burden of premature coronary artery disease(CAD)is increasing among the young population.Premature CAD generally refers to the occurrence of obstructive coronary atherothrombotic lesions in me...To the Editor:The global burden of premature coronary artery disease(CAD)is increasing among the young population.Premature CAD generally refers to the occurrence of obstructive coronary atherothrombotic lesions in men and women aged<55 years and<65 years,respectively,and particularly in those aged<45 years.[1]The incidence of CAD in the younger population has remained stable or has increased,despite the declining incidence in older adults.Patients with premature CAD have a poor long-term prognosis,experiencing a high rate of recurrent ischemic events,rapid progression to multivessel disease,and frequent premature death.[1]Thus,it is crucial to identify the underlying causes of premature CAD that are distinct from those of age-related CAD and improve patient outcomes through precise diagnosis and treatment.展开更多
Scavenger receptor class B,member 2(SCARB2)is linked to Gaucher disease and Parkinson’s disease.Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy(PME),a rare group of inherited neurodegenerative dis...Scavenger receptor class B,member 2(SCARB2)is linked to Gaucher disease and Parkinson’s disease.Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy(PME),a rare group of inherited neurodegenerative diseases characterized by myoclonus.We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption,accompanied with vitamin E deficiency.Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool,leading to hyperactivation of FXR in intestine.Hyperactivation of FXR impairs epithelium renewal and lipid absorption.Patients with SCARB2 mutations have a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E.Finally,inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice.These data indicate that gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration,and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.展开更多
The ORF9b protein,derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2,serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response.Despite it...The ORF9b protein,derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2,serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response.Despite its significance,the precise regulatory mechanisms underlying its function remain elusive.In the present study,we unveil that the ORF9b protein of SARS-CoV-2,including emerging mutant strains like Delta and Omicron,can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway,despite certain mutations present among these strains.Moreover,our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70(TOM70)as a substrate receptor,bridging ORF9b with heat shock protein 90 alpha(HSP90α)and Cullin 5(CUL5)to form a complex.Within this complex,CUL5 triggers the ubiquitination and degradation of ORF9b,acting as a host antiviral factor,while HSP90αfunctions to stabilize it.Notably,treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b,leading to a pronounced inhibition of SARS-CoV-2 replication.Single-cell sequencing data revealed an up-regulation of HSP90αin lung epithelial cells from COVID-19 patients,suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90αto evade the host immunity.Our study identifies the CUL5-TOM70-HSP90αcomplex as a critical regulator of ORF9b protein stability,shedding light on the intricate host–virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.展开更多
Mosquito-borne diseases,encompassing threats like dengue,Zika virus(ZIKV)infection,and malaria,pose a sig-nificant challenge to global public health security,evoking widespread concern.The gravity of the situation is ...Mosquito-borne diseases,encompassing threats like dengue,Zika virus(ZIKV)infection,and malaria,pose a sig-nificant challenge to global public health security,evoking widespread concern.The gravity of the situation is un-derscored by some staggering statistics:over 3.9 billion people in more than 120 countries confront the imminent threat of some of the most epidemiologically significant mosquito-borne viruses;in 2021 alone,malaria accounted for 247 million cases,resulting in an estimated 619,000 deaths globally.展开更多
Plants employ sophisticated mechanisms to interact with pathogenic as well as beneficial microbes. Of those, membrane trafficking is key in establishing a rapid and precise response. Upon interaction with pathogenic m...Plants employ sophisticated mechanisms to interact with pathogenic as well as beneficial microbes. Of those, membrane trafficking is key in establishing a rapid and precise response. Upon interaction with pathogenic microbes, surface-localized immune receptors undergo endocytosis for signal transduction and activity regulation while cell wall components, antimicrobial compounds, and defense proteins are delivered to pathogen invasion sites through polarized secretion. To sustain mutualistic associations, host cells also reprogram the membrane trafficking system to accommodate invasive structures of symbi- otic microbes. Here, we provide an analysis of recent advances in understanding the roles of secretory and endocytic membrane trafficking pathways in plant immune activation. We also discuss strategies deployed by adapted microbes to manipulate these pathways to subvert or inhibit plant defense.展开更多
Apart from their primordial role in protein synthesis,t RNAs can be cleaved to produce t RNA-derived small RNAs(ts RNAs).The biological functions of ts RNAs in plants remain largely unknown.In this study,we developed ...Apart from their primordial role in protein synthesis,t RNAs can be cleaved to produce t RNA-derived small RNAs(ts RNAs).The biological functions of ts RNAs in plants remain largely unknown.In this study,we developed Rtc B ligation-based small RNA(s RNA)sequencing,a method that captures and distinguishes between 3′-2′,3′-cyclic-phosphate(c P)/phosphate(P)-terminated s RNAs and 3′-OH-terminated s RNAs,and profiled 5′ts RNAs and 5′t RNA halves in Arabidopsis thaliana.We found that Arabidopsis 5′ts RNAs and 5′t RNA halves predominantly contain a c P at the 3′end and require S-like RNase 1(RNS1)and RNS3 for their production.One of the most abundant 5′ts RNAs,5′ts R-Ala,by associating with AGO1,negatively regulates Cytochrome P45071 A13(CYP71 A13)expression and camalexin biosynthesis to repress anti-fungal defense.Interestingly,5′ts R-Ala is downregulated upon fungal infection.Our study provides a global view of 5′ts RNAs and 5′t RNA halves in Arabidopsis and unravels an important role of a 5′ts RNA in regulating anti-fungal defense.展开更多
Arrhythmogenic right ventricular dysplasia/cardiomyopathy(ARVD/C)is a genetic cardiac muscle disease that accounts for approximately 30%sudden cardiac death in young adults.The Ser358Leu mutation of transmembrane prot...Arrhythmogenic right ventricular dysplasia/cardiomyopathy(ARVD/C)is a genetic cardiac muscle disease that accounts for approximately 30%sudden cardiac death in young adults.The Ser358Leu mutation of transmembrane protein 43(TMEM43)was commonly identified in the patients of highly lethal and fully penetrant ARVD subtype,ARVD5.Here,we generated TMEM43 S358L mouse to explore the underlying mechanism.This mouse strain showed the classic patholo.gies of ARVD patients,including structural abnormalities and cardiac fibrofatty.TMEM43 S358L mutation led to hyper-activated nuclear factor kB(NFkB)activation in heart tissues and primary cardiomy.ocyte cells.Importantly,this hyper activation of NF-κB directly drove the expression of pro-fibrotic gene,transforming growth factor beta(TGFβ),and enhanced downstream signal,indicating that TMEM43 S358L mutation up-regulates NF-κB-TGFβ signal cascade during ARVD cardiac fibrosis.Our study partially reveals the regulatory mechanism of ARVD development.展开更多
Autophagy is an evolutionarily conserved lysosome-based degradation process.Atg5 plays a very important role in autophagosome formation.Here we show that Atg5 is required for biogenesis of late endosomes and lysosomes...Autophagy is an evolutionarily conserved lysosome-based degradation process.Atg5 plays a very important role in autophagosome formation.Here we show that Atg5 is required for biogenesis of late endosomes and lysosomes in an autophagy-independent manner.In Atg5 cells,but not in other essential autophagy genes defecting cells,recycling and retrieval of late endosomal components from hybrid organelles are impaired,causing persistent hybrid organelles and defective formation of late endosomes and lysosomes.Defective retrieval of late endosomal components from hybrid organelles resulting from impaired recruitment of a component of V1-ATPase to acidic organelles blocks the pH-dependent retrieval of late endosomal components from hybrid organelles.Lowering the intracellular pH restores late endosome/lysosome biogenesis in Atg5 cells.Our data demonstrate an unexpected role of Atg5 and shed new light on late endosome and lysosome biogenesis.展开更多
Dear Editor,Animal models,most commonly mice,that lack a protein of interest play an important role in phenotypic and functional studies of a target gene,allowing researchers to answer various biological questions(Cha...Dear Editor,Animal models,most commonly mice,that lack a protein of interest play an important role in phenotypic and functional studies of a target gene,allowing researchers to answer various biological questions(Chaible et al,2010).At pre-sent,a variety of tools act at the DNA or RNA level to enable researchers to model gene function(and thus protein)deficiency,including nucleic acid based RNA interference(EI-bashir et al.,2001),antisense oligonucleotides(Schoch and Miller,2017),and genome editing-based CRISPR-Cas9(Doudna and Charpentier,2014)strategies.However,challenges remain.展开更多
Mosquito-borne diseases present a significant threat to human health,with the possibility of outbreaks of new mosquito-borne diseases always looming.Unfortunately,current measures to combat these diseases such as vacc...Mosquito-borne diseases present a significant threat to human health,with the possibility of outbreaks of new mosquito-borne diseases always looming.Unfortunately,current measures to combat these diseases such as vaccines and drugs are often either unavailable or ineffective.However,recent studies on microbiomes may reveal promising strategies to fight these diseases.In this review,we examine recent advances in our understanding of the effects of both the mosquito and vertebrate microbiomes on mosquito-borne diseases.We argue that the mosquito microbiome can have direct and indirect impacts on the transmission of these diseases,with mosquito symbiotic microorganisms,particularly Wolbachia bacteria,showing potential for controlling mosquito-borne diseases.Moreover,the skin microbiome of vertebrates plays a significant role in mosquito preferences,while the gut microbiome has an impact on the progression of mosquito-borne diseases in humans.As researchers continue to explore the role of microbiomes in mosquito-borne diseases,we highlight some promising future directions for this field.Ultimately,a better understanding of the interplay between mosquitoes,their hosts,pathogens,and the microbiomes of mosquitoes and hosts may hold the key to preventing and controlling mosquito-borne diseases.展开更多
Arboviruses,a diverse group of vector-borne pathogens transmitted by various vectors such as mosquitoes,ticks,and flies,encompass members of the Flaviviridae,Togaviridae,Phenuviridae,Peribunyaviridae,Reoviridae,Asfarv...Arboviruses,a diverse group of vector-borne pathogens transmitted by various vectors such as mosquitoes,ticks,and flies,encompass members of the Flaviviridae,Togaviridae,Phenuviridae,Peribunyaviridae,Reoviridae,Asfarviridae,Rhabdoviridae,Poxviridae,and Orthomyxoviridae families[1].展开更多
Gene expression regulation, including loss-of-function and gain-of-function assays, is a powerful method to study developmental and disease mechanisms. Drosophila melanogaster is an ideal model system particularly wel...Gene expression regulation, including loss-of-function and gain-of-function assays, is a powerful method to study developmental and disease mechanisms. Drosophila melanogaster is an ideal model system particularly well-equipped with many genetic tools. In this review, we describe and discuss the gene expression regulation techniques recently developed and their applications, including the CRISPR/Cas9-triggered heritable mutation system, CRISPR/dCas9-based transcriptional activation(CRISPRa) system,and CRISPR/dCas9-based transcriptional repression(CRISPRi) system, as well as the next-generation transgenic RNAi system. The main purpose of this review is to provide the fly research community with an updated summary of newly developed gene expression regulation techniques and help the community to select appropriate methods and optimize the research strategy.展开更多
基金supported by the Sanming Project of Medicine in Shenzhen(No.SZSM202011014)Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(No.SZGSP013)+1 种基金Shenzhen Key Medical Discipline Construction Fund(No.SZXK072)Shenzhen Science and Technology Research and Development Fund for Sustainable Development Project(No.KCXFZ20201221173613036).
文摘Objective Non-suicidal self-injury(NSSI)has a higher prevalence in adolescents with depressive disorders than in community adolescents.This study examined the differences in NSSI behaviors between adolescents with unipolar depression(UD)and those with bipolar depression(BD).Methods Adolescents with UD or BD were recruited from 20 general or psychiatric hospitals across China.The methods,frequency,and function of NSSI were assessed by Functional Assessment of Self-Mutilation.The Beck Suicide Ideation Scale was used to evaluate adolescents’suicidal ideation,and the 10-item Kessler Psychological Distress Scale to estimate the anxiety and depression symptoms.Results The UD group had higher levels of depression(19.16 vs.17.37,F=15.23,P<0.001)and anxiety symptoms(17.73 vs.16.70,F=5.00,P=0.026)than the BD group.Adolescents with BD had a longer course of NSSI than those with UD(2.00 vs.1.00 year,Z=−3.39,P=0.001).There were no statistical differences in the frequency and the number of methods of NSSI between the UD and BD groups.Depression(r=0.408,P<0.01)and anxiety(r=0.391,P<0.01)were significantly and positively related to NSSI frequency.Conclusion Adolescents with BD had a longer course of NSSI than those with UD.More importantly,NSSI frequency were positively and strongly correlated with depression and anxiety symptoms,indicating the importance of adequate treatment of depression and anxiety in preventing and intervening adolescents’NSSI behaviors.
基金supported by the National Natural Science Foundation of China(81930063,82221004,T2225005,21927802,and 32022016)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-040,2020-I2M-CoV19-011,2021-I2M-1-038,and 2022-I2M-CoV19-005)+1 种基金the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2019PT310029)the Fundamental Research Funds for the Central Universities(3332021092).
文摘The long-term consequences of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,known as the post-acute sequelae of COVID-19(PASC),have been a growing concern.A significant proportion of COVID-19 patients experience persistent health issues even six to twelve months after recovering from acute infection[1],[2],[3],[4].Therefore,understanding the immune reconstitution process and identifying the molecular and cellular mechanisms underlying PASC is crucial.
文摘Dear Editor,Different from normal differentiated cells,metabolic reprogramming was spotted in cancer cells,due to increased demand for energy and macromolecule synthesis during their rapid proliferation(Hanahan and Weinberg,2011;Pavlova and Thompson,2016).Most cancer cells prefer anaerobic glycolysis even with oxygen in the environment due to its higher speed to produce macromolecular materials required for biosynthesis(Vander Heiden et al.,2009;DeBerardinis and Chandel,2016).But to compensate for the lower efficiency of anaerobic glycolysis in producing ATP,these cancer cells demand much higher glucose supply(Warburg,1956;Vander Heiden et al.,2009).These metabolic characteristics point to the huge demand of cancer cells for carbohydrate substrates,which creates the possibility of treating tumors by exploiting this feature(Patra et al.,2013;DeBerardinis and Chandel,2016).
基金supported by the grants from the National Key Research and Development Plan of China(2021YFC2300200,2020YFC1200104,and 2018YFA0507202)The National Natural Science Foundation of China(32188101,31825001,81730063,81961160737,and 82102389)+5 种基金Tsinghua University Spring Breeze Fund(2020Z99CFG017)Shenzhen San-Ming Project for prevention and research on vector-borne diseases(SZSM201611064)the Yunnan Cheng gong expert workstation(202005AF150034)Innovation Team Project of Yunnan Science and Technology Department(202105AE160020)Tsinghua-Foshan Innovation Special Fund(2022THFS6124)Young Elite Scientists Sponsorship Program(2021QNRC001).
文摘Mosquito-borne viruses(MBVs)are a large class of viruses transmitted mainly through mosquito bites,including dengue virus,Zika virus,Japanese encephalitis virus,West Nile virus,and chikungunya virus,which pose a major threat to the health of people around the world.With global warming and extended human activities,the incidence of many MBVs has increased significantly.Mosquito saliva contains a variety of bioactive protein components.These not only enable blood feeding but also play a crucial role in regulating local infection at the bite site and the remote dissemination of MBVs as well as in remodeling the innate and adaptive immune responses of host vertebrates.Here,we review the physiological functions of mosquito salivary proteins(MSPs)in detail,the influence and the underlying mechanism of MSPs on the transmission of MBVs,and the current progress and issues that urgently need to be addressed in the research and development of MSP-based MBV transmission blocking vaccines.
文摘Dear Editor,Despite myriad successful applications of gene editing in plant functional genomics research and precision breeding,many challenges persist around the efficiency of gene-editing tools for many plant species.For instance,soybean(Glycine max)is a major crop providing oil and protein to human diets and feedstock,but its gene-editing efficiency remains relatively low(Bai et al.,2019).
基金supported by the National Natural Science Foundation of China(32150023)。
文摘A common approach in therapeutic protein development involves employing synthetic ligands with multivalency,enabling sophisticated control of signal transduction.Leveraging the emerging concept of liquid-liquid phase separation(LLPS)and its ability to organize cell surface receptors into functional compartments,we herein have designed modular ligands with phase-separation modalities to engineer programmable interreceptor communications and precise control of signal pathways,thus inducing the rapid,potent,and specific apoptosis of tumor cells.Despite their simplicity,these“triggers”,named phase-separated Tumor Killers(hereafter referred to as psTK),are sufficient to yield interreceptor clustering of death receptors(represented by DR5)and tumor-associated receptors,with notable features:LLPSmediated robust high-order organization,well-choreographed conditional activation,and broad-spectrum capacity to potently induce apoptosis in tumor cells.The development of novel therapeutic proteins with phase-separation modalities showcases the power of spatially reorganizing signal transduction.This approach facilitates the diversification of cell fate and holds promising potential for targeted therapies against challenging tumors.
基金supported by the National Natural Science Foundation of China(92254302,91854116,31771529 and 32170685)the Fundamental Research Funds for the Central Universities(5003510089 and 2023BR028)。
文摘Stimulator of interferon genes(STING),also known as MITA,ERIS,MPYS or TMEM173,is a key player in innate immunity,specifically in the typeⅠinterferon response[1-3].It is also involved in a range of non-canonical biological functions,including autophagy,cellular metabolism,translation,and DNA repair,and has implications in many diseases[4-9].After activation by its ligands,STING translocates from endoplasmic reticulum(ER),via ERGIC,Golgi apparatus and endosomes,finally to lysosomes for degradation[4-9].However,the mechanisms by which STING is delivered to lysosomes and whether this delivery process regulates STING activity remain elusive.
基金supported by grants from the National Key Research and Development Program of China(Nos.2022YFC2703100,2020YFC0861000,and 2016YFC0901500)National Natural Science Foundation(No.82170486)+1 种基金Beijing Natural Science Foundation(No.L202046)CAMS Innovation Fund for Medical Sciences(Nos.2021-I2M-1-003 and 2017-I2M-2-001),and Center for Rare Diseases Research,Chinese Academy of Medical Sciences,Beijing,China.
文摘To the Editor:The global burden of premature coronary artery disease(CAD)is increasing among the young population.Premature CAD generally refers to the occurrence of obstructive coronary atherothrombotic lesions in men and women aged<55 years and<65 years,respectively,and particularly in those aged<45 years.[1]The incidence of CAD in the younger population has remained stable or has increased,despite the declining incidence in older adults.Patients with premature CAD have a poor long-term prognosis,experiencing a high rate of recurrent ischemic events,rapid progression to multivessel disease,and frequent premature death.[1]Thus,it is crucial to identify the underlying causes of premature CAD that are distinct from those of age-related CAD and improve patient outcomes through precise diagnosis and treatment.
基金supported by Tsinghua-Peking Center for Life Sciences,the National Key Research and Development Program of China(2018YFE0207300,2017YFA0503403)the National Natural Science Foundation of China(Grant Nos.31730028,82001681,81870889,82071258)+1 种基金Training Program of the Big Science Strategy Plan(2020YFE0202200)the Research Fund from Vanke School of Public Health of Tsinghua University.
文摘Scavenger receptor class B,member 2(SCARB2)is linked to Gaucher disease and Parkinson’s disease.Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy(PME),a rare group of inherited neurodegenerative diseases characterized by myoclonus.We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption,accompanied with vitamin E deficiency.Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool,leading to hyperactivation of FXR in intestine.Hyperactivation of FXR impairs epithelium renewal and lipid absorption.Patients with SCARB2 mutations have a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E.Finally,inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice.These data indicate that gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration,and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.
基金supported by the National Key Research and Development Program of China(2021YFC2300103)the National Natural Science Foundation of China(U21A20384 and 82072293)+1 种基金the Natural Science Foundation of Hunan Province,China(2022JJ30692)the China Postdoctoral Science Foundation(2023M731520).
文摘The ORF9b protein,derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2,serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response.Despite its significance,the precise regulatory mechanisms underlying its function remain elusive.In the present study,we unveil that the ORF9b protein of SARS-CoV-2,including emerging mutant strains like Delta and Omicron,can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway,despite certain mutations present among these strains.Moreover,our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70(TOM70)as a substrate receptor,bridging ORF9b with heat shock protein 90 alpha(HSP90α)and Cullin 5(CUL5)to form a complex.Within this complex,CUL5 triggers the ubiquitination and degradation of ORF9b,acting as a host antiviral factor,while HSP90αfunctions to stabilize it.Notably,treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b,leading to a pronounced inhibition of SARS-CoV-2 replication.Single-cell sequencing data revealed an up-regulation of HSP90αin lung epithelial cells from COVID-19 patients,suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90αto evade the host immunity.Our study identifies the CUL5-TOM70-HSP90αcomplex as a critical regulator of ORF9b protein stability,shedding light on the intricate host–virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.
基金supported by grants from the National Key Research and Development Plan of China(2021YFC2300200,2021YFC2302405,2022YFC2303200,and 2022YFC2303400)the National Natural Science Foundation of China(32188101 and 82102389)+4 种基金Tsinghua University Initiative Scientific Research Program(20233080060)Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases(SZSM202211023)Yunnan Provincial Science and Technology Project at Southwest United Graduate School(202302A0370010)the New Cornerstone Science Foundation through the New Cornerstone Investigator Programthe Xplorer Prize from Tencent Foundation.
文摘Mosquito-borne diseases,encompassing threats like dengue,Zika virus(ZIKV)infection,and malaria,pose a sig-nificant challenge to global public health security,evoking widespread concern.The gravity of the situation is un-derscored by some staggering statistics:over 3.9 billion people in more than 120 countries confront the imminent threat of some of the most epidemiologically significant mosquito-borne viruses;in 2021 alone,malaria accounted for 247 million cases,resulting in an estimated 619,000 deaths globally.
文摘Plants employ sophisticated mechanisms to interact with pathogenic as well as beneficial microbes. Of those, membrane trafficking is key in establishing a rapid and precise response. Upon interaction with pathogenic microbes, surface-localized immune receptors undergo endocytosis for signal transduction and activity regulation while cell wall components, antimicrobial compounds, and defense proteins are delivered to pathogen invasion sites through polarized secretion. To sustain mutualistic associations, host cells also reprogram the membrane trafficking system to accommodate invasive structures of symbi- otic microbes. Here, we provide an analysis of recent advances in understanding the roles of secretory and endocytic membrane trafficking pathways in plant immune activation. We also discuss strategies deployed by adapted microbes to manipulate these pathways to subvert or inhibit plant defense.
基金supported by the National Natural Science Foundation of China(31801074,31788103)。
文摘Apart from their primordial role in protein synthesis,t RNAs can be cleaved to produce t RNA-derived small RNAs(ts RNAs).The biological functions of ts RNAs in plants remain largely unknown.In this study,we developed Rtc B ligation-based small RNA(s RNA)sequencing,a method that captures and distinguishes between 3′-2′,3′-cyclic-phosphate(c P)/phosphate(P)-terminated s RNAs and 3′-OH-terminated s RNAs,and profiled 5′ts RNAs and 5′t RNA halves in Arabidopsis thaliana.We found that Arabidopsis 5′ts RNAs and 5′t RNA halves predominantly contain a c P at the 3′end and require S-like RNase 1(RNS1)and RNS3 for their production.One of the most abundant 5′ts RNAs,5′ts R-Ala,by associating with AGO1,negatively regulates Cytochrome P45071 A13(CYP71 A13)expression and camalexin biosynthesis to repress anti-fungal defense.Interestingly,5′ts R-Ala is downregulated upon fungal infection.Our study provides a global view of 5′ts RNAs and 5′t RNA halves in Arabidopsis and unravels an important role of a 5′ts RNA in regulating anti-fungal defense.
基金grants from National Natural Science Foundation of China(81570211 to X.Lin)China Postdoctoral Science Foundation(023221010 to G.Zheng).
文摘Arrhythmogenic right ventricular dysplasia/cardiomyopathy(ARVD/C)is a genetic cardiac muscle disease that accounts for approximately 30%sudden cardiac death in young adults.The Ser358Leu mutation of transmembrane protein 43(TMEM43)was commonly identified in the patients of highly lethal and fully penetrant ARVD subtype,ARVD5.Here,we generated TMEM43 S358L mouse to explore the underlying mechanism.This mouse strain showed the classic patholo.gies of ARVD patients,including structural abnormalities and cardiac fibrofatty.TMEM43 S358L mutation led to hyper-activated nuclear factor kB(NFkB)activation in heart tissues and primary cardiomy.ocyte cells.Importantly,this hyper activation of NF-κB directly drove the expression of pro-fibrotic gene,transforming growth factor beta(TGFβ),and enhanced downstream signal,indicating that TMEM43 S358L mutation up-regulates NF-κB-TGFβ signal cascade during ARVD cardiac fibrosis.Our study partially reveals the regulatory mechanism of ARVD development.
基金supported by the National Basic Research Program of China(2010CB833704 and 2011CB910100)the National Natural Science Foundation of China(31030043,30971484,31125018)Tsinghua University(2010THZ0 and 2009THZ03071)to Yu Li
文摘Autophagy is an evolutionarily conserved lysosome-based degradation process.Atg5 plays a very important role in autophagosome formation.Here we show that Atg5 is required for biogenesis of late endosomes and lysosomes in an autophagy-independent manner.In Atg5 cells,but not in other essential autophagy genes defecting cells,recycling and retrieval of late endosomal components from hybrid organelles are impaired,causing persistent hybrid organelles and defective formation of late endosomes and lysosomes.Defective retrieval of late endosomal components from hybrid organelles resulting from impaired recruitment of a component of V1-ATPase to acidic organelles blocks the pH-dependent retrieval of late endosomal components from hybrid organelles.Lowering the intracellular pH restores late endosome/lysosome biogenesis in Atg5 cells.Our data demonstrate an unexpected role of Atg5 and shed new light on late endosome and lysosome biogenesis.
文摘Dear Editor,Animal models,most commonly mice,that lack a protein of interest play an important role in phenotypic and functional studies of a target gene,allowing researchers to answer various biological questions(Chaible et al,2010).At pre-sent,a variety of tools act at the DNA or RNA level to enable researchers to model gene function(and thus protein)deficiency,including nucleic acid based RNA interference(EI-bashir et al.,2001),antisense oligonucleotides(Schoch and Miller,2017),and genome editing-based CRISPR-Cas9(Doudna and Charpentier,2014)strategies.However,challenges remain.
基金This work was funded by the grants from the National Key R&D Program of China(Nos.2021YFC2300200,2018YFA0507202,2020YFC1200104,2021YFC2302405,2022YFC2303200,and 2022YFC2303400)National Natural Science Foundation of China(Nos.32188101,31825001,and 81961160737),Yunnan Chenggong expert workstation(Nos.202005AF150034)+2 种基金Innovation Team Project of Yunnan Science and Technology Department(Nos.202105AE160020)Tsinghua-Foshan Innovation Special Fund(TFISF)(Nos.2022THFS6124)Shenzhen San-Ming Project for prevention and research on vector-borne diseases.
文摘Mosquito-borne diseases present a significant threat to human health,with the possibility of outbreaks of new mosquito-borne diseases always looming.Unfortunately,current measures to combat these diseases such as vaccines and drugs are often either unavailable or ineffective.However,recent studies on microbiomes may reveal promising strategies to fight these diseases.In this review,we examine recent advances in our understanding of the effects of both the mosquito and vertebrate microbiomes on mosquito-borne diseases.We argue that the mosquito microbiome can have direct and indirect impacts on the transmission of these diseases,with mosquito symbiotic microorganisms,particularly Wolbachia bacteria,showing potential for controlling mosquito-borne diseases.Moreover,the skin microbiome of vertebrates plays a significant role in mosquito preferences,while the gut microbiome has an impact on the progression of mosquito-borne diseases in humans.As researchers continue to explore the role of microbiomes in mosquito-borne diseases,we highlight some promising future directions for this field.Ultimately,a better understanding of the interplay between mosquitoes,their hosts,pathogens,and the microbiomes of mosquitoes and hosts may hold the key to preventing and controlling mosquito-borne diseases.
基金supported by the National Key R&D Program of China(2021YFC2300200,2021YFC2302405,and 2022YFC2303200)the National Natural Science Foundation of China(32188101,31825001,81961160737,and 82102389)+7 种基金the Young Elite Scientists Sponsorship Program(2021QNRC001)the Yunnan Cheng Gong Expert Workstation(202005AF150034)the Innovation Team Project of Yunnan Science and Technology Department(202105AE160020)the Tsinghua-Foshan Innovation Special Fund(2022THFS6124)the Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseasesthe Research Fund-Vanke School of Public HealthTsinghua University(2023JC002)the XPLORER PRIZE from Tencent Foundation。
文摘Arboviruses,a diverse group of vector-borne pathogens transmitted by various vectors such as mosquitoes,ticks,and flies,encompass members of the Flaviviridae,Togaviridae,Phenuviridae,Peribunyaviridae,Reoviridae,Asfarviridae,Rhabdoviridae,Poxviridae,and Orthomyxoviridae families[1].
基金supported by the National Natural Science Foundation of China(Nos.31571320,31872818,and 31801079)the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2016YFE0113700)the China Postdoctoral Science Foundation(2017M620747)
文摘Gene expression regulation, including loss-of-function and gain-of-function assays, is a powerful method to study developmental and disease mechanisms. Drosophila melanogaster is an ideal model system particularly well-equipped with many genetic tools. In this review, we describe and discuss the gene expression regulation techniques recently developed and their applications, including the CRISPR/Cas9-triggered heritable mutation system, CRISPR/dCas9-based transcriptional activation(CRISPRa) system,and CRISPR/dCas9-based transcriptional repression(CRISPRi) system, as well as the next-generation transgenic RNAi system. The main purpose of this review is to provide the fly research community with an updated summary of newly developed gene expression regulation techniques and help the community to select appropriate methods and optimize the research strategy.
